J.1610-0379.2011.07680.supp.x.pdf Jsessionid .f04t03 PDF

DOI: 10.1111/j.1610-0379.2011.07680.supp.
Guidelines on the Treatment of Psoriasis Vulgaris
Guidelines on the Treatment of Psoriasis Vulgaris
S3 Guidelines on the treatment of psoriasis vulgaris

Update 2011
Alexander Nast1, Wolf-Henning Boehncke2, Ulrich Mrowietz3, Hans-Michael Ockenfels4, Sandra Philipp5,
Kristian Reich6, Thomas Rosenbach7, Adel Sammain1, Martin Schlaeger8, Michael Sebastian9, Wolfram Sterry10,
Volker Streit11, Matthias Augustin12, Ricardo Erdmann1, Joachim Klaus13, Joachim Koza13, Siegrid Mller14,
Hans-Dieter Orzechowski15, Stefanie Rosumeck1, Gerhard Schmid-Ott16, Tobias Weberschock2,
Berthold Rzany1
(1) Division of Evidence Based Medicine (dEBM), Klinik fr Dermatologie, Vene-rologie und Allergologie,
Charit Universittsmedizin Berlin, Germany
(2) Zentrum der Dermatologie und Venerologie, Klinikum der Johann Wolfgang Goethe Universitt, Frankfurt/Main, Germany
(3) Klinik fr Dermatologie, Venerologie, Allergologie, Universittsklinikum Schleswig-Holstein, Campus Kiel, Germany
(4) Haut- u. Allergieklinik, Klinikum Hanau, Germany
(5) Psoriasisstudienzentrum, Klinik fr Dermatologie, Venerologie und Allergologie, Charit Universittsmedizin
Berlin, Germany
(6) Dermatologikum Hamburg, Germany
(7) Dermatologist in private practice, Osnabrck, Germany
(8) Dermatologist in private practice, Oldenburg, Germany
(9) Dermatologist in private practice, Mahlow, Germany
(10) Klinik fr Dermatologie, Venerologie und Allergologie, Charit Universittsmedizin Berlin, Germany
(11) Niedergelassener Dermatologe, Buchholz, Germany
(12) Universittsklinikum Hamburg-Eppendorf, Klinik und Poliklinik fr Dermatologie und Venerologie, Hamburg, Germany
(13) Deutscher Psoriasis Bund e.V., Germany
(14) Nursing care representative, Ravenstein, Germany
(15) Institut fr Klinische Pharmakologie und Toxikologie, Charit Universittsmedizin Berlin, Germany
(16) Berolina Klinik, Lhne, Germany
1 Preface
Alexander Nast, Berthold Rzany
1.1 Needs analysis/challenges in
patient care
Psoriasis vulgaris is a common and almost
always chronic skin disease.
The prevalence of psoriasis in Western
industrialized nations is 1.5 2 % [1]
About 80 % of psoriasis patients have the
plaque form of disease. In Germany, the
disease affects an estimated 1.6 million
people. More than 90 % have chronic disease [1].
Patients with plaque psoriasis have a substantially impaired quality of life.
Studies on the impairment of quality of
life in psoriasis patients have shown that,
depending on the severity of disease, related disability or psychosocial stigmatization can present a considerable burden for the patient [2]. Patient surveys
have found that the impact on quality of
life is comparable to that experienced by
JDDG; 2011 9 (Suppl. 2): S1S95

Psoriasis-Leitliniengruppe der DDG JDDG Blackwell Verlag GmbH
patients with type 2 diabetes or chronic

lung disease [3].
believed that this led to inadequate treatment with systemic therapies [8].
Patient satisfaction with current therapies

is low and compliance is poor.
Based on the results of patient surveys,
only about one-fourth of patients report
being very satisfied with the results of
therapy; about 50 % are moderately satisfied, and about one-fifth are not very satisfied [4]. There is also a high rate of medication non-compliance (up to 40 %)
[5]. Reasons for non-compliance include
poor tolerability, fear, lacking information about potential side effects, low efficacy, and complicated usage [6, 7].
There is inadequate use of systemic therapy

options in patients with moderate-to-severe
psoriasis.
Nast et al. reported in a study from 2006
with 54 dermatologists in private practice that in visits with 2,294 patients
with moderate-to-severe psoriasis, about
50 % of patients were treated with
topical therapies alone. 17 % received
additional UV therapy and only about
30 % were taking some form of systemic
therapy [9].
There is uncertainty concerning the use of

systemic therapies.
Nast et al. reported in a small survey of
39 dermatologists in private practice
that, according to their own self-assessment, 76 % of doctors surveyed had
some uncertainty about prescribing systemic medications. 79 % said they
The economic costs of disease are high.

The costs of psoriasis, including the costs
of statutory health care and other forms
of insurance (e.g., unemployment coverage) as well as the costs for the patient
himself (e.g., for basic therapies), are
about 2,866 per patient per year [10].
In 2002, about 20,000 patients with
psoriasis vulgaris were hospitalized,
JDDG | Supplement 2 2011 (Band 9)
S1
S2
Preface
primarily for initial treatment as well as

for severe flare-ups. One German statutory health insurer (AOK West) reported that the number of disability cases
for psoriasis vulgaris per year was 7.35
for men and 4.94 for women / 10,000
insured persons (28 and 27 days) [11].
1.2 Goal of the guidelines
The overall goal of the guidelines is
to provide dermatologists in private
practice and clinicians with an accepted,
evidence-based tool that can aid decision-making in the selection and implementation of appropriate and adequate
therapies for patients with psoriasis vulgaris. The focus of the guidelines is on
induction therapy for mild to severe psoriasis vulgaris in adult men and women.
Improved patient care though implementation of guideline recommendations and
optimization of physician knowledge of
reported treatment efficacies
The personal experience of physicians
and the use of traditional treatment concepts for psoriasis vulgaris should be augmented or even replaced by an evidencebased assessment of the anticipated
results of a given therapy option based
on medical science.
Assistance with optimal treatment
implementation
The detailed description of systemic therapies, phototherapies, and photochemotherapy, including precise descriptions of
their use and safety aspects, should help reduce any reservations on the part of doctors and patients with regard to certain
therapies and ensure prompt, sufficient,
and optimal treatment. The timely provision of information and prompt induction
of adequate therapy should help prevent
severe disease which frequently involves
hospitalization and lost work days.
Improved patient awareness of current
therapy options
A further version of the guidelines, designed for use by the patient, is currently
being developed. The aim is to give patients an overview of possible therapies in
terms of complications and optimal usage.
Enhancing compliance
Adequate patient compliance / adherence are often related to a good ratio
between the benefits of therapy and the
related effort, costs, and potential side ef-
fects. The choice of an effective therapy

by the patient and doctor, taking into account the quality of life variables measured in recent studies, should help ensure
a high treatment benefit. Providing information on the prevention and management of adverse effects should help limit or even prevent them. This in turn
also increases compliance.
1.3 Quality of care indicators
Radtke et al. have proposed eight indicators based on the Delphi method for measuring the quality of care of psoriasis patients [12]. These quality indicators may be
applied to the total population of psoriasis
patients or used as indicators for monitoring changes in quality of care as a result
of the guidelines: 1) average PASI in the
total population 2) average DLQI in the
total population 3) proportion of patients
out of the total population with severe
psoriasis vulgaris as measured by PASI
(>20) 4) proportion of patients out of the
total population who have severe psoriasis
vulgaris as measured by DLQI (>10) 5)
proportion of patients out of the total population who have previously received systemic therapy 6) proportion of patients
with severe psoriasis (PASI >20) who report prior or current systemic therapy 7)
proportion of patients out of the total population who have been hospitalized in
the last 5 years due to psoriasis 8) average
number of lost work days due to psoriasis
among the total population.
1.4 Note on use of the guidelines
These guidelines are intended for use by
dermatologists in private practice and by
clinicians and other specialists involved in
the treatment of patients with psoriasis
vulgaris. An update of the patient version
of the guidelines is currently underway.
Finally, the guidelines also provide a guide
for health insurers and policy makers.
The description of selected therapies is
intentionally restricted to the most relevant aspects in the opinion of the guidelines expert committee. Those aspects
that are not specific to a certain intervention, such as assessing drug intolerance
or allergies, ruling out contraindications,
etc. are not listed separately but are instead assumed to be a part of the physicians duty of care.
Physicians are advised to carefully read the
package insert and manufacturer information and to determine whether dosage recommendations and other information
contained in the guidelines, such as contraindications and drug interactions, is

complete and current. Correct dosage and
administration are solely the responsibility of the administering physician.
The authors and the publisher kindly ask
readers to alert them to any apparent
inaccuracies.
Like any science, the field of medicine is
in constant flux. Our knowledge of present therapies as well as new treatment options is constantly growing. The utmost
care was taken to ensure that the information contained in the guidelines was current at the time of their completion. The
reader is advised to keep abreast of current
information after their publication.
1.5 Methods
A detailed description of the methods
and procedures used for developing the
guidelines may be found in the methods
report (www.psoriasis-leitlinie.de).
The present guidelines are an updated
version of the S3 guidelines on the treatment of psoriasis vulgaris which were published in 2006 and a brief update published in 2009. The present update also
includes information from the current
versions of the EU guidelines as well as
the British guidelines on biological
therapy [13-17].
The basis of the concept for the first version of the guidelines was a Dutch paper
entitled Richtlijn foto(chemo)therapie
en systemische therapie bij ernstige chronische plaque psoriasis [18].
Chapter structure
The order of the chapters is as follows:
topical therapy, phototherapy, systemic
therapy, and other therapies. Within the
chapters sub-sections are arranged alphabetically. The order of chapters bears no
relation to the efficacy of a given therapy,
nor does it indicate a preference for
usage.
Basis of data
A systematic literature search of published articles up to November 2009 was
performed to evaluate the efficacy of
various individual therapies. In addition
to the 6,224 publications yielded by the
literature search in the first version of the
guidelines, we identified 1,443 new
studies. Of these, 155 studies fulfilled
the criteria for inclusion in the current
guidelines (see Appendix 1) and were
included in the evaluations of treatment
JDDG; 2011 9 (Suppl. 2): S1S95

Preface
efficacy. The methodological quality of

the chosen studies was determined using
a literature evaluation form (LEF).
Other aspects included in the guidelines
were evaluated on the basis of information from the literature (without a systematic assessment) as well as on the basis
of the personal experience of the guidelines expert committee. For 2006/2007
the results of the literature search for the
EU guidelines were also included. For
biological therapies, this includes publications up to 16 October 2007 and for
the remainder of systemic therapies up to
15 August 2006.
Systematic review of topical therapies
[19]
In a systematic review of topical therapies, Mason et al. performed an evaluation of placebo-controlled studies and
head-to-head trials. The further away a
given therapy was from zero, the more
effective it was deemed to be (maximum
values: 1.5 2). The effect was considered statistically significant if the 95 %
confidence interval did not overlap zero.
Studies that were already evaluated by
Mason et al. were not re-evaluated using
the LEF. Therapies from the Mason paper were only eligible for the maximum
evidence grade A1 if at least three studies
were included in the meta-analysis.
Calculation of daily medication costs
In the interest of standardization for
comparative analysis of the costs of
anti-psoriasis drugs, the guidelines
used a model patient with the following
characteristics:
Man, age: 45 years, height: 1.80 m,
weight: 75 kg
Involvement of 10 % of body surface
area
PASI score: 10
No co-morbidities
No current pre-therapy measures
Average use of topical ointments was
5 g per use or 10 g for twice daily application. In general, the cost of a given
medication was based on the price
of a medium-sized package of that
drug according to the Red List 2010
(N2) [20].
The costs of induction therapy were based on the amounts required for effective
medication use. No other costs other
than the cost of the drug itself were
included. For calculating the annual
costs of therapy, a pro-rata figure was
JDDG; 2011 9 (Suppl. 2): S1S95

used if the therapeutic effect was longer

than 12 months.
Evidence assessment
The efficacy of each intervention was
systematically assessed using evidencebased criteria.
The methodological quality of each study
was assessed using grades of evidence
(Table 1).
Evidence levels were also determined
as part of evaluating the effectiveness
of a drug given as monotherapy. This
consisted of an evaluation of the overall
evidence on the intervention (Table 2).
Passages requiring consensus
The authors of the guidelines have
defined certain particularly relevant
sections as requiring consensus. These
passages were agreed on in consensus
conferences and are highlighted in gray
boxes.
Treatment recommendations
At present there is no clear step-by-step
procedure or strict clinical algorithm
for the treatment of psoriasis vulgaris.
The criteria for selecting an appropriate
therapy are complex. Certain aspects
related to selecting a suitable treatment
must be assessed and weighed individually. The decision for or against
a therapy is made on an individual
basis. The guidelines provide a scientifically-based aid for decision-making
and selection of an appropriate treatment. As such they constitute a medical
tool for the optimal use of a necessary
therapy.
Key recommendations formulated
in the text are augmented by symbols
representing the strength of the
treatment recommendation. Symbols
have been used to help standardize
the
treatment
recommendations
(Table 3).
Table 1: Grades of evidence.

A1
Meta-analysis containing at least one randomized grade A2 study.

The results of the various studies included must be consistent
A2
Randomized, double-blind, high-quality clinical comparative study (e.g.,

sample size calculation, flow chart, ITT analysis, sufficient sample size)
Randomized clinical study of lesser quality or other comparative study

(non-randomized: cohort study or case-control study)
Non-comparative study
Table 2: Evidence levels.

1
Intervention is supported by grade A1 studies or mostly consistent

results from grade A2 studies
Intervention is supported by grade A2 studies or grade B studies with

mostly consistent results
Intervention is supported by grade B studies or grade C studies with

mostly consistent results
Little or no systematic empirical evidence
Table 3: Standardized wording for recommendation.

is recommended
may be recommended
may be considered
cannot be recommended
should be avoided
strongly recommended
recommended
neutral recommendation
recommendation against its use
strongly disadvised
S3
S4
Preface/Introduction
2 Introduction
Due to the focus of the guidelines on induction therapy, the recommendations
in the update are limited to this phase.
Some recommendations from the previous version are thus no longer included. This is in the interest of standardization and does not indicate any
change to the recommendation level of a
previously described drug.
The strength of recommendation takes
into account various aspects concerning
its effectiveness, including evidence
level, safety aspects , feasibility, cost-tobenefit ratio, etc. The strength of the
recommendations was agreed on in the
framework of a consensus conference.
Consensus procedure
Consensus was reached by a group of
guideline experts who were nominated
by the appropriate professional associations (see under Responsibilities). The
consensus conference was moderated by
Prof. Dr. med. Berthold Rzany, MSc,
who has the appropriate qualifications
through AWMF. First, the available evidence was presented and discussed. Based on a hand-out, proposed recommendations were commented on by each
member of the group and suggested
changes were noted. The comments were
discussed by each member, followed by a
preliminary vote, then debate/discussion, and then a final vote. The goal was
strong consensus (> 90%). If there was
still lacking consensus after a thorough
discussion and renewed presentation of
the evidence, this was noted alongside
the corresponding recommendation. All
authors and representatives from other
fields as well as a representative from a
caregiving organization and patient representatives (see under Responsibilities)
were eligible to vote during the consensus conference. When consensus could
not be reached during the conference on
a certain intervention due to time limitations, the vote was done using the Delphi method. This involved sending a
standardized ballot to the participants.
After the votes were counted, the results
were sent anonymously to the group until a high level of consensus was reached.
(For further details please see the methods
report at: www.psoriasis-leitlinie.de)
Ulrich Mrowietz, Kristian Reich

Psoriasis in all its various clinical forms is
one of the most common chronic inflammatory diseases of the skin. For
most patients, the disease means decades-long restriction of various aspects of
everyday life at an enormous personal
cost and sometimes with severe stigmatization and discrimination. The socioeconomic impact is characterized by the
chronicity of disease, diminished productivity, and significant treatment
costs. Suitable treatment of psoriasis can
effectively alleviate the skin symptoms
and improve the quality of life of affected
patients. Optimized care of patients with
psoriasis is one of the primary concerns
of the German Society of Dermatology
(Deutsche Dermatologische Gesellschaft) and the Federal Association of
German Dermatologists (Berufsverband
der Deutschen Dermatologen).
2.1 Epidemiology and accompanying
diseases
Psoriasis may be divided based on its clinical appearance into a pustular form
and a plaque form (psoriasis vulgaris),
which is the most common of the two.
In Germany the prevalence of plaque
psoriasis is more than 2% [21], affecting
about 1.5 million people. The vast majority of treatment studies deal with psoriasis vulgaris, and hence the information
contained in the present guidelines pertains to plaque psoriasis unless otherwise
stated.
Psoriasis vulgaris may be further sub-divided based on phenotype i.e., based
on the acuteness of lesions and disease
course into an acute eruptive variant
and a chronic stationary type [22]. The
latter has been more thoroughly investigated in studies given inclusion and
exclusion criteria. There is also an older
classification that classifies psoriasis by
course and prognosis. In this system,
type 1 psoriasis refers to disease with an
initial manifestation before age 40, a positive family history, a strong association
with HLA-Cw6, and a tendency toward
a more severe disease course (Henseler
and Christophers). Type 2 psoriasis (delayed onset) manifests after age 40, often
in patients with a negative family history
and without a strong association with genetic markers. The course of disease is
usually less severe.
Today, psoriasis is understood as a systemic disease that encompasses skin symptoms, possible joint involvement and
characteristic co-morbidities. Psoriatic
arthritis (PsA) is diagnosed in one out of
five patients under the care of a dermatologist for psoriasis [23]. Typical co-morbidities include other chronic inflammatory diseases, possibly with overlapping
disease mechanisms that occur with greater frequency in patients with psoriasis
such as rheumatoid arthritis (about four
times as common), chronic inflammatory bowel diseases (about twice as common), and metabolic changers such as
metabolic disturbances, a tendency toward diabetes, obesity, and arterial hypertension [21, 24-30]. An increased risk
of cardiovascular diseases, such as heart
attack and stroke, as well as increased
mortality consisting of a reduced life expectancy by about three to four years,
have been reported in younger patients
with severe psoriasis [28]. The co-morbidities related to psoriasis often require
co-medication which must be taken into
account, especially when choosing a systemic therapy in order to avoid drug interactions [31]. Certain psychiatric disorders, including affective disorders and
depression, are also believed to be associated with psoriasis [32].
2.2 Genetics
Psoriasis has a multifactorial etiology.
Genetic factors and environmental influences (infection, smoking, taking certain
drugs) act together in the pathogenesis of
disease. Twin and family studies have
shown that the genetic component in
psoriasis account for 60%-70% of risk.
The interactions between various genetic
factors are believed to be complex and
their effect cumulative. Linkage studies
have identified different susceptibility
loci (PSORS). Of these, PSORS1 on
chromosome 6p21 has been associated
with disease across all studies. The HLACW*0602 allele located in this region
has the strongest association with the
disease and with type 1 in particular.
Heterozygote carriers of this allele have a
9-fold increased risk of psoriasis vulgaris
and homozygote carries have about a
23-fold increased risk of disease [33].
Other studies have shown an association
with genetic variations that affect cytokine pathways which are important in
psoriasis, including TNF- [34] und
IL-23 [35, 36].
JDDG; 2011 9 (Suppl. 2): S1S95

Introduction
2.3 Pathogenesis
The tissue reaction seen in psoriasis
involves a complex immunological reaction of the skin with a severe inflammatory component and epidermal hyperproliferation with abnormal keratinocyte
differentiation. Following activation of
elements of the innate immune system
such as keratinocytes and dendritic cells,
there is activation of T cells which predominantly migrate into the skin. Homing
receptors involved in this process are expressed on the surface of inflammatory
cells, such as cutaneous lymphocyteassociated antigen (CLA). Under the
influence of cytokines such as IL-12
and IL-23 there is growth of certain
functional T-cell subpopulations. These
include Th1 cells and Th17 cells that
in turn secrete pro-inflammatory cytokines such as TNF-, IL-17, and IL-22.
These promote the inflammatory process in psoriasis, involving local cells
such as endothelial cells, fibroblasts, and
keratinocytes that in turn enhance the
cutaneous immune response through expression of adhesion molecules and other
mediators. As a result of this cascade,
there is significant migration of neutrophilic granulocytes that can lead to
formation of typical sterile epidermal
microabscesses. Increased proliferative
activity and abnormal maturation of keratinocytes causes the hyperparakeratosis
that is characteristic of psoriasis. In clinical forms of pustular psoriasis, there is a
stronger cutaneous inflammatory reaction and more pronounced migration of
neutrophilic granulocytes [37].
2.4 Clinical appearance
Psoriasis vulgaris / chronic stationary plaque
psoriasis
The most common clinical manifestation
of psoriasis is psoriasis vulgaris or plaque
psoriasis. Plaque psoriasis causes solitary
and later confluent, erythemato-squamous plaques mainly at certain predilection sites. Lesions may persist for several
years or they may spread, usually slowly
but occasionally very rapidly, affecting the
entire surface of the skin. This is usually
the result of exogenous factors such as infection, stress, or the use of certain medications that can provoke psoriasis.
Psoriasis guttata
The clinical appearance of psoriasis gutta
consists of acute exanthematous disease
with lentil-sized lesions (0.1 1.5 cm)
JDDG; 2011 9 (Suppl. 2): S1S95

that can cover the entire surface area of

the skin. This is often the first manifestation of disease seen during childhood or
adolescence. It usually occurs after an infection, particularly streptococcal infection. The disease can transition into psoriasis vulgaris.
Intertriginous psoriasis
Intertriginous psoriasis involves exclusively or predominantly areas where there
are folds in the skin, i.e. the axillae, abdominal folds, submammary region, and
inguinal and anal regions. This type of
psoriasis is rather rare.
Psoriasis inversa
Another very rare type of psoriasis affects
the flexural surfaces of the major joints,
without involving predilection sites on
the extensor aspects of the joints. This is
known as psoriasis inversa.
Pustular psoriasis
Pustular psoriasis consists of several
clinical variants. Generalized spread of
solitary pustules which later coalesce,
along with fever, a strong feeling of being
unwell, and dermopathic lymphadenopathy is known as psoriasis pustulosa
generalisata (von Zumbusch pustular
psoriasis).
As a result of acute exacerbation of psoriasis vulgaris, eruptive onset at the site
of existing lesions can occur. This is referred to as psoriasis cum pustulatione.
Palmoplantar pustulosis (PPP)
Palmoplantar pustulosis is a separate disease entity. Today it is included among
the group of acropustular forms of psoriasis. In this disease, pustules develop on
the palms of the hands and/or soles of
the feet, sometimes coalescing to form a
lake of pus. A similar clinical appearance is sometimes seen in patients with
Reiter disease. There are apparently
forms that overlap, however, in which
patients with psoriasis develop PPP. PPPlike lesions may also develop in patients
taking TNF-antagonists.
Acrodermatitis continua suppurativa
(Hallopeau)
This very rare disease causes lakes of pustules in acral regions. There is severe inflammation, and loss of the nails and nail
matrix occurs rapidly. Destruction of the
distal phalanges can occur over the
course of disease.
2.5 Diagnosis
Psoriasis vulgaris is almost always diagnosed by the typical lesion morphology. To
confirm diagnosis, eliciting the Auspitz
sign may be useful (candle-wax scales
punctate bleeding when last covering
skin is removed pinpoint bleeding).
Psoriasis occasionally resembles nummular eczema or tinea. Mycosis fungoides
and pityriasis rosea should be ruled out.
If there is involvement of the skin in
intertriginous areas, intertrigo and candidiasis should be excluded.
Diagnosis may be aided by inspection of
predilection sites and the nails.
Only in exceptional instances should
a biopsy be performed to confirm the
clinical diagnosis.
2.6 Definition of severity of psoriasis
vulgaris
There are established scoring systems for
evaluating the severity of measurable
physical symptoms of psoriasis vulgaris.
Yet there is still no generally accepted
definition of the degree of severity of
psoriasis vulgaris. It should be emphasized that when evaluating disease severity,
along with scoring schemes for quantifying skin and/or joint symptoms, or
impairment of quality of life (see
section 2.7), a number of other parameters should also be considered individually. These include the affected site (visible
area, genital region), certain symptoms
(pruritus), treatment response, burden
of disease, prior need for inpatient and
rehabilitative measures, as well as the
necessity of continued care and therapy.
A straightforward method for assessing
the degree of involvement is to assess the
percentage of involvement of the body
surface area (BSA). Clinical studies frequently use the Psoriasis Area and Severity Index (PASI) score. PASI evaluates
the severity of the symptoms erythema
(redness), infiltration, and scaling, as
well as the extent of involvement of the
head, arms, trunk, and legs. The parameters for a reduction in disease are PASI
50, 75 or 90 referring to the percentage
of improvement in PASI by a certain
point in time (at least 50 %, 75 %
90 %). At present, most treatment
studies on drug efficacy consider a reduction of at least 75 % (PASI 75) as clinically meaningful for the patient. Thus,
while a reliable assessment of the severity
of psoriasis vulgaris using PASI scores is
possible for moderate-to-severe disease,
S5
S6
Introduction
for milder disease (<5 10 % affected

BSA), certain assessment of disease
severity is no longer ensured with PASI.
In mild cases of psoriasis, e.g., only at
predilection sites, local PASI (LPSI) is
often used which assesses only the
severity of individual symptoms.
Clinical studies also often include a standardized global physician evaluation
(physicians global assessment; PGA).
The PGA measures disease severity at a
specific point in time (static PGA;
sPGA) or retrospectively in order to evaluate treatment response (dynamic
PGA). Newer studies also use surveys
on generic quality of life (SF-36), disease-specific quality of life (DLQI,
Skindex), or psoriasis-specific symptoms
(PsoQol, PDI).
There is a European consensus decision
on the definition of mild psoriasis as
BSA 10 and PASI 10 and DLQI
10, moderate-to-severe psoriasis as
(BSA >10 or PASI >10) and DLQI >10
[38].
2.7 Quality of life
There are numerous studies on the quality of life in patients with psoriasis vulgaris. Most have been conducted with validated questionnaires (instruments).
One such study compared the level of impairment of quality of life in psoriasis
with patients who have other diseases.
The results of this study showed that the
quality of life of patients with psoriasis
vulgaris was more severely impaired than
that of patients with diabetes, coronary
heart disease, and cancer. Only depression, according to this study, led to a
more strongly diminished quality of life.
Clinical studies routinely measure quality of life, along with clinical parameters
such as PASI score, as an important criterion for measuring the success of treatment. Various internationally established
instruments may be used.
2.8 Treatment goals
Kristian Reich, Ulrich Mrowietz
Studies on the quality of psoriasis treatment in Germany have shown that the
average severity of disease remains high
and that, even for psoriasis patients in regular dermatological care, there can be
significant impairment of quality of life.
This suggests that, for too long, patients
have been receiving ineffective medications and other therapies.
The definition of treatment goals, and

their application, is intended to prevent
sub-optimal treatment. Together with
the present guidelines, these will help
create the foundations for improved treatment of psoriasis.
Currently, the PASI score and body surface area (BSA) involvement are the most
commonly used parameters in Europe
for evaluating the clinical severity of psoriasis vulgaris. The health-related quality
of life (HRQoL) is another important
tool for measuring the severity of disease.
HRQoL is primarily determined using
the Dermatology Life Quality Index
(DLQI). These instruments are therefore
also suitable for the definition of treatment goals.
The fundamental goal of any therapy is
to achieve complete clearance of symptoms, that is, the absence of cutaneous
symptoms of psoriasis. This goal is not
realistically achievable in all patients at
this time, however. In recent years,
clinical studies have used PASI 75as the
goal of therapy, i.e., a 75 % reduction
from baseline PASI. The majority of
patients with PASI 75 also have a relevant improvement in quality of life
(measured as improved DLQI). In most
studies the primary endpoint for achieving the targeted PASI 75 score was at
10-16 weeks of therapy. The results
from such studies form the basis for the
evaluations of clinical efficacy in the
present guidelines. PASI 75 thus also
seems to be a reasonable therapy goal at
the end of induction therapy, and one
that can be regularly assessed over the
course of treatment.
The successful establishment of treatment goals requires that a minimum target be defined which must be achieved
by therapy. If the lowest hurdle is not
reached within a given amount of time,
the therapy must be modified. Various
forms of adjustment include increasing
the dosage, initiation of combination
therapy, or transition ing to another drug
or procedure. Like other European guidelines, PASI 50 is taken as the minimum target, i.e., a 50 % reduction from
the baseline clinical appearance. In regard to quality of life, treatment goals
may be defined using the assistance of
the DLQI. The goal of therapy is to
achieve a DLQI score of 0 or 1, if possible, meaning that the patient no longer
experiences any impairment of quality of
life due to the skin symptoms of psoria-
sis. A DLQI score of less than 5 may be

taken as the lowest hurdle.
For fast-acting drugs (e.g., infliximab),
treatment goals should be set at 10 weeks
for induction therapy. For slower-acting
drugs (e.g., fumaric acid esters, MTX)
the endpoint should be 16 weeks. During maintenance therapy, assessment is
at the same intervals as for treatment,
i.e., usually every eight weeks.
Data from treatment of rheumatoid
arthritis and preliminary reports on
psoriasis underscore the importance of
treatment goals. The data show that
long-term, adequate control of disease
activity also helps reduce cardiovascular
complications resulting from accompanying metabolic diseases.
In a European consensus paper, the
therapy goals for systemic therapy of
moderate-to-severe psoriasis and the
resulting treatment decisions are outlined [38] (Figure 1).
2.9 Treatment costs and risk-tobenefit ratio
Matthias Augustin
The financial resources of the healthcare
system are limited, and in Germany they
are no longer sufficient for adequately
covering the costs of medical care.
Various costly innovations in all areas of
medicine have further depleted the
already limited healthcare resources.
Faced with this shortage, the statutory
health insurance system has introduced
measures to regulate the allocation of
funds.
In the treatment of psoriasis vulgaris,
pharmaco-economic costs must also be
taken into consideration. Yet the only
larger scientific studies that have addressed the costs of psoriasis have dealt specifically with the costs of disease. In Germany the total average annual costs of
psoriasis vulgaris per patient with mild
disease range from 500 to 2,000
and for severe disease from 4,000 to
10,000 [10, 39]. The average costs of
treatment of severe psoriasis alone are
around 4,400 , and the indirect costs
(including lost productivity, early retirement) are about 1,600 [39].
Neither fixed budget amounts and
benchmarks, nor restrictions on approvals are suitable measures for ensuring
medically and economically sound treatment of psoriasis vulgaris. Rather, the
cost-effectiveness of a given therapy
JDDG; 2011 9 (Suppl. 2): S1S95

Introduction
Figure 1: Therapy goals in the treatment of psoriasis. Reproduced and adapted with permission (38).
fit to the patient. There is also international consensus that this includes an improved quality of life, a reduced burden
of disease, and prevention of undesirable
adverse effects [41].
For the cost-benefit analysis there are internationally agreed-upon procedures in
which cost-effectiveness analyses in particular will become important in the future. In the area of psoriasis therapy, however, as yet only a limited number of
studies with cost-benefit analyses have
been published. Unlike in Anglo-Saxon
countries, in Germany there is no systematic method for determining the relationship between costs and quality of life
such as QALYs (quality-adjusted life
years).
There is still no consensus on how to define a clinically relevant benefit (minimum relevant improvement) and at
what point the cost-benefit relationship
is considered favorable or unfavorable in
psoriasis therapy. The decision as to the
cost-benefit analysis is thus made individually on a case-by-case basis.
should be taken into account in the individual decision-making process on appropriate treatment.
Determining whether a therapy makes
sense economically is not accomplished
by merely assessing therapy costs, but by
balancing these costs against the potential benefits of therapy. Thus an expensive therapy with a potentially significant
benefit could make economic sense [39].
The clinical course of disease and the patient benefit do not always match [40].
Any economic assessment should take
into account both outcomes. An assessment of treatment effectiveness is an
important figure against which the costs
of therapy should be weighed. According
to the German Social Security Code (Sozialgesetzbuch; SGB V) and the code of
procedures of the Institute for Quality
and Efficiency in Health Care (IQWiG),
the usefulness of a treatment measure is
defined as the usefulness that is relevant
to the patient. Thus any therapeutic
measure for psoriasis vulgaris must be
considered taking into account the bene-
Nevertheless, the following study results

are important with regard to the costbenefit analysis of a given psoriasis
therapy:
Given the high incidence of disease,
psoriasis vulgaris and related co-morbidities are economically important
diseases in Germany [21, 23, 42]
Psoriasis vulgaris is a serious disease according to the German Social Security
Code (SGB V) as it is related to significant, long-lasting impairment of
quality of life [43]
The drug costs of psoriasis therapies
should be considered in relation to
their benefit
The therapies discussed in the present
guidelines have been shown by clinical
trials to be clinically effective and
usually also significantly improve the
quality of life of the patient and thus
have a high patient benefit [44]
The data from international pharmacoeconomic studies are not entirely applicable to the situation in Germany given
differences between the systems and
costs. The following results have been
published so far on the cost-effectiveness
of psoriasis therapy in Germany. These
are based on induction therapy.
Biologics
Based on the cost-effectiveness model by
Nelson et al. (2008, [45]) the results for
the induction phase of therapy are shown
in table 4.
Topical therapy
From a pharmaco-economic standpoint,
topical therapy with combination
therapy of calcipotriol and betamethasone was significantly superior to the use
of each therapy alone and was also superior to tacalcitol [47, 48].
Table 4: Cost-effectiveness for biologics.

Medication
CE Nelson et al. [45]

(/patient with
PASI 75)
CE Germany
(/patient with
PASI 75)
7,864.57
12,187.17
16,020.99
7,521.44
8,910.81
11,286.51
16,895.57
22,724.93
10,568.19
12,501.29
Adalimumab
Etanercept 25 mg 2 x/weekly
Etanercept 50 mg 2 x/weekly
Infliximab 3 mg/kg
Infliximab 5 mg/kg
C/E = cost-effectiveness relationship
JDDG; 2011 9 (Suppl. 2): S1S95

S7
S8
Basic treatment/Therapy options and treatment evaluation
3 Basic treatment
Ulrich Mrowietz, Matthias Augustin
Basic treatment of psoriasis vulgaris consists of topically applied non-medicated
ointment bases and topical preparations
containing urea (3 10 %) or salicylic
acid (3 10 %). These basic therapies represent the international standard of care
as part of treatment of acute psoriasis of
all severity levels as well as interval
therapy [49-63]. Only a small number of
controlled, comparative clinical studies
of sufficient quality have tested the efficacy of these topical therapies [64-67].
The present guidelines assume the appropriate use of basic therapies, depending
on disease stage, although they are not
specifically addressed in the evaluation.
4 Therapy options and

treatment evaluation
4.1 Treatment options
Figure 2 provides an overview of
evaluated treatment options in plaque
psoriasis.
4.2 Evaluation tables (Table 5, 6)
- For further details, please refer to
the methods report at: www.psoriasisleitlinie.de The list of studies included in the following tables is intended to serve as a
rough guide for evaluating therapy
options. Cumulative calculations of individual aspects in the overall evaluation are not possible and cannot be
used for a conclusive evaluation of a
given therapy option. Each column
should be viewed separately. The evaluation may vary significantly on a
case-by-case basis. The varying degrees
of severity of psoriasis render a direct
comparison between systemic and topical therapies impossible. The evaluations are based on a literature review and
expert opinion.
a) Efficacy
The value in the column efficacy reflects
the percentage of patients who achieved a
reduction in PASI score > 75 % (Table 7).
b) Safety/tolerability of
induction/maintenance therapy
The risk of severe side effects or the likelihood of side effects resulting in discontinuation of therapy.
c) Feasibility (patient)
Evaluated factors include the amount of
time involved in using the therapy, its actual usage, and ease of administration.
d) Feasibility (doctor)
Factors that are evaluated include the
amount of work involved (documentation, educating the patient, monitoring),
requirements for equipment and personnel, time involved for doctor/patient interactions, reimbursement of treatment
measures, invoicing problems/risk of
recourse claims by insurers.
e) Cost/benefit
This is assessed according to the costs of
induction or maintenance therapy.
The assessment of safety/tolerability for
induction or maintenance therapy, as well
as the feasibility of therapy for the doctor
and patient, and costs/benefits are measured on a scale of (poor) to ++++ (good).
Grades are based on information from a
literature review and expert opinion. No
evidence level is cited since it was not specifically included in the literature search.
JDDG; 2011 9 (Suppl. 2): S1S95

Therapy options and treatment evaluation
Figure 2: Overview of therapy options under evaluation for use in chronic plaque psoriasis (the order of therapies is alphabetical and does not represent a
ranking).
JDDG; 2011 9 (Suppl. 2): S1S95

S9
S10
4.2.1 Topical monotherapy

Table 5: Topical monotherapy
Efficacy
Evidence level
Safety/tolerability of
induction therapy
Safety/tolerability for
maintenance therapy
Feasibility (patient)
Feasibility (doctor)
Cost/Benefit
Therapy
Calcineurin
inhibitors
++
2/3
++
Not indicated
++
- 1)
++
+ 2)
+ 2)
- 3)
- 3)
+++
++
Not indicated
++++ 4)
+++
++
+++
+++
Coal tar
+/-
Not indicated
+/-
Tazarotene
++
++
++
+/-5)
+/-5)
++
Vitamin D3
derivatives
+++
+++
+++
++
+++
++
++
+++
Good
++++
Dithranol
Corticosteroids
Global
assessment:
Poor
-
+/-
+++
1)
No strong consensus (> 75%) was achieved using the DELPHI method. The recommendation was therefore made based on a majority vote of 54 % (guideline
expert committee). Alternatively, members voted for ++. The reason for the
discussion was off-label prescribing. The opinions on the effort involved diverged significantly.
2)
Inpatient
3)
Outpatient
4)
At least class III steroids; also applies to fixed dose drug combinations.
5)
No strong consensus (> 75%) was achieved using the DELPHI method. The
recommendation was therefore made based on a majority vote of 69 % (guideline
expert committee). Alternatively, members voted for -. The reason for the discussion was the poor availability, i.e., available only via international pharmacies.
The opinions on the effort involved diverged significantly.
JDDG; 2011 9 (Suppl. 2): S1S95

4.2.2 Phototherapy and systemic monotherapy
Table 7: Perccentage of patients achieving a PASI reduction

> 75%
Table 6: Phototherapy and systemic therapy.
PUVA
+++ to
++++
+++
Not
indicated
+/-
++
Not
indicated
+/-
++
++
++
+++
++
++
++
+++
++
+/-
Cyclosporine ++ to +++
+++
++
++
Fumarate
++
+++
++
+++
+++
Infliximab
+++ to
++++
++
+++
+/-
Methotrexate
+ to ++
++
++
++
+++
++
+/-
+++
++
++
+++
++
Phototherapy
Cost/Benefit7)
Safety/tolerability of induction
therapy
+++
Feasibility (doctor)
Evidence Level
2
Feasibility (patient)
Efficacy
+++
Safety/tolerability of maintenance
therapy
Therapy
UVB
Adalimumab
+
Etanercept
+ 1)
++
2)
Scale
Systemic
therapy
Topical
therapy
++++
ca. 90 %
ca. 60 %
+++
ca. 70 %
ca. 45 %
++
ca. 50 %
ca. 30 %
ca. 30 %
ca. 15 %
+/-
ca. 10 %
ca. 5 %
n.d. (not
defined)
n.d. (not
defined)
The evidence level applies to

demonstrated efficacy.
4)
+ 5)
+++ 6)
Retinoids 3)
(systemic)
Ustekinumab
Global
assessment:
Poor
-
+/-
++
+++
Good
++++
1)
Systemic PUVA
Bath/cream PUVA
3)
Retinoid therapy is generally not advised for women of childbearing age
4)
For 1 25 mg
5)
For 1 50 mg
6)
For 2 50 mg
7)
For a 12-week regimen of induction therapy
2)
JDDG; 2011 9 (Suppl. 2): S1S95

S11
S12
Calcineurin inhibitors
5 Topical therapy
5.1 Calcineurin inhibitors
Ulrich Mrowietz, Hans-Michael
Ockenfels
(based on Ulrich Mrowietz, HansMichael Ockenfels, Inga Kreiselmaier)
Introduction
Topical calcineurin inhibitors (Table 8)
are approved in Germany for the treatment of atopic dermatitis. Their use in
psoriasis vulgaris is based on the results
from clinical studies. In 1998 one clinical study reported that the use of pimecrolimus under occlusion was highly
effective against plaque psoriasis [68]
and in 1999 another study showed the
same for tacrolimus [69]. The use of
tacrolimus ointment without occlusion
has not been shown to be effective psoriasis vulgaris, however [70].
Later studies demonstrated the effectiveness of topical calcineurin inhibitors
in the therapy of psoriasis lesions with
involvement of the face, intertriginous
areas, and the anogenital region [71-73].
Calcineurin inhibitors are not approved
for use in psoriasis vulgaris. Alternative
names include topical immunomodulatory drugs and macrolides.
Two drugs are available in Germany:
tacrolimus (Protopic) and pimecrolimus (Elidel). Tacrolimus is available as
an ointment in concentrations of 0.03 %
and 0.1 %. Pimecrolimus 1 % is available as a cream.
The efficacy of calcineurin inhibitors is
similar to that of class II corticosteroids.
An advantage over steroids is that calcineurin inhibitors do not have atrophogenic effects and thus may be used in areas
that are sensitive to steroids, such as the
face, flexures, and anogenital region.
Tacrolimus is also available as a systemic
therapy (Prograf) and is used to prevent
rejection in patients who have undergone organ transplantation. Although a
multi-center study has shown the effect
of systemic tacrolimus, it is not currently
used for systemic therapy of psoriasis
vulgaris [74].
Mechanism of action
The calcineurin inhibitors tacrolimus
and pimecrolimus have similar mechanisms of action. The most important
pharmacological effect is the inhibition
of the ubiquitous cytoplasm enzyme calcineurin phosphatase. In T lymphocytes,
Table 8: Summary table.

Approval in Germany
Pimecrolimus
Tacrolimus
2002 (atopic dermatitis, not approved

for use in psoriasis vulgaris)
2002 (atopic dermatitis, not approved
for use in psoriasis vulgaris)
Recommended initial dosage
Protopic for use on the face: begin

with 0.03 % ointment, later increase
dosage to 0.1 % ointment
Elidel cream: 1 - 2 x/daily
Recommended maintenance dosage Individual treatment modification

Onset of clinical effect
After about 2 weeks
Response rate
40 - 50 % of patients have significant

im-provement or complete clearance
after 6-12 weeks (evidence level: 2)
Main contraindications
Contraindicated in pregnant or nursing

women due to lacking data
Important UAEs
Burning of the skin, increased rate

of skin infections
Important drug interactions
No known drug interactions
Misc.
Important note: do not combine with

phototherapy
the inhibition of calcineurin phosphatase

inhibits the translocation of nuclear factors of activated T cells (NFATs). This
transcription factor is primarily responsible for increased production of IL-2, the
most important autocrine growth factor
for T cells. Along with IL-2, the production of other pro-inflammatory cytokines such as TNF- and IFN- is also
reduced [75, 76]. This mechanism is
similar to that of cyclosporine.
The inhibition of enzyme activity is mediated by calcineurin through binding of
tacrolimus and pimecrolimus to the
same binding protein, macrophilin-12
(synonym: FK-binding protein 12,
FKBP12) [77].
In addition to their effects on T cells, calcineurin inhibitors also inhibit the activation of mast cells [78]. Although
tacrolimus also interferes with antigen
presentation, pimecrolimus does not appear to do so [79, 80].
Dosage and dosing scheme
Topical tacrolimus and pimecrolimus are
generally administered once or twice
daily. Brief pre-therapy with topical
steroids is often performed first. Calci-
neurin inhibitors may also be used for

maintenance or interval therapy.
For treatment of affected areas on the
face, initial therapy is with Protopic
0.03 % ointment, and if there is no irritation, then therapy may continue with
Protopic 0.1 %. This does not apply to
pimecrolimus cream, which is available
in only one concentration.
Treatment with topical calcineurin inhibitors should continue until there is
nearly complete clearing of lesions.
Therapy then continues with topical
emollients.
Efficacy
Four studies were identified that met the
inclusion criteria of the present guidelines. There was one grade A2 on calcineurin inhibitors monotherapy [81], two
grade B studies [82, 83], and one grade
C study [84]. This resulting evidence level is 2. There are no studies available on
combination therapy. The Cochrane Review from Mason was also included [19].
Tacrolimus monotherapy
A study on plaque psoriasis by Carroll
et al. (evidence grade [EG] B) compared
JDDG; 2011 9 (Suppl. 2): S1S95

the use of combination of topical

tacrolimus ointment 0.1 %/6 % salicylic
acid gel versus the use of salicylic acid gel
alone [82]. An improvement of at least
75 % was reported in 56 % (11/24) of
patients who were given the combination therapy compared with 17 %
(4/24) who were treated with salicylic
acid gel alone. Ortonne et al. (EG B, n =
124) compared tacrolimus 0.3 % gel,
tacrolimus 0.5 % cream, and calcipotriol ointment against each other. The
efficacy levels were similar for all three,
with a PGA of much better (tacrolimus gel 0.3 %: 44 %; tacrolimus cream
0.5 %: 45.2 %; calcipotriol ointment:
48.6 %) [83].
Liao et al. (EG A2, n = 50) studied the
efficacy of tacrolimus on facial and anogenital regions in patients with chronic
plaque psoriasis and compared it with
calcitriol. 60 % of patients in the tacrolimus group had complete clearing of lesions (PGA) compared with 33 % in the
calcitriol group [81].
Pimecrolimus monotherapy
Certain publications which did not
meet the guideline inclusion criteria
have investigated the use of topical
tacrolimus and pimecrolimus in patients
with psoriasis vulgaris [68, 69, 85]. One
double-blind, randomized vehicle-controlled study on patients with intertriginous psoriasis reported that pimecrolimus-based cream (1 %) demonstrated a
strong, statistically significant effect
compared to vehicle alone. After eight
weeks of therapy, 71.4 % of patients
who were treated with topical pimecrolimus had nearly complete clearance /
complete clearance; only 20.7 % of
patients in the vehicle group had the
same level of improvement [73]. The
Cochrane Review by Mason found that
pimecrolimus was significantly superior
to placebo. The 95 % confidence interval of -0.45 to -1.69 and the mean
of -1.07 (SWMD) for the comparison of
efficacy are clearly within significant
ranges [19].
Combination therapy
There are as yet no studies on combination therapy in psoriasis vulgaris using
topical calcineurin inhibitors with other
topical or systemic therapies. Combination therapy with UV phototherapy
should be avoided for the reasons mentioned below.
JDDG; 2011 9 (Suppl. 2): S1S95

Table 9: Selected UAEs.

Very
common
Burning sensation, pruritus at the application site
Excessive warmth, redness, pain, irritation, paresthesia,

erythema at the site of application, herpes virus infections,
folliculitis
Molluscum contagiosum, papilloma, increased desquamation,
Occasionally
dry skin, edema, exacerbation of atopic dermatitis
Common
Rare
Very rare
Undesirable adverse effects / safety

The most common undesirable adverse effect of calcineurin inhibitors is a burning
sensation immediately after applying the
drug. This effect seems to be somewhat
more pronounced for tacrolimus than pimecrolimus. In most patients, burning occurs only at the beginning of therapy and
disappears with continued treatment. In a
few patients the effect persists, however,
and treatment must be discontinued.
Given their inhibitory effect on T-cell activation, calcineurin inhibitors interfere
with the skins local immune system. The
use of topical calcineurin inhibitors can
lead to an increased risk of bacterial skin
infections (folliculitis) and viral skin infections (HPV-induced diseases such as
verrucae vulgares and herpes simplex infections).
Animal models have suggested that concomitant use of calcineurin inhibitors and
exposure to UV light can increase the rate
of epithelial tumors. Although a similar
effect has not yet been shown in human
subjects, the use of calcineurin inhibitors
in combination with UVB phototherapy
or PUVA should be avoided.
Pregnancy / birth defects / nursing
There are no reports of birth defects related to the use of calcineurin inhibitors.
Given lacking experience, however, the
use of topical pimecrolimus and tacrolimus is not advised for pregnant or nursing women.
Prevention / management of UAEs
Treatment should be discontinued in patients who experience severe burning or
other side effects associated with the
drug. Short-term use of topical corticosteroids or antiseptics can lead to rapid
improvement of symptoms.
Main contraindications / Limitations

for use
Absolute contraindications
None
Important relative contraindications
Current skin infections (e.g., herpes
simplex, folliculitis)
Immunosuppression
Pregnancy and nursing
Drug interactions
There are no known drug interactions
(see combination therapy).
Notes on usage
At present there are no special notes on
the use of topical calcineurin inhibitors
in the treatment of psoriasis vulgaris.
Pre-treatment procedures
None
Measures during therapy
Protect against exposure to sunlight
Post-therapy measures
None
Use with occlusion is not advised.
Feasibility (doctor / patient)
Most patients can use topical calcineurin
inhibitors without any problems. Patients may experience a burning sensation,
but this generally disappears a few days
after starting therapy. The patient should
be informed of this potential side effect.
The use of tacrolimus on the face is
sometimes cosmetically disturbing due
to the oily ointment base. Physicians
must carefully consider whether to
prescribe this off-label therapy. Careful
S13
S14
Calcineurin inhibitors/Dithranol
documentation and justification for prescribing the drug are warranted.

Costs
The drug costs for therapy with tacrolimus ointment (Protopic 0.1 %) for 2
5 g are 15.60 per day or 436.85 per
month. The drug costs for pimecrolimus
ointment (Elidel) are 12.89 [23] per
day or 386.70 per month.
Special considerations
None.
Dithranol
Approval in Germany
Psoralon
Psoradexan
Micanol
1983 (psoriasis vulgaris)

Recommended control parameters
Intensity of skin irritation
Start with 0.5 % preparation for longterm therapy or 1 % for short-contact

therapy, increase if tolerated
Recommended maintenance dosage Not recommended for long-term therapy
Summary evaluation
Out of eight studies on topical calcineurin inhibitors (pimecrolimus,
tacrolimus), four met the inclusion criteria of the guidelines. These studies
reported a significant improvement or
complete clearance of lesions in 40 50 % of patients after six to twelve
weeks (EL 2).
Topical calcineurin inhibitors may be
used in psoriasis patients for the treatment of areas that are sensitive to steroids, especially the face, flexures, and
anogenital region.
Undesirable adverse effects such as
burning and irritation can occur. The
feasibility for the patient is good, but it
is limited for the physician due to offlabel use of the drug.
Since calcineurin inhibitors are not approved for the treatment of psoriasis
vulgaris, off-label-use is the only available option at this time.
Treatment recommendation
Topical application of tacrolimus
or pimecrolimus 1 - 2 /daily
may be considered for the treatment of psoriasis vulgaris invol-
ving certain areas such as the face,
intertriginous regions, and anogenital region.
Their use on other areas of the

body is not advised, given other
alternatives, as the data are insufficient and there is lacking approval for their use in psoriasis.
5.2 Dithranol
Ockenfels
(based on Ulrich Mrowietz, HansMichael Ockenfels, Inga Kreiselmaier)
After 2 - 3 weeks
Response rate
Significant improvement or complete

clearance in 30 - 70 % of patients (EL 2)
Acute, erythrodermic psoriasis, pustular

psoriasis
Important UAEs
Burning and redness of the skin in >10 %
Misc.
Introduction
The synthetic tar derivative dithranol
(Table 10) was introduced in 1916 by Galewski and Unna. Until the early 1980s
dithranol (1,8-dihydroxy-9-anthrone;
synonyms: anthralin and cignolin) was
the most common topical therapy for
psoriasis vulgaris in Europe. Newer
topical therapies (steroids, vitamin D3
derivatives) have increasingly replaced
dithranol, especially in outpatient care,
which had irritative effects and caused
skin discoloration. Dithranol is now primarily used in inpatient care of patients
with psoriasis vulgaris. It is also approved
for use in Germany as a component in
the following topical therapies:
Psoradexan, Psoradexan mite and
Psoradexan forte with 1 %, 0.5 %, or
2 % dithranol
Psoralon MT 0.5 %, 1 %, 2 %, and
3%
Micanol cream 1 % and 3 %
Mechanism of action
Dithranol suppresses cell proliferation in
vitro and in vivo. It also inhibits neutrophilic granulocytes and monocytes [86,
87], the migration of leukocytes, and lymphocyte proliferation [88]. Finally, it also
strong antiproliferative effects on keratinocytes [89]. The antiproliferative effect on
keratinocytes is due to the inhibition of
the epidermal growth factor receptor

(EGF) and binding of the ligand to the
EGF receptor, the inhibition of cytokine
TGF- secretion by keratinocytes, and the
inhibition of necessary signaling cascades
by protein tyrosine kinase (PTK) [90-92].
There is also significant inhibition of the
pro-inflammatory cytokines IL-6 and IL-8
from monocytes, perhaps exclusively due
to a DNA-inhibiting effect [87].
Topically applied dithranol is not detectable in significant amounts in the
blood. Dithranol is a lipophilic substance which binds rapidly to cells. It
breaks down just as rapidly into its autooxidation products danthron and dianthrone and is excreted by the kidneys.
The oxidation of anthralin to free radicals, the rapid binding to cells, and the
resulting inhibition of DNA synthesis,
cellular enzymes, and mitochondria are
considered to be the main mechanisms
of drug action [93, 94].
Dithranol reportedly also causes healing
of treated and untreated lesions. This is
not attributed to dithranol levels in the
blood, but rather is considered an indirect effect of circulating T-lymphocytes
from treated plaques [95].
Outpatient treatment is preferably
performed with short-contact therapy
JDDG; 2011 9 (Suppl. 2): S1S95

Dithranol
(Psoralon MT and Micanol). For inpatient therapy, or for outpatient care of

patients who have previously taken dithranol, the drug may be given in its
classic form.
The initial dosage is based on skin sensitivity (patient history) and prior use of
dithranol.
Short-contact therapy
Psoralon MT ointment or Micanol
1 % cream is applied for ten minutes
during the first few days of therapy to
the affected area of the skin and then
rinsed off with lukewarm water. Soap
should not be used. Over the following days, the length of application
(for either drug) is then gradually increased to 30 minutes. Psoralon MT
ointment is then increased to 1, 2, or
3 %. It should be applied if possible
for 10-20 minutes on three to four
days each time. Micanol should be
increased from 1 to 3 % after about
one week. If the event of an adverse
drug reaction (skin reaction, irritation) the concentration should be reduced to 1 %.
Classic dithranol therapy
Treatment of plaques begins with the
lowest concentration (0.1 %), applying a thin layer of the drug 2 /daily
(morning and evening). The ointment
should not be washed off. Therapy is
increased based on the degree of skin
irritation. The concentration is generally doubled every three days, depending on the level of irritation. The target concentration is 1 3 %. If severe
skin irritation occurs, the dosage
should be reduced.
The treatment regime lasts four to six
weeks. Two to three weeks of therapy are
usually necessary before there is any notable improvement.
There are no reports of rebound effects
after stopping therapy. There are no studies on intermittent use (e.g., 2 4
x/month) as maintenance, and such use
is not recommended.
Efficacy
A total of 15 studies fulfilled the criteria
for inclusion in the guidelines. For
dithranol monotherapy, there was
one grade A2 study [96], 11 grade B studies [97-107], and 1 grade C study
[108]. The result is an evidence level of
2. Two grade B studies investigated
combination therapy with dithranol.
JDDG; 2011 9 (Suppl. 2): S1S95

The Cochrane review by Mason was also

included [19].
Dithranol monotherapy
Statements such as these on dithranol
are commonplace in the literature: one
of the oldest and most effective topical
therapies in the treatment of plaque
psoriasis [108]. The amount of clinical
experience with dithranol is far greater
than the documentation of its efficacy
in clinical studies. Studies on dithranol
monotherapy report complete or nearly
complete clearance in 30 75 % of
patients [97, 98, 100, 102, 108]. The
range of percentages on treatment
success is due to variable study design,
sometimes with very small samples,
and different definitions of treatment
success.
The Cochrane review by Mason et al.
(EG A1) includes three studies on
topical therapy of psoriasis vulgaris with
dithranol [19]. With a 95 % confidence
interval of -0.46 to -1.65 the mean
(SWMD) for comparison of efficacies of
verum versus placebo is at -1.05 clearly
in the significant range and thus is evidence of the efficacy of local dithranol
therapy.
In studies on short-contact therapy,
Monastirli et al. (EG A2) showed that in
23 patients, after six weeks, there was a
reduction in the PASI score of 8.01
1.44 to 1.21 1 [96]. The efficacy of
short-contact dithranol therapy was
also reported in studies by Agrup et al.
(EG B; 27 of 36 patients had complete
or nearly complete healing of lesions
after five weeks using dithranol pen vs.
dithranol paste), Prins et al. (EG B; eight
out of eight after an average of 12.3
weeks or six out of eight after 13.1
weeks, 2 /daily vs. 3 /weekly), and de
Mare et al. (EG B; 14 of 20 patients had
complete or nearly complete clearance
after six weeks) [97, 98, 103].
The available data failed to show the
superiority of classic therapy over
short-contact therapy [105] or the superiority of the modern preparation
Micanol over traditional dithranol
preparations.
Combination therapy
Studies have been published on combination therapy with dithranol and phototherapy (see also Phototherapy) as well
as combination use with calcipotriolbased creams and corticosteroids.
Dithranol and topical vitamin D3

derivatives
Monastirli et al. (EG A2) compared 1
/daily short-contact dithranol therapy
with combination use of an identical dithranol therapy plus 2 /daily calcipotriol ointment. None of the 23 patients
given dithranol monotherapy achieved
total remission (PASI reduction of 100 %);
23 out of 23 achieved partial remission
(PASI reduction of 75 %) after six weeks.
Combination therapy achieved complete
remission in all 23 patients [96]. The
Cochrane review by Mason showed
compared dithranol with vitamin D3
derivatives (tacalcitol, calcitriol, and
calcipotriol). With a confidence interval
of -0.53 to 0.61 and a mean of -0.04
(SWMD), there was no significant difference between vitamin D3 derivatives
and dithranol [19]. Van de Kerkhoff
et al. compared dithranol, in increasing
dosages, with calcipotriol and reported
that the latter was superior after four
weeks; after 12 weeks dithranol was more
effective (PASI reduction of about
58.5 % for calcipotriol and 63.8 % for
dithranol after 12 weeks) [107].
It should be recalled that calcipotriol may
be inactivated by the salicylic acid in dithranol preparations. Salicylic acid 0.2 %
is added to commercially-available dithranol preparations (Psoralon MT ointment) as an antioxidant; higher concentrations of salicylic acid (e.g., 2 %) have
no added therapeutic effect according to a
study by de Mare et al. (EG B) [98].
Dithranol and topical steroids
Swinkles et al. (EG B) performed a study
on the efficacy of monotherapy with
5 /weekly clobetasol applied to three
plaques per patient versus 1 /daily
dithranol or 5 /weekly combination
use of dithranol and clobetasol [104].
Each monotherapy resulted in complete
remission in 80 % of plaques, while
combination therapy achieved full remission in 100 %.
The most common side effects are
redness and burning involving the lesion
site and the surrounding skin. There are
conflicting results on the effects of classic
therapy versus short-contact therapy.
While some studies report a lower rate of
irritation with Micanol [109], other
studies [105] have found no difference
between lesional and perilesional
S15
S16
Dithranol

Very
common
Common
Skin irritation,
e.g., burning,
itching
Brown
discoloration
of treated areas
and surrounding
skin and clothing
Brown
Occasionally discoloration
of hair and nails
Rarely
Post-inflammatory
loss of
pigmentation
Very rarely
Contact allergy,
blistering and
necrosis
burning and irritation in short-contact

therapy versus longer treatments. In a
study by de Mare et al. (EG B), only 10
% of patients reported skin irritation
[98]. Similar findings have been reported
by a few other authors as well. Yet in a
study by Berth-Jones et al., 80 % of patients reported highly unpleasant skin irritation associated with long-term therapy
[110].
Discoloration of the treated areas as well
as surrounding skin, which can persist
for four to six weeks, discoloration of the
hair and nails, and discoloration of clothing are other possible side effects. Temporary loss of pigmentation after healing
of lesions generally reverses after four to
six weeks.
Blistering and necrosis are rare, and
usually only occur due to overdose [111113]. A very rare complication is the development of a contact allergy to dithranol: 16 cases were reported worldwide
between 1982 and 1994 [114].
Pregnancy/birth defects/nursing
In pregnant women, these preparations
should not be used on large areas of the
skin, nor should they be applied to more
than 30 % of the body surface area. They
should only be prescribed after carefully
weighing the risks and benefits. There is
no information available on the safety of
these drugs for the fetus. Women who
are nursing should not apply these preparations to the breast.
Patients with kidney or liver insufficiency

There are no data suggesting that unaltered dithranol is absorbed through the
skin in humans. Oxidized anthrone, dithranol dimers, and other insoluble polymerization products are excreted by the
kidneys. According to Rotstein and
Baker, the level of excreted anthralin
does not pose a potential risk to the kidneys [115].
Notes on use

There is greater likelihood of side effects
such as mild burning, mild inflammation of the treated skin and surrounding
area, brown discoloration of the hair, clothing, textiles, in classic forms of
therapy compared to short-contact
therapy. The healthy skin surrounding
smaller plaques may be protected with
soft zinc paste. Topical steroids may be
applied for one or two days to relieve
symptoms of skin irritation such as burning and redness. Patients should be
thoroughly informed about possible
symptoms. Patients without prior experience with dithranol therapy should be
given short-contact therapy at the beginning of treatment rather than classic
dithranol therapy.
Contact with the eyes can result in severe
irritation or iritis. In the event of accidental contact, the eyes should be
thoroughly rinsed with water or isotonic
saline solution. A topical steroid may be
applied afterward.
Given the irritative effects of dithranol, a

fingerling or glove should be worn to protect the hands when applying the drug.
Dithranol should not be used on the face
or around the eyes. For use in intertriginous zones (axillae, navel, submammary
fold, groin area), caution should be exercised given the potential for severe skin
irritation.
Primary contraindications/
Limitations for use
Erythrodermic psoriasis
Psoriasis pustulosa
Psoriasis lesions near the mucous
membranes or eyes
Relative contraindications include pregnancy and therapy of infants and children, due to lacking studies.
Drug interactions
The simultaneous use of topical preparations containing salicylic acid or urea
enhances the effect of topical dithranol
due to increased absorption. Dithranol
can enhance the photosensitizing effects
of photosensitizing agents. There are no
reports of other drug interactions.
None
Control irritation of the skin by
adjusting dosage
None
Feasibility (doctor/patient)
The use and dosage of dithranol is limited by is instability (rapid oxidation), local adverse effects (e.g., skin irritation),
and brown discoloration of the skin and
clothing.
The feasibility differs for outpatient and
inpatient therapy. Outpatient therapy is
often considered unpleasant. In addition
to skin irritation and burning, the discoloration of clothing and the need to rinse
off the preparation are considered unpleasant. The feasibility is very good in
hospitalized patients.
Costs
The drug costs of daily dithranol (Psoradexan 1 5 g) are 2.31 or 64.54
per month. Short-contact therapy with
dithranol (Micanol) [23] (1 5 g) costs
2.28 per day or 63.81 per month.
Summary evaluation
Out of 67 evaluated studies, 11 studies
on dithranol monotherapy met the criteria for inclusion in the guidelines.
The results of these studies show total
remission (PASI reduction of 100 %)
in 30 to 70 % and partial remission
(PASI reduction of 75 %) in 26 to 100
% of patients after five to eight weeks
(EL 2). Drug efficacy may be increased
by combining it with calcipotriol-based creams or UVB phototherapy.
Therapy should be conducted for four
to eight weeks. Maintenance or longterm therapies are not feasible with dithranol and do not offer any benefit.
JDDG; 2011 9 (Suppl. 2): S1S95

Dithranol/Corticosteroids
The safety of the drug is very good.

Burning, redness and transitory brown
discoloration are the only adverse effects reported. There are no reports of
adverse systemic effects.
Feasibility is limited for outpatient use.
Its use is feasible in hospitalized patients, and there is a good cost-tobenefit ratio.
For the treatment of severe psoriasis
vulgaris, combination use with phototherapy or other topical preparations
(calcipotriol) may enhance the treatment
response and is thus recommended.
Dithranol monotherapy may be recommended for induction therapy
in hospitalized patients with mild
to moderate plaque psoriasis.
Steroids
Approval in Germany
None
1 - 2 x/daily
Recommended maintenance dosage
Taper after drug takes effect
After 1-2 weeks
Response rate
For, e.g., beta methasone

dipropionate 2 x/daily marked
improvement or complete clearance
in 46 - 56 % of patients after four
weeks (EL 1)
Bacterial, viral skin diseases
Important UAEs
Folliculitis, perioral dermatitis, skin

atrophy
None
Misc.
Monotherapy may be considered

for outpatient induction therapy
in patients with mild or moderate
plaque psoriasis.
5.3 Corticosteroids
Kristian Reich, Thomas Rosenbach
(based on Kristian Reich, Thomas
Rosenbach, Johannes Mohr)
Note: For simplicity s sake, the term
steroids is used in place of corticosteroids.
Introduction
In 1952 a cortisone-based topical
therapy containing an 11-hydroxy derivative of hydrocortisone, was approved
(Table 12) for the treatment of various
skin disorders. In the mid-1950s, fluorinated derivatives were introduced. These
have stronger anti-inflammatory effects.
More than 200 different steroid-based
dermatological products were on the
market in North America by 1960 (and
somewhat later in Germany). Modern
preparations are being developed with
the goal of achieving metabolism of the
drug in the target organ and thus avoid
systemic effects. At the same time, there
is the goal of a high therapeutic index,
i.e., effective use with few adverse effects.
A number of products have been approved for use as topical therapy, usually in
different galenical preparations. Steroids
are most often used for general inflammatory, allergic or pruriginc skin symptoms rather than for specific treatment
of individual skin diseases.
JDDG; 2011 9 (Suppl. 2): S1S95

Mechanism of action
The bodys own steroids are synthesized
from cholesterol and, like their synthetic
derivatives, act via nuclear receptors belonging to the receptor superfamily of retinoid, thyroid, and steroid receptors. As
a result of gene expression, but also
partly post-transcriptionally, the activity
of a number of proteins is modulated in
the cell. This leads to wide-reaching inhibition of inflammatory reactions, immunosuppression, inhibition of DNA synthesis, and vasoconstriction. These
processes also influence the therapeutic
effect in psoriasis vulgaris.
Systemic absorption of the topically applied drug varies strongly. Absorption
depends on the modification and substitutions in the steroid molecule. There are
also effects due to the vehicle, which influences the penetration depth. Lipophilic bases enhance penetration and thus
absorption. Occlusion, for instance, under a plastic covering, increases absorption by five to ten times.
The dosage and maximum treatment duration depend on the preparation and
should thus be based on the current manufacturer information. Application is
normally 1 /daily to the affected site.
Once improvement occurs, it is advisable
to extend the treatment intervals or tran-
sition to a lower-concentration topical

steroid.
A typical protocol for betamethasone
dipropionate would be application 1 /
daily for three weeks. Next the drug is
tapered over one week, applying it only
once every two days, followed by one
week of application every third day, and
then discontinuation of the drug.
Efficacy
A total of 36 studies met the criteria for
inclusion in the guidelines. Ten grade A2
studies on topical steroid monotherapy
were included [116-125], 17 grade B
studies [104, 126-141], and two grade C
studies [142, 143]. Seven of the 35 included studies focused on combination
therapies only. The Cochrane Review by
Mason et al. (EG A1) on the evaluation
of topical steroid therapy was also included [19]. Based on the studies available,
the overall rating of efficacy of monotherapy with topical therapies was given
a level 1 evidence rating.
Due to the vast number of topical steroids, the following discusses only the most
commonly used preparations.
Class III topical steroid monotherapy
Monotherapy with betamethasone
dipropionate
Eight out of 10 studies on monotherapy
with betamethasone dipropionate examined
S17
S18
Corticosteroids
the efficacy of the drug for two to four

weeks of treatment. In one study, patients were given the drug for up to six
weeks [116]. The shortest length of
treatment was one week. Treatment success with betamethasone dipropionate
0.05 mg/g ointment 2/daily was seen
after two to three weeks; marked improvement was seen after only one week
[117, 124, 137]. The efficacy of betamethasone dipropionate is confirmed by
all studies; studies report significant improvement or complete clearance after
two to four weeks in 25 77.8 % [126,
141]. The comprehensive studies by
Douglas et al. (EG A2) and Papp et al.
(EG A2) with more than 300 patients in
each arm reported that within four weeks
there was significant improvement or
complete clearance in 46.6 % or 55.8 %
of patients who used betamethasone dipropionate 2 /daily [118, 124]. Unlike
class IV steroids, studies on class III
steroids barely examine the mode of
administration (see below).
The Cochrane Review by Mason et al.
(EG A1) includes six studies on therapy
with beta methasone dipropionate compared with placebo. The 95 % confidence interval of -0.32 to -1.68 and the
mean of -1.00 (SWMD), when comparing verum against placebo, are clearly
within significant ranges and thus
demonstrate the good efficacy level of
topical betamethasone [19].
Application 1 daily vs. 2 daily
There are no included studies, other than
the Cochrane Review by Mason et al.
(EG A1) [19] comparing the efficacy of
1 /daily application versus 2 /daily
application. The 95 % confidence interval of -0.66 to -1.00 and mean of -0.83
(SWMD) for 1x daily application and 1.14 to -1.54 and mean of -1.34
(SWMD) are both clearly within significant ranges and thus support the efficacy of
topical betamethasone versus placebo [19].
For 1 /daily application, Kaufmann et
al. (EG A2) reported that after four weeks
there was significant improvement or
complete clearance in 37 % of patients
[121], which is at the lower end of the
range of therapy success reported for
2 /daily use in 25 78 % in other
studies (see above).
Mometasone furoate monotherapy
Four studies on mometasone furoate met
the criteria for inclusion in the guidelines.
The Cochrane Review by Mason et al.

(EG A1) included one study on mometasone furoate versus placebo. The 95 %
confidence interval of 0.34 to 1.17 and
the mean of -0.75 (SWMD) are clearly
in significant ranges and thus also
demonstrate good efficacy of topically
applied mometasone furoate [19].
1 daily vs. 2 daily application:
A study by Peharda et al. (EG B) [135]
reported that 1x daily application led to
at least a 75 % improvement in lesions in
64 % of patients (n = 28) after four
weeks. For 2x daily application, Koo et
al. (EG A2) reported similar improvement (75 %) after three weeks in 36.3
% of patients (n = 193) [122]; 68,4 % of
patients had improvement 50 %. In a
study by Katz et al., 2x daily application
for three weeks led to at least 50 % improvement in 77 % of patients (n = 127)
[120]. Based on available studies, it is too
soon to say whether 1 /daily or 2 /
daily treatment is more effective. Studies
on the efficacy of mometasone versus
other topical preparations were not available or did not meet the criteria for
inclusion in the guidelines.
Class IV topical steroid monotherapy
Clobetasol 17-propionate
Eleven studies on clobetasol 17-propionate met the criteria for inclusion in the
guidelines. The maximum level of treatment success with clobetasol 17-propionate 0.05 % 2 /daily is reached after two
to three weeks of therapy; significant improvement is already evident after one
week [128, 131]. The Cochrane Review
by Mason et al. (EG A1) includes six studies comparing clobetasol 17-propionate
with placebo. The 95 % confidence interval of -0.98 to -1.50 and the mean of
-1.24 (SWMD) for the comparison of efficacy of verum versus placebo are clearly
within significant ranges and also demonstrate the very good efficacy level of topical clobetasol 17-propionate therapy [19].
The included studies examined different
vehicles. The drug may be administered
as an ointment, cream, lotion, foam, or
spray. Only two studies directly compared the difference in vehicles (cream vs.
lotion) [123] (EG A2), [128] (EG B).
Differences in galenics
Cream vs. lotion:
In a direct comparison of clobetasol 17propionate given as a cream or lotion
versus placebo, Decroix et al. (EG B, n =

222) reported significant improvement
or complete clearance after four weeks in
77.9 % (cream), 74.5 % (lotion) and 15
% (placebo). Lowe et al. (EG A2) reported the opposite tendency [123] using
the Global Severity Score. Treatment was
successful (GSS 0 1) in 73.2 % of patients given the lotion and 75.3 % of patients who were given the cream. Neither
study found a significant difference in
terms of efficacy (EL 2).
Ointment:
Weston et al. (EG B) reported that 2 /
daily use of clobetasol-17-propionate
ointment led to >75 % clearance in 89 %
of patients after two weeks [141].
Foam:
Use of clobetasol 17-propionate as a
foam 2 /daily, in a study by Lebwohl et
al. (EG B), led to significant improvement or complete clearance in 27 % of
patients (n = 60) after two weeks [131].
Significantly higher remission rates were
reported by Gottlieb et al. (EG A2, n =
139) with the use of 2 /daily therapy:
68 % of patients had complete clearance
or only minimal residual lesions [119].
Spray:
Menter et al. reported that the use of a
spray 2 daily for four weeks achieved
nearly complete or complete clearance in
75 % of patients [133] (EG B). In another study, after four weeks of using the
spray 2 daily, there was complete clearance or only mild remaining lesions in
all patients [127].
Due to the low number of included studies and their mixed results, it is impossible to say for certain whether clobetasol
17-propionate is most effectively administered as a cream, lotion, or foam.
1 daily vs. 2 daily application
Nearly all included studies (nine out of
eleven) report on 2 daily application,
irrespective of the form in which it is
given. Thus it is impossible to make an
evidence-based statement on whether
1 /daily or 2 /daily application is
more effective.
Comparison of efficacy
Class III vs. class IV steroids
One study directly comparing the efficacy
of class III versus class IV steroids was included in the guidelines [141] (n = 37).
JDDG; 2011 9 (Suppl. 2): S1S95

Corticosteroids
After two weeks of therapy with clobetasol 17-propionate 2 daily, 89.4 % of

patients had at least a 75 % improvement of skin lesions compared with
77.8 % of patients who were given 2
daily betamethasone dipropionate [141].
A direct comparison of all studies on
class III or IV steroids in the Mason paper (EG A1) shows that class IV steroids
are clearly superior with a 95 % confidence interval of -1.76 to -1.25 and a
mean of -1.51 [19].
Menter et al. reported for 2 /daily use
of clobetasol spray for four weeks that it
was clearly superior to the combination
drug betamethasone diproprionate/calcipotriol [133] (EG B). 75 % versus 45 %
of patients achieved nearly complete or
complete resolution of skin symptoms.
there is the added risk of rosacea and

steroid acne.
The remainder of the skin is moderately
sensitive, with the exception of the palms
of the hands, soles of the feet, and scalp.
Long-term use of high-dose steroids can
cause atrophy. Moderate-strength and
low-dose steroids are tolerated over a
longer period of time.
Sensitivity of the skin is low on the scalp
and the palms of the hands and soles of
the feet. Steroid therapy may be given for
months or years, even at higher concentrations, without resulting atrophy.
Greater drug efficacy is also associated
with a higher risk of side effects. Very
high efficacy: clobetasol 17-propionate.
High efficacy: betamethasone 17-valerate, betamethasone diproprionate. Moderately strong: triamcinolone acetonide,
prednicarbate, hydrocortisone aceponate. Weak: hydrocortisone, prednisolone, hydrocortisone acetate.
The therapeutic index for the eight
most commonly used steroids was
published in an S1 guideline to help
better evaluate their effectiveness versus
the risk of side effects. For more detail,
the reader is referred to the DDG guideline: Topical dermatotherapy with
corticosteroids- therapeutic index (Topische Dermatotherapie mit Glukokortikoiden- Therapeutischer Index) at
www.awmf-online.de.
breast milk. Depending on the class of

steroid being used and the duration of
therapy, patients should discontinue
nursing. Nursing women should not apply topical steroids to their nipples as
otherwise the drug may be ingested by
the infant during breastfeeding.
Drug interactions
None
Topical steroids and other systemic/topical

therapies
See corresponding sections
Important UAEs
Given the previously mentioned high variability related to steroid strength and
application site, it would be difficult to
list the UAEs by frequency of occurrence
in a table. Potential undesirable adverse
effects include:
Burning, itching, redness, blistering, folliculitis, secondary infection, hypertrichosis, perioral dermatitis, loss of pigmentation, striations, atrophy of the
skin, wound healing disorders.
With long-term usage on larger areas of
the skin, there is the potential for systemic absorption and adrenal suppression.

The risks of adverse effects and their frequencies vary according to application
site, drug potency, and duration of use.
Highly sensitive areas include the face,
genital region, neck, and intertriginous
areas. Atrophy of the skin is the biggest
risk. In intertriginous there is the additional risk of superinfection. On the face

The use of steroids has not been associated with birth defects. Sufficiently strong
topical steroids applied to large areas of
the skin over an extended period of time
may inhibit the growth of the fetus. In
later stages of pregnancy, there is an additional risk of adrenal cortex atrophy in
the fetus. Topical steroids are secreted in
Class III and IV steroids vs. vitamin D3

derivatives
See under Calcipotriol (efficacy)
Combination therapy
Use of topical steroids with salicylic acid
Two studies were included that directly
compared the efficacy of topical steroids
with and without 5 % salicylic acid. Katz
et al. (EG A2) reported that use of mometasone 2 /daily with salicylic acid
yielded a good healing rate or complete
clearance in 86 % of patients (n = 121)
compared with only 77 % of patients
(n = 127) who were given the drug without
salicylic acid [120]. Koo et al. (EG A2,
n = 383) confirmed the enhanced efficacy
of added salicylic acid and reported that
in 53 % of patients who were given the
drug containing salicylic acid, compared
with only 36 % of patients who were
given the plain drug, there was >75 %
improvement in skin lesions after three
weeks. Thus the addition of salicylic acid
seems to significantly increase the effectiveness of topical steroid therapy [122].
JDDG; 2011 9 (Suppl. 2): S1S95

Prevention / treatment of UAEs

Undesirable long-term effects such as
atrophy of the skin and telangiectasia are
not reversible and are difficult to treat if
at all. The treatment strategy should thus
be geared toward prevention of adverse
effects. Treatment with steroids should
follow the current manufacturers information and should be appropriate to the
site. A suitable strength therapy should be
chosen and should not exceed the maximum recommended treatment duration.
for use
None
Rosacea, perioral dermatitis
Skin infections due to bacteria (tuberculosis, syphilis), fungal infection, viruses (herpes simplex and zoster, varicella)
Vaccine reactions of the skin
Notes on use
None
None
None
Overdose / management of overdose
If there is an overdose, the patient must
stop taking steroids. No special therapy
is needed to counteract an overdose.
Topical steroids are well tolerated by
the patient. Doctors should be aware
of when potential long-term effects
associated with the drug may start to be
an issue. There is no need for special
monitoring.
S19
S20
Corticosteroids/Coal tar
Cost
The drug costs per day for 1 5 g topical steroids (based on the 10 most commonly prescribed preparations; fixed prices) are 1.47 [23]. The drug costs for a
four-week treatment regime are 41.20 .
Patients are often very concerned about
using steroids. The physician must carefully inform and educate the patient on
steroid use and associated risks.
Summary evaluation
Out of 122 studies, 36 met the criteria
for inclusion in the guidelines.
Significant improvement or complete
clearance was found in 25 77.8 %
of patients who used betamethasone
dipropionate (EL 1).
Among patients who were given mometasone there was >75 % improvement in lesions in 36.3 - 64 % (EL 1)
Most studies on class IV steroids (clobetasol 17-propionate 2 x/daily) reported PASI 75 in 68 - 89 % of patients
(EL 1).
The effectiveness of topical steroids
may be enhanced by additive use of salicylic acid (EL 1).
The combination with other systemic
or topical therapies also leads to improved remission rates. Common
combinations include topical vitamin
D3 derivatives (see under Vitamin D3
derivatives, EL 1).
No serious adverse effects have been
reported during induction therapy.
Long-term use steroids can cause
various typical side effects such as skin
atrophy and telangiectasias.
Feasibility is good for the patient and
doctor.
Induction therapy with class III
topical steroids is recommended
for patients with mild to moderate psoriasis vulgaris.
Induction therapy with class IV
topical steroids may be recommended for patients with mild
to moderate psoriasis vulgaris
after carefully considering the
increased efficacy and theoretically increased risk of adverse effects.
5.4 Coal tar

Tobias Weberschock, Wolf-Henning
Boehncke, Martin Schlaeger
Introduction
Coal tar (Table 13) is a distillation product from coal with a large number of
different ingredients, of which 400 have
been characterized, including benzols,
naphthaline, and phenols [144]. Its mechanism of action in topical therapies is
uncertain. Coal tar is included in antipsoriatics, antiseptics, and antipruriginous
therapies. In Germany there are 63 commercially-available preparations containing coal tar. They are approved for use
in various diseases.
According to the German Drug Codex
(DAC) 2000, coal tar may be used [...]
only after carefully weighing the therapeutic benefit against the risk of cancer
and taking into account lower-risk
therapy alternatives for chronic eczema,
neurodermatitis, psoriasis vulgaris, and
pityriasis simplex capillitii [...] If, after
carefully weighing the options, coal tar
therapy is determined to be the best option, the use of a commercially-available

preparation appears justified. Some
pharmacists may refuse, however, to prepare a coal-tar-based preparation.
Mechanism of action
The coal tar components are absorbed
through the skin and continue to act
even after removal of the preparation.
They are fat-soluble and are metabolized
and then excreted by the kidneys. It is
still unclear whether the phenols and
benzpyrene bound to the bodys own
proteins can cause cancer in the excretory pathway, e.g., in the urinary passages.
Coal tar has mainly been used in psoriasis to increase the effectiveness of subsequent UV light therapy. A therapeutically effective dose of UV radiation
causes mild phototoxic erythema. The
mechanism of action is uncertain. Antiproliferative and anti-inflammatory effects of the components in coal tar are
under discussion [144].

Coal tar
Approval in Germany
Listed since 2000 (German Drug Codex [DAC]

code: S-170), historical use, various tar-based
topical therapies are approved, tar used as an
anti-psoriasis drug after 1925 following publication
by Goeckermann
Recommended control
parameters
Long-term use / large areas of the skin:

possible clinical controls of potential development
of carcinoma of the skin(see text)
Recommended initial
dosage
5 - 20 % ointment or gels for local therapy,

1 x/daily for a few hours
Recommended
maintenance dosage
Not suitable for long-term use (max. four weeks,

DAC 2000)
After 4-8 weeks, combination use with UV therapy

increases effectiveness
Response rate
Insufficient data for assessing response rate

to monotherapy (EL 4).
Important UAEs
Color, odor, carcinogenic risk (see UAEs / safety),

phototoxicity which is part of the desirable effect
Important drug
interactions
No known interactions with external use
Misc.
DAC 2000 (DAC code: S-170), hazardous

materials appendix 4, no. 13
JDDG; 2011 9 (Suppl. 2): S1S95

Coal tar

In the treatment of plaque psoriasis vulgaris, coal tar is usually administered as
an ointment in various dosages. In the
included studies the active ingredient
concentration was 5 %. Therapy is often
based on what is known as the Goeckermann scheme and consists of application for one hour or more of a tar-based
topical therapy, immediately followed by
UVB exposure after removing the preparation. A suberythematous UVB dose is
selected. Erythema, if it occurs, may be a
helpful guide for adjusting the dosage.
Long-term application and long-term
therapy are not recommended in the
Goeckermann scheme.
Efficacy
A total of six studies met the criteria for
inclusion in the guidelines. Only one
study (grade C) examined coal tar monotherapy [145]. This results in an evidence level of 4. For combination
therapy, all six studies were included
(four grade B, two grade C studies) [145150]. The Cochrane Review by Mason
was also taken into account [19].
Monotherapy
The only included study on coal tar monotherapy, by Frost, with six arms and
only 19 patients, showed coal tar gel to
be inferior to all other interventions in
the study [145]. In a study by Kanzler
and Gorsulowsky in the Cochrane Review, a bilateral comparison in 18 patients with 5 % liquor carbonis detergent
preparation versus a base alone, there was
moderate improvement of around 48 %
after four weeks compared with an improvement of around 35 % for use of the
base [19]. The use of coal tar was not statistically superior, however (95 % CI 1.15 to 0.18, mean -0.48). The
Cochrane Review included data on calcipotriol monotherapy versus coal tar monotherapy and showed that calcipotriol
was significantly superior to coal tar
therapy (n = 42, 95 % CI -1.13 [-1.60 to
-0.67]), although the results were based
on only two studies.
Combination therapy
The data available on combination
therapy with coal tar are mixed. There
are only six studies available. The
Cochrane Review by Mason also included combination therapy with coal
tar [19].
JDDG; 2011 9 (Suppl. 2): S1S95

Combination with UV phototherapy

The results of the studies described above
document the effectiveness of UVB phototherapy (for efficacy: see above) in
combination with topical therapy with
coal tar, although an additive or synergistic effect of coal tar is not sufficiently
demonstrated. It should be noted that
UV light and tar are considered co-carcinogens. In a study by Belsito and Kechijian (EG B) on the use of 5 % coal tar
ointment 2 /daily versus the ointment
base, bilateral comparison with subsequent UVB irradiation led to identical
results for the plaques on both sides: two
out of 17 patients had 90 % improvement after 17 or 54 days and seven out of
17 had 75 % improvement after 14 (maximum 22) days [148].
In another study, Diette et al. (EG B)
compared 12 hospitalized patients who
applied 5 % coal tar Vaseline for one
hour, rinsed it off, and then were exposed
to 6 /weekly UVB versus 13 outpatient
patients who were treated with coal tar
gel and exposed synchronously 3 /weekly to UV therapy. Ten out of the 13 outpatient patients were free of lesions after
about 26 ( 5.9) sessions; a 75 % improvement in skin lesions occurred in 12
out of 13 patients. Among the inpatient
patients, six out of 10 had complete clearance, and seven out of 10 had more
than 75 % improvement after 21 ( 4.4)
sessions. Both groups were additionally
exposed, after UVB irradiation, to UVA
on one side until the appearance of
erythema [149]. This failed to enhance
the effectiveness of therapy.
In a study with 25 hospitalized patients,
LeVine and Parrish (EG B) performed a
bilateral comparison in small groups
with the use of 5 % coal tar Vaseline 5 /
weekly verus fluocinonide ointment or
vehicle alone followed by daily UVB irradiation until erythema appeared [150].
All modalities achieved complete clearance of plaques after 18 20 treatment
sessions. Fluocinolone in addition to
coal tar or Vaseline led to more rapid
clearance of lesions in the first five to 10
treatment sessions.
In another bilateral comparison, Frost et
al. (EG C) investigated the effect of UVB
and coal tar gel in three very small
groups. In the first group, the effect of
high versus low UVB dosages in combination with tar gel were studied in six
patients. In the second group, four patients were treated with coal tar gel and
low-dose UVB versus tar gel without UV

therapy, and in the third group three patients were treated with tar gel and UVB
versus the gel base and UV therapy
[145]. Low-dose UVB exposure combined with tar gel led to an improvement
of the symptom index of about 81 % (ca.
72 92 %), and the minimal erythematous dose by about 74 % (ca. 61 87 %).
In the second group, UVB therapy combined with coal tar gel led to improvement of the symptom index of around
70 % (ca. 53 81 %), while coal tar gel
alone reduced symptoms by about 48 %
(ca. 43 59 %). In the third group,
therapy with UVB and coal tar gel
improved the symptom index by around
70 % (ca. 56 81 %). UVB therapy with
the gel base led in this last group to an
improvement of around 54 % (ca. 43
60 %) [145].
A single-arm study by Andrys et al. (EG
C) with 44 patients with moderate to
severe psoriasis reported an average reduction in PASI of 72.2 % after threeand-a-half weeks of 5 % coal tar therapy
followed by combined UVA/UVB exposure [146].
In the most recent study included, Bagel
et al. (2009) compared three times weekly narrow spectrum UVB therapy with
or without liquor carbonis detergens for
12 weeks in a bilateral comparison with
12 patients (EG B) [147]. Both forms of
treatment led to complete or nearly complete clearance in about 92 % of patients
by the end of treatment. The significant
effect (p = 0.025) of a more rapid response with liquor carbonis detergens after four weeks reported by this study,
which was funded by the manufacturer,
was not confirmed by any other twoweek interim analysis.
The combination of coal tar therapy and
subsequent UVB exposure, based on the
Goeckermann scheme on induction
therapy, has been variously evaluated.
With four grade B studies, and two grade
C studies, the resulting level of evidence
is 3.
Combination therapy with
hydrocortisone and allantoin
A study by Pinheiro, which is included
in the Cochrane Review, investigated the
efficacy of a preparation containing 5 %
coal tar, 2 % allantoin, and 0.5 % hydrocortisone versus 0.05 % calcipotriol
twice daily. Of the 63 patients who were
given the coal tar preparation, 49.1 %
S21
S22
Coal tar/Tazarotene
had significant improvement or clearance compared with 72.3 % of the 69

patients who were given calcipotriol. The
NNT for calcipotriol was five and the
difference significantly superior (95 %
CI -0.83 to -0.11, mean -0.47) [19].
Even for commercially-available coal
tar treatments, patients complain of the
permanent brown/black stains on
clothing and the unpleasant odor of the
preparation.
Long-term safety
Animal studies have shown coal tar to
have a carcinogenic effect. In humans, a
carcinogenic effect has been demonstrated in squamous cell cancer of the scrotum [151, 152], but has not been associated with therapeutic use on the skin.
Coal tar products are contraindicated in
pregnant and nursing women.
Prevention / treatment of UAEs
The combination with UV therapy can
cause dermatitis solaris. For prevention
and therapy of dermatitis solaris: see under Phototherapy
for use
Xeroderma pigmentosum, dysplastic
nevus cell nevus syndrome, basal
dell nevus syndrome
High level of UV exposure
History of carcinoma
Drug interactions
Drug interactions are not relevant to topical coal tar therapies. Due to the photosensitizing effect of coal tar, potential
additive effects with the use of systemic
photosensitizers should be recalled (see
under Phototherapy).
Notes on use
Inform the patient of the potential
carcinogenic effects as described above
Patients must be advised of the photosensitizing effect of coal tar
Table 14: Important UAEs.

Very common Color, odor
Common
Photosensitization
Occasionally
Rarely
Very rarely

Avoid excessive exposure to UV light
Avoid concomitant use of photosensitizing agents
Depending on the duration and
extent of treatment, longer-term follow-up of the skin may be advisable
The use of coal tar is limited by its presumed cancerous effects. The color and
odor of coal tar products also decrease
their acceptance by patients. For combined use with phototherapy, please see
Chapter 6 (Phototherapy).
Cost
The daily cost of therapy with 1 5 g
coal tar (Linola) is 4.94 [23] which corresponds to monthly costs of 138.32 .
Summary evaluation
Of the 21 studies that were evaluated,
six met the criteria for inclusion in the
guidelines.
Given that there is only one monotherapy (grade C) study available, it is
impossible to make any conclusive statements on the efficacy of coat tar monotherapy (EL 4).
Clinical studies on coal tar with phototherapy have reported mixed results.
Studies report that after 15 - 20 treatments with UV therapy, 45 - 80 % of
patients achieve at least PASI 75.* The
additive effect of coal tar, compared
with UV therapy alone, has not been
sufficiently proven, however.
The acceptance of coal tar preparations
is low due to their color and odor. Given the availability of more effective,
lower-risk, and more practical treatment alternatives, the use of coal tar
monotherapy for the treatment of plaque psoriasis is largely outdated.
Only after careful consideration of the

therapeutic benefit, and after considering lower-risk therapy alternatives,
may coal tar perhaps be used in combination with UVB for the treatment of
refractory plaque psoriasis.
*[148, 153]
Coal tar monotherapy is not recommended for the treatment
of psoriasis vulgaris.
Under exceptional circumstances, the use of a coal tar preparation in combination with
UV therapy may be considered
in individual patients for the
treatment of psoriasis.
5.5 Tazarotene
Sandra Philipp, Michael Sebastian
(based on Markus Friedrich, Michael
Sebastian)
Introduction
Tazarotene (Table 15) has been available
in Germany since 1997 as tazarotene gel
0.05 % and 0.1 % for the treatment of
mild to moderate psoriasis vulgaris. The
lower concentration has not been marketed since November 2007, and the 0.1 %
formulation is only available as a reimported preparation from Spain or
France. Tazarotene is a potent third generation retinoid. The effect of the drug is
seen soon after starting therapy and continues for up to12 weeks after ending
therapy.
Mechanism of action
Tazarotene is hydrolyzed in the skin by
esterases to form its active metabolite, tazarotenic acid. This binds to the nuclear
retinoic acid receptors RAR- and RAR and thus affects epidermal proliferation and differentiation. The precise
mechanism of its anti-psoriatic effect is
not fully understood. Therapy leads to
reduced expression of inflammatory
mediators in the epidermis and dermis.
The effects of tazarotene may be due to
inhibition of inflammation as well as
diminished epidermal proliferation.
After topical application without occlusion,
the systemic absorption of tazarotene is
less than 1 %. The drug is not stored
in fatty tissue. Tazarotene is 1000 times
JDDG; 2011 9 (Suppl. 2): S1S95

Tazarotene

Tazarotene
Approval in Germany
Recommended control parameters Check for development of skin irritation

Recommended initial dose
Start with 1 x/daily (evenings)

tazarotene gel 0.1 % for ca. 1 - 2 weeks
Recommended maintenance dose Tazarotene gel 0.1 % 1 x/daily

After 1 - 2 weeks
Response rate
After 12 weeks of tazarotene gel 0.1 %

roughly half of patients show at least
50 % improvement (EL 2)
Pregnant and nursing women
Important UAEs
Pruritus, burning, erythema, irritation
Avoid simultaneous use of preparations

with irritative and strong drying effects
Misc.
Tazarotene is approved for use in

Germany, but is no longer sold
and is currently available only as a 0.1 %
formulation through international
pharmacies.
less lipophilic than etretinate. It breaks

down into sulfoxide and other polar metabolites which are rapidly eliminated
from the body. The drug half-life is
18 hours. Animal experiments have
shown that it does not cause increased
risk of mutagenicity or birth defects.
Dosage and dosage scheme
Tazarotene gel 0.1 % is applied in a thin
film 1 /daily (evenings) to the affected
sites (no more than 10 % of the body
surface area). The drug should be applied
directly to the lesion, avoiding contact
with healthy skin or skin folds given its
irritative effects.
Efficacy
Seven studies on tazarotene monotherapy met the criteria for inclusion in
the guidelines. Two were two grade A2
studies [154, 155], four grade B studies
[156-159], and one grade C study [160].
The resulting evidence level is 2.
In regard to combination therapy with
tazarotene, one grade A2 study [154] and
four grade B studies [156-159] were
evaluated.
In the meta-analysis of topical substances
in the Cochrane Review in Mason et. al.
(EG A1) tazarotene monotherapy was
JDDG; 2011 9 (Suppl. 2): S1S95

found to be more effective than placebo

(SWMD) at -0.91, 95 % Cl: -0.67 to
-1.16 (one study) and comparable to
calcipotriol (SWMD) at -0.74, 95 % CI:
-0.93 to -0.55 (10 studies) [19]. Given
the limited number of studies it is
impossible to say whether twice daily use
is superior to once daily use.
Monotherapy
Tazarotene cream
Weinstein et al. (EG A2) compared the
efficacy of tazarotene cream 0.05 % and
0.1 % versus placebo. 58.8 % of patients
who were treated with 0.1 % cream and
47.6 % who were given 0.05 % cream
had a >50 % improvement in lesions after 12 weeks. The same rate was achieved
by 26.2 % of patients in the placebo
group [155]. In this study 0.1 % tazarotene cream appeared to be more effective, although the difference was not statistically significant. There are no other
studies available on tazarotene cream
monotherapy.
Tazarotene gel
The results of tazarotene gel monotherapy are mixed. Gollnick and Menter
(EG A2) reported that after 12 weeks of
therapy with 0.1 % tazarotene gel, 80 %
of patients had at least a 50 % global

improvement, while Green et al. (EG B)
reported the same result for only 35 % of
patients [154, 156]. Yet another study
(EG B), also on 1 daily use for the
same length of time reported a 50 %
improvement in 60 % of patients [159].
Combination therapy
Given its potentially irritative effects on
the skin, tazarotene is often combined
with topical steroids. Class III steroids
such as mometasone furoate are commonly used. One study reported that the
application of tazarotene in the evenings
and steroid in the mornings could
increase the response rate, reduce side
effects, and increase the length of remission [158].
Green and Sadoff (EG B) compared
various combinations of tazarotene and
topical steroids over a period of 12
weeks. The best results were achieved by
combinations with betamethasone dipropionate cream (78 % of patients had
a 50 % improvement) and mometasone
(66 % of patients had a 50 % improvement), while therapy with tazarotene
0.1 % monotherapy achieved a 50 %
improvement or better in only 35 % of
patients [156].
In a study by Lebwohl et al. (EG B),
83 % of patients had nearly complete
clearance after 12 weeks if they applied
tazarotene 0.1 % and mometasone
0.1 % in the morning and then in the
evening applied tazarotene 0.1 % again
[158].
Gollnick and Menter (EG A2) examined
combination therapy with tazarotene
and different steroid classes and reported
a 50 % improvement in 81 % of patients
who were given tazarotene and low-dose
steroids, in 91 % who where given medium-strength steroids, and in 95 % who
took high-dose steroids [154]. There are
no data available on the combination
topical retinoids with systemic therapies.
Topical application of tazarotene frequently causes dose-dependent skin irritation. Commonly reported side effects
include itching, burning, and redness at
the application site. There are no reports
of phototoxic or photoallergic reactions
(Table 16).
The adverse effects typically seen with
oral retinoid use do not occur with
topical application. Even after topical
S23
S24
Tazarotene/Vitamin D3 and vitamin D3-analogues
None

Very common
Pruritus (20 - 25 %), erythema and irritation (10 - 20 %)
Common
Burning, worsening of psoriasis vulgaris (5 - 10 %),

inflamed and dry skin (1 - 3 %)
Occasionally
Desquamation, irritative contact dermatitis, stinging
Rarely
Very rarely
treatment for one year, there are or radiologically evident osseous changes.
on up to 20 % of body surface area are

scarce
Long-term safety
The safety of daily topical application
(for up to one year) of tazarotene gel has
been tested on mice, rats, and guinea
pigs. The majority of observed side effects consist of reversible skin irritation.
Drug interactions
Use of other preparations which have an
irritative or strong drying effect (medications and cosmetics) should be avoided
during tazarotene therapy.
Notes on use

The safety of the drug in pregnant women is uncertain. In rat and rabbit studies, oral administration has led to birth
defects and embryotoxic effects. Studies
on topical tazarotene therapy have reported skeletal changes during embryonic
development as well as low weight at
birth and at the end of lactation. Animal
studies have shown that tazarotene and
its active metabolites are present in breast
milk and could pass the placental barrier.
In vitro and in vivo studies with tazarotene have not suggested a mutagenic potential.
Prevention / therapy of UAEs
Care should be taken to avoid applying
the drug to unaffected areas of the skin.
Management of side effects: see also
overdose measures.
for use
Patients under 18 years of age
Due to lacking clinical experience, the
drug should not be used in psoriasis
pustulosa or exfoliativa, in intertriginous regions, or on the face or scalp
Do not apply to more than 10 % of
the body surface area; reports on use
None
Measures during treatment
Patients should avoid excessive UV
light exposure and should wear
protective clothing against sunlight
during therapy
None
Overdose / measures against overdose
An overdose of tazarotene gel can cause
severe redness, scaling, or local skin symptoms. In the even of an overdose, the
drug should be discontinued and local
anti-inflammatory therapy, e.g., topical
steroids, should be initiated.
Feasibility
The feasibility of tazarotene use is limited. Tazarotene is approved for use in
Germany, but is no longer available on
the market. Tazarotene may be ordered
from an international pharmacy. There is
no special need for educating the patient
other than to instruct patients to apply
the drug only to the affected site and to
avoid contact with healthy surrounding
skin.
Cost
Tazarotene is not currently sold in Germany, and there are no reliable cost estimates available.
Summary evaluation
Seven of the 12 studies evaluated met
the criteria for inclusion in the guidelines. After about 12 weeks of treatment
with tazarotene 0.1 % 1 x/daily about
50 % of patients achieve at least a 50 %
improvement in skin lesions (EL 2).
Combination therapy with topical
steroids can help optimize treatment
success and reduce commonly reported skin irritation (EL 2).
There are no reports of serious side
effects related to the drug. Contact
with healthy skin should be avoided to
prevent irritation.
Tazarotene is approved for use in Germany, but is no longer on the market.
The drug may be ordered through an
international pharmacy. This limits the
feasibility of its use.
Topical use of tazarotene may be
considered in the treatment of mild
to moderate psoriasis vulgaris.
5.6 Vitamin D3 and vitamin D3analogues
(based on Reich, Thomas Rosenbach,
Johannes Mohr)
Note: For simplicity s sake, the guidelines
use the term vitamin D3 derivatives.
Table 17 presents a summary of vitamin
D3 preparations and analogues.
Introduction
In 1992 calcipotriol (Psorcutan, Daivonex) became the first vitamin
D3-analogue to be approved for use as
topical therapy in patients with mild to
moderate plaque psoriasis. Tacalcitol
(Curatoderm) and the naturally-occurring vitamin D3 calcitriol (Silkis) were
later also approved. Calcipotriol is available as a cream, ointment, or solution.
Tacalcitol comes as an ointment or
lotion (emulsion), and calcitriol as an
ointment. In 2002 the combination of
calcipotriol / betamethasone (Daivobet,
Psorcutan Beta) was approved for initial
treatment of psoriasis vulgaris.
Mechanism of action
The effect of 1, 25-dihydroxy vitamin
D3 (1,25(OH)2D3) and its synthetic
JDDG; 2011 9 (Suppl. 2): S1S95

Vitamin D3 and vitamin D3-analogues

Vitamin D3 and analogues
Approval in Germany
Calcipotriol
Tacalcitol
Calcitriol
Calcipotriol / betamethasone

Recommended control parameters Check for development of skin irritation
Calcipotriol: 1 - 2 x/daily on affected

areas of the skin, maximum 30 % of BSA
Tacalcitol: 1 x/ daily on affected areas of
the skin, maximum 20 % of BSA
Calcitriol: 2 x/ daily on affected areas of
the skin, maximum 35 % of BSA
Recommended maintenance
dosage
Calcipotriol: 1 - 2 x/daily, up to 100 g/

weekly up to one year
Tacalcitol: 1 x/daily for eight weeks to 18
months maximum 15 % of BSA with up
to 3.5 g/daily
Calcitriol: lacking experience with use for
longer than six weeks
After 1-2 weeks
Response rate
30 - 50 % patients experience significant

improvement or complete clearance after
4-6 weeks (EL 1)
Disorders with altered calcium

metabolism, severe liver and kidney
disease
Important UAEs
Skin irritation (redness, itching, burning)
Drugs that elevate calcium levels (e.g.,

thiaz-ide diuretics), avoid concomitant
use of topi-cal salicylic acid (inactivation)
Misc.
analogues is mediated by the vitamin D

receptor which belongs to the same superfamily of nuclear receptors as retinoids, thyroid, and steroid hormones.
The receptors, which also interact with
each other, and are present in virtually all
skin cells, bind after activation via the ligands to regulatory sections of DNA and
influence the expression of target genes.
Vitamin D3 derivatives suppress the production of pro-inflammatory cytokines
such as IL-8, which play a role in the
inflammatory process in psoriasis, and
induce the binding of anti-inflammatory
cytokines such as IL-4 and IL-10 [161].
In addition, vitamin D3 signal transduction interferes with other transcription
factors such as NFAT and NF kappa B
JDDG; 2011 9 (Suppl. 2): S1S95

[162], which are considered important

for the increased formation of inflammatory mediators in psoriasis vulgaris.
There are also non-genomic effects of
vitamin D3 that are not mediated by
receptors.
A significant part of the antipsoriatic
effect is presumably due to the inhibition
of keratinocyte proliferation and increased differentiation. There are also
further immunomodulatory effects on
T lymphocytes, Langerhans cells, and
monocytes.
In psoriasis patients, percutaneous
absorption is less than 1 % for calcipotriol and tacalcitol. The half-life of intravenously administered calcipotriol is
four minutes.

Calcipotriol is started at 2 /daily and
then increased to 1 2 /daily. Tacalcitol is given 1 /daily and calcitriol 2 /
daily. The selected preparation should be
applied in a thin layer to the affected
areas of the skin. For longer-term daily
use of calcipotriol, no more than 15 g
should be administered or not more than
100 g cream or ointment weekly (maximum body surface area of about 30 %).
For tacalcitol, the daily maximum is 10 g
on 15 20 % of the body surface area,
and for calcitriol 30 g ointment daily on
up to 35 % of the body surface area.
If used for long-term therapy, calcipotriol should preferably be given intermittently, for up to one year and not exceeding the limits mentioned above. If
tacalcitol is administered for more than
eight weeks (up to 18 months), a maximum of 15 % of the body surface area
should be treated with up to 3.5 g/daily.
For calcitriol there is still insufficient experience on use of the drug for more
than six weeks.
In the initial weeks of therapy, the clinical response may be enhanced by additive use of 1 2 /daily topical steroids,
generally class II and III steroids. The
combination of calcipotriol and the class
III steroid betamethasone dipropionate
(Daivobet, Psorcutan Beta) is given
1 /daily for up to four weeks.
Efficacy
inclusion in the guidelines. For vitamin
D3 derivative monotherapy, eight grade
A2 studies were evaluated [81, 116, 118,
121, 124, 163-165] and nine grade B
studies [83, 100, 106, 107, 136, 166169]. The Cochrane Review in Mason
et al. (EG A1) was also included in the
evaluation of topical therapies [19]. This
results in an evidence level of 1. Ten studies on concomitant or sequential combination therapies were also included.
Monotherapy with vitamin D derivatives
Calcipotriol monotherapy
There are 13 studies available for the evaluation of calcipotriol monotherapy [83,
106, 107, 118, 121, 124, 136, 163, 164,
166-169].
Calcipotriol 2 daily:
It takes up to 12 weeks to reach the
maximum treatment success for calcipotriol 0.05 mg/g ointment 2 /daily [169]
S25
S26
(EG B), [164] (EG A2), [107] (EG B).

Significant improvement is seen after 1-2
weeks [164, 166, 170]. The efficacy of
calcipotriol is confirmed by all studies.
The Cochrane Review in Mason et al.
(EG A1) included 15 studies on calcipotriol versus placebo [19]. The 95 % confidence interval of -0.83 to -1.21 and the
mean of -1.02 (SWMD) for the comparison of efficacy of verum against placebo
are clearly within significant ranges and
thus confirm the effectiveness of topical
calcipotriol therapy. The efficacy of calcipotriol monotherapy has also been confirmed by other studies. Three grade A2
studies reported that 33.4 50.7 % of
patients had significant improvement or
complete clearance after twice daily application of calcipotriol (PGA = marked
improvement or clear) [118, 124, 163].
After eight weeks of twice daily therapy,
the effectiveness increases to 40.7 %
[164] (EG A2) or 58 % [166] (EG B)
and then continues to increase until
week 12 of treatment [107, 164, 169].
Calcipotriol 1 daily:
The efficacy of 1 /daily versus 2 /
daily is not directly studied in any of the
included studies save for Masons
Cochrane Review (EG A1) [19]. In a
study by Kaufmann et al. (EG A2) without a direct comparison arm, that authors reported that after four weeks of
1 /daily use there was significant
(PGA = marked improvement or clear)
in 22.3 % of patients, which is significantly lower than the reported range of
33.4 50.7 % for twice daily use for four
weeks [121]. In the statistical assessment
by Mason et al. (EG A1), this was confirmed in two studies with a mean of -0.19,
which was statistically significant given
the 95 % confidence interval from -0.37
to -0.02 [19]. Thus 2 /daily therapy
appears to be more effective than 1 /
daily use.
Calcipotriol vs. calcitriol:
A comparison study by Zhu et al. [169]
(EG B) measured the reduction in the
Dermatological Sum Score (degree of
severity 0 12) in patients who used calcipotriol or calcitriol. Calcipotriol received a score of 6.27 points and calcitriol
5.56 points. The difference was not significant, however, and the opposite tendency was seen in the same patients if the
Global Assessment of Improvement
and its percentages were taken into consideration. Here, too, the differences
were not significant. Thus the two preparations appear equal based on the results
of the study. In the Cochrane Review, direct comparison of calcitriol versus calcipotriol in two studies (with a total of 165
patients) showed them to be roughly
equal at -0.16 (95 % confidence interval
of -1.83 to 1.51).
Calcipotriol vs. tacalcitol:
The Cochrane Review in Mason (EG A1)
reported a calculation on the basis of one
study with a large number of patients
(n = 287). This study directly compared
tacalcitol and calcipotriol and found calcipotriol to be statistically significantly
superior with a value of -0.47 (95 %
confidence interval -0.21 to -0.73) [19],
suggesting that calcipotriol monotherapy
is more effective than tacalcitol monotherapy.
The included studies reveal similar results, with calcipotriol tending to be
more effective. Calcipotriol 1 daily for
four weeks led to significant improvement or clearance in 22.3 % of patients
while tacalcitol achieved the same effect
in only about 18 % [121, 165].
Calcipotriol vs. tacrolimus:
Ortonne et al. (EG B) compared calcipotriol with tacrolimus gel or ointment
and reported a comparable response rate
after 12 weeks (Physician Global Assessment much better in 48.6 % for calcipotriol, 44.4 % for tacrolimus gel 0.3 %,
and 45.2 % for tacrolimus cream 0.5 %)
[83].
Calcipotriol vs. class III steroids:
There are four studies [118, 121, 124,
136], as well as the Cochrane Review calculations in Mason [19] based on nine
studies, on the efficacy of calcipotriol
compared with class III topical steroids.
The results of Mason on calcipotriol vs.
betamethasone diproprionate show a
slight advantage for steroid therapy of
0.19 (SWMD) with a 95 % confidence
interval of -0.17 to 0.55 (the results are
not statistically significant).
A direct comparison showed that after
four-week-long therapy with class III
steroids, with once daily application of
each treatment, about 14.7 % more patients had a significant improvement or
complete healing of lesions with steroid
use compared with calcipotriol mono-
therapy [121]. With 2 daily application each, depending on the study, the
percentages were 7.7 % [118] (EG A2) or
22.4 % [124] (EG A2). Thus, based on
the included studies, topical class III
steroids appear superior to calcipotriol
monotherapy.
Calcipotriol vs. dithranol:
Only two studies were included on the
efficacy of calcipotriol compared with dithranol [106, 107]. In a study by van de
Kerkhof et al. (EG B), after four weeks of
treatment about 61 % of patients taking
calcipotriol had significant improvement
or clearance compared with 27 % of
patients who were given short-contact
dithranol [106]. The more rapid initial
response to calcipotriol has been confirmed by van de Kerkhof et al. (EG B)
who reported a mean reduction in PASI
score after four weeks of calcipotriol of
47.3 % compared with 33.9 % for dithranol cream [107]. After 12 weeks,
therapy success was greater for dithranol
than for calcipotriol (63.8 % reduction
in PASI score dithranol/ 59.8 % for calcipotriol). In the Cochrane Review by
Mason (EG A1), five studies were included in the analysis which yielded a mean
of -0.01 with a 95 % confidence interval
of -0.71 to 0.69, showing that calcipotriol was not more effective than dithranol therapy [19]. It should be noted that
the type of dithranol therapy was not
specified (classic versus short-contact
therapy).
Calcitriol monotherapy
Five studies evaluating calcitriol met the
criteria for inclusion in the guidelines
[81, 100, 116, 167, 169]. Camarasa
et al. (EG A2) showed significant improvement or complete clearance in 52 % of
patients after a maximum of six weeks of
therapy [116]. Hutchinson et al. (EG B)
showed this in 32 % of patients after
eight weeks of 2 daily application [100].
The results of the Cochrane Review on
calcitriol versus placebo failed to show
calcitriol to be significantly superior to
placebo with a value of -1.03 (SWMD)
and a 95 % CI of -2.25 to 0.19 (five studies were included in the analysis including the highly divergent results by Ber
Perez et al. [171]).
Calcitriol vs. tacalcitol:
Most studies show calcipotriol to be superior to tacalcitol. Given that calcipotriol
JDDG; 2011 9 (Suppl. 2): S1S95

and calcitriol are roughly equally effective, it may be assumed that calcitriol
therapy is more effective than tacalcitol.
Tacalcitol monotherapy
Only one study on tacalcitol monotherapy met the criteria for inclusion in
the guidelines. Ortonne et al. (EG A2)
reported significant improvement or
complete healing of lesions in about 18
% of patients after four weeks and in about 25 % of patients after six weeks
[165]. In the Cochrane Review, the three
included studies showed tacalcitol to be
significantly more effective than placebo
(CI 95 % -1.34 to -0.29, mean -0.82)
[19]. For weighting against other vitamin D analogues, see under Calcipotriol
or Calcitriol below.
Combination therapy with vitamin D
derivatives
Eight grade A2 studies [116, 118, 121,
124, 163-165, 172], nine grade B studies
[130, 133, 136, 166, 168, 173-176], and
three grade C studies [177-179] were included on combination therapy with vitamin D and other topical or systemic
therapies. A general distinction may be
made between topical combination
therapy, combination drugs (i.e., different active ingredients in one preparation), and sequential combinations of
different preparations (i.e., agents in two
different preparations). Vitamin D derivatives may be combined with topical or
systemic therapies.
Combination therapy: calcipotriol plus
betamethasone dipropionate
Combination therapy with calcipotriol
and betamethasone given 1 or 2
/daily was evaluated by 12 studies
[118, 121, 124, 133, 136, 163-165, 168,
172, 175, 178].
For 1 /daily application there was significant improvement or complete clearance in 45 % [133] (EG B) to 63.3 %
[163] (EGA2) of patients after four
weeks [133] (EG B), [163] (EG A2),
[121] (EG A2), [165] (EG A2). In a study
by Kragballe et al. 55.3 % of patients
achieved the same result [164] after eight
weeks (EG A2). Once daily therapy for
four weeks was also reported on by
White et al. [172] (EG A2), Kragballe et
al. [164] (EG A2) and Cassano et al.
[175] (EG B) for a total of 1,890 patients. The reported reduction in PASI
score was between 64.7 and 72 %.
JDDG; 2011 9 (Suppl. 2): S1S95

Three grade A2 studies reported significant improvement or clearance after

four weeks in 68.0 76.1 % patients
who were given twice daily treatment
[124] (EG A2), [118] (EG A2), [163]
(EG A2).
Compared with twice daily use of calcipotriol monotherapy, which resulted in
significant improvement or clearance in
33 51 % of patients, combination
therapy with once daily calcipotriol and
betamethasone was successful in 55 % to
63 % of patients, and with twice daily
use in 68 76 % of patients, showing it
to be clearly superior. Other (grade B)
studies also reported a clear therapeutic
advantage in the first four weeks of
therapy if betamethasone was combined
with calcipotriol compared to calcipotriol monotherapy [168, 175]. The
Cochrane Review (EG A1) confirmed
these results. In the two included studies,
once daily combination therapy was significantly superior to calcipotriol monotherapy at 0.67 (SWMD, 95 % CI 0.36
to 0.97).
In the first four weeks, not only is combination therapy superior to calcipotriol
monotherapy superior, it is also superior
to betamethasone monotherapy. In 2009
Rosina et al. [136] (EG B) reported that
in 30 patients in the first four weeks after
beginning treatment, combination
therapy with betamethasone and calcipotriol is significantly more effective
than either betamethasone or calcipotriol alone (PASI reduction of 88.6 % for
combination therapy vs. 66.7 % for calcipotriol alone or 70.6 % for betamethasone alone. These results are congruent
with those reported by other large studies such as by Douglas 2002 [118] (EG
A2), Kaufmann 2002 [121] (EG A2),
Guenther [163] (EG A2), Kragballe
[164] (EG A2), and Papp 2003 [124]
(EG A2) with a sum total of 5,481 patients and an each with an evidence grade
of A2. Yet in a further study, in which
combination therapy was compared with
a class IV steroid monotherapy arm
(Clobetasol spray), 75 % of patients who
used only Clobetasol spray achieved an
Overall Disease Severity Score (ODS,
0 = clear, 4 = severe), while only up to
45 % (p=0.003) of patients who were
given combination therapy achieved the
same score [133] (EG B).
A few larger studies have investigated
two common treatment schemes follo-
wing a 4-week induction phase with a

combination drug, one with an additional eight weeks of 1 2 daily calcipotriol monotherapy and one with 2 weekly use of a combination drug and 5
weekly calcipotriol monotherapy until
week 12. This study found that during
week 12 the patients who continued to
receive the combination drug 2 weekly achieved a reduction in PASI of 58.4
% compared with 44.5 % of those who
were given only vitamin D therapy [172]
(EG A2).
The combination with topical class III
steroids in the first four weeks of therapy
is also useful since this can accelerate the
onset of drug action and also simultaneously suppress any potential skin irritation. After the first four weeks, in addition to daily calcipotriol monotherapy,
2 weekly use of a combination drug
(e.g., on the weekends) also appears to be
superior to calcipotriol monotherapy.
Nevertheless treatment with a combination drug appears to be inferior to class
IV steroids.
Combination therapy: clobetasol and
calcipotriol
Combination therapy with the class IV
corticosteroids clobetasol and calcipotriol also appears to be superior to calcipotriol monotherapy [130] (EG B). This
was confirmed by the Cochrane Review
with a 96 % CI of 0.18 to 1.02 and a
mean of 0.60 (SWMD) [19].
Combination therapy: calcipotriol with
other topical preparations
Calcipotriol may be combined with
other topical therapies. Use with salicylate-based keratolytics or dithranol preparations can diminish the effectiveness
of the drug. Local irritative effects may
be exacerbated if calcipotriol is used together with vitamin A derivatives (tazarotene).
Combination therapy with tacalcitol
Two studies on combination therapy
with tacalcitol ointment have been included in the guidelines. Brazzelli et al.
[174] (EG B) reported a significant
change in trans-epidermal water loss
(TEWL) and on corneometry, but not on
visual scores. In other words, in terms of
visible lesions, an eight-week regimen of
tacalcitol with UV therapy does not appear to be superior to UV monotherapy.
Yet a study on combination therapy with
S27
S28
tacalcitol and cyclosporine reported that

patients who were given daily tacalcitol
had an average reduction in PASI score of
50.9 % after 12 weeks compared with
39.1 % of patients who were given tacalcitol only 3 weekly in addition to cyclosporine [173] (EG B). The difference
was not significant, however.
Clinical studies report side effects in about
25 % of patients. The majority of these effects involve mild discomfort at the application site. For approved use of the drug,
the rate of adverse effects is about one incident per 10,000 uses (0.01 %). Side effects
are more likely to occur with use of
the drug in intertriginous areas and on the
face, although this does not rule out its use
in these areas. Most local side effects are
transitory and are usually manageable by
briefly reducing the drug dose of the drug.
Skin irritation is less common with use of
tacalcitol than with calcipotriol.
If used properly, disorders of calcium
metabolism do not occur. Increased calcium absorption from the intestine, resorption of bone substance, as well as uroliths and kidney failure can occur if the
maximum dosage is exceeded, or with
long-term use of higher drug dosages.
For combination therapy with betamethasone, the potential side effects associated with topical steroids also apply.
Long-term safety
Long-term use of the drug may also lead
to reversible skin irritation. Hypercalcemia is very rare and is associated with
overdose. No significant effects on serum
calcium levels are seen with dosages below the maximum dosage of 100 g calcipotriol per week, even after 52 weeks of
use. There are no longitudinal animal
studies available.
Vitamin D3 derivatives have not been
shown in animal studies to have toxic effects on the embryo or to cause birth defects. Due to lacking experience in human beings, they should not be used
during pregnancy. It is unclear whether
vitamin D3 derivatives are secreted in
breast milk. Their use should therefore
be avoided by nursing women.
The drug should not be applied to
healthy areas of the skin. If irritation oc-

Very common Common
Pruritus, burning, stinging, erythema
Occasionally
Eczema, allergic contact dermatitis
Rarely
Very rarely
Transient photosensitivity, transient loss of pigmentation or

hyperpigmentation, hypersensitivity reactions, hypercalcemia,
hypercalcinuria
curs, treatment should be applied less frequently or even briefly stopped. Topical
steroids may be given for severe irritation.
In the initial phase, e.g., in the first one or
two weeks, concomitant topical steroids
or combination therapy may be given.
Main
contraindications
/ Limitations
Absolute
contraindications
for
use
None
Psoriasis pustulosa and punctata
Diseases involving disorders of
calcium metabolism
Taking medications that promote
hypercalcemia
Serious kidney or liver disease
Use in pregnant or nursing women
should be avoided due to lacking studies
Drug interactions
Concomitant use with salicylic-based
topical therapies blocks the action of
vitamin D3 derivatives. Additional use of
topical therapies with a potential irritative
effect should be avoided. For simultaneous systemic use with calcium or vitamin D3, serum calcium levels should be
regularly checked. The same applies to
drugs that can elevate calcium levels in the
blood such as thiazide diuretics. There are
no known interactions with other drugs.
Notes on use
Pre-treatment measures
None
Do not apply before phototherapy
as each therapy may diminish the effects of the other
None

If skin irritation occurs, the dose
should be reduced or therapy stopped
briefly. The symptoms are generally
mild and can be quickly reversed.
Topical steroid therapy may be used
if necessary. Hypercalcemia is very rare.
If it occurs, therapy must be discontinued and serum calcium levels checked
once weekly until they normalize. Additional internistic management may
be necessary.
Feasibility
Use of vitamin D3 derivatives is largely
unproblematic for the patient. A certain
limitation in feasibility lies in the relatively high rate of local adverse effects that
can also appear some time after treatment has begun. Use of the drug is also
limited by the percentage of the body
surface area (and thus total weekly dose)
requiring therapy. Once daily combination therapy with calcipotriol / betamethasone is feasible.
Costs
The daily drug costs for calcipotriol
(Daivonex and Psorcutan) ointment,
with an average 1.5 applications per day,
are 2.80 [23]. For the cream, the costs
are 4.66 . The monthly costs of therapy
are around 78.40 (ointment) or
130.46 (cream). The daily costs of calcitriol (Silkis) 2 /daily are 8.59
[23] or 240.55 per month. The drug
costs per day for once daily use of tacalcitol (Curatoderm) are 4.92 [23] or
137.66 per month.
Sufficient time must be allowed between
the use of vitamin D3 derivatives and UV
therapy as each therapy diminishes the
effects of the other.
JDDG; 2011 9 (Suppl. 2): S1S95

Vitamin D3 and vitamin D3-analogues/Phototherapy
Summary evaluation
Out of 68 evaluated studies, 27 met the
criteria for inclusion in the guidelines.
The majority of data are on calcipotriol. For treatment of mild to moderate
psoriasis, 30 - 50 % of patients treated
with calcipotriol achieve significant
within a few weeks (EL 1).
The efficacy of calcitriol and calcipotriol appears comparable based on available studies (EL 1).
The efficacy and tolerability of vitamin
D3 derivatives can be further enhanced
by combining them with topical steroids (EL 1).
There are only a few clinical studies
available on the use of tacalcitol (EL 3).
Topical use of vitamin D3 derivatives
(tacalcitol) has been shown to have
synergistic effects with systemic
cyclosporine in the treatment of severe
psoriasis (EL 3).
Local therapy with vitamin D3 derivatives is generally well tolerated by the
patient and feasible for doctors and patients. Use may be limited by potential
transitory skin irritation, especially in
treatment of the face or intertriginous
zones.
Vitamin D3 derivatives are recommended for use in induc-
tion therapy for mild to moderate psoriasis.
Combination therapy with vitamin D3 derivatives and steroids
is recommended in the first four
weeks as induction therapy for
mild to moderate psoriasis.
6 Phototherapy
Martin Schlaeger, Wolf-Henning
Boehncke, Tobias Weberschock
Introduction
Various UVB and UVA wavelengths may
be used for the treatment of psoriasis vulgaris. Photochemotherapy (Table 19)
combines initial topical application or
systemic administration of a photosensitizer followed by phototherapy with the
appropriate wavelength, usually UVA.
Originally, broadband UVB light with
wavelengths of 280 315 nm was used
for treatment of psoriasis. Since the
1980s, however, phototherapy has increasingly focused on using a narrower
spectrum. Hence the term selective UV
therapy (SUP) which has been used to
describe the combined use of various UV
components. In the following, the term
SUP is used according to the guidelines
on phototherapy (www.awmf-online.de)
to denote the use of polychromatic beams with a maximum emission range
between 300 and 320 nm. Narrow-band
UVB therapy became possible with the
development of fluorescent narrowband
UVB tubes with a peak emission of
around 311 nm. In recent years, excimer
lasers have been tested which emit
monochromatic UVB light (308 nm).
Since the 1970s, the administration of
photosensitizing psoralens followed by
whole-body or partial-body UVA phototherapy (315 400 nm), has been supported by scientific findings. Psoralens
may be given systemically, as oral PUVA
therapy, or topically as a bath or cream.
Mechanism of action
Phototherapy triggers various biological
effects which probably contribute to its
anti-psoriatic effects. These include

Phototherapy
Approval in Germany
Clinical experience >50 years depending on

modality
Recommended control
parameters
Regular inspection of the skin (especially for

dermatitis solaris)
Recommended initial
dosage
Individual dosage based on skin type,

alter-natively:
UVB: 70 % of minimal erythema dose (MED)
Oral PUVA: 75 % of minimal phototoxic
dose (MPD)
Bath/cream PUVA: 20 - 30 % minimal
phototoxic dose (MPD)
Increase depending on erythema
dosage
After 1-2 weeks
Response rate
UVB: 50 - 75 % of patients achieve PASI 75

after 4-6 weeks (EL 2)
PUVA: 75 - 100 % of patients achieve PASI 75
after 4-6 weeks (EL 2)
Photodermatoses / photosensitivity, skin cancer,

immunosuppression
Only PUVA: pregnant or nursing women
Important UAEs
Erythema, itching, blistering, malignancy

Only oral PUVA: nausea
Important drug interactions Important note: photosensitizing drug

Misc.
JDDG; 2011 9 (Suppl. 2): S1S95

Combination with topical preparations has

synergistic effects; phototherapy should not be
combined with cyclosporine A
S29
S30
Phototherapy
anti-inflammatory effects, such as

reduced mobility of antigen-presenting
Langerhans cells, inhibition of T lymphocyte activation, and the induction of
programmed cell death (apoptosis) of
activated T lymphocytes. In addition,
epidermal hyperproliferation is inhibited
by interactions with keratinocyte DNA.
PUVA also interferes with DNA synthesis. There are also potentially relevant
anti-angiogenetic effects.
Performing phototherapy requires comprehensive clinical experience on the part
of the physician. Given the number of
variables involved, there is a wide array
of treatment protocols. Tables 20 24
provide several examples of different
modalities:
Efficacy
inclusion in the guidelines. The studies
vary greatly in terms of radiation dose,
number of exposures, and study length,
making it very difficult to evaluate their
Table 20: UVB phototherapy:

examples of initial dosages [180].
Skin
type
UVB
UVB 311
(broad
nm
spectrum)
(mJ/cm2)
2
(mJ/cm )
20
200
II
30
300
III
50
500
IV
60
600
results as a group. In many studies, the

number of sessions until clearance is reported. In order to enable comparison
with the other studies, PASI 75 response
rates or comparable remission data are
discussed.
UV phototherapy (monotherapy)
A total of 35 studies on UV phototherapy as monotherapy fulfill the criteria for inclusion in the guidelines. There
were three grade A2 studies on monotherapy, 26 grade B studies, and six grade
C studies.
UVB (broadband)
Studies on broadband UVB reported the
results of two [181], three [182-186],
five [187, 188], and seven [189] exposures weekly. The proportion of patients
who achieved a 75 % improvement
varied among included studies. The
majority of studies reported a PASI 75
response in 50 75 % of patients. The
amount of time needed to achieve this
level of improvement decreased with
increasing number of exposures (EL 2).
times [147, 184, 195, 196], or four times

weekly [193, 197]. Clearance within
20 weeks was reported in 51 %, 63 %,
and 75 % of patients treated twice weekly. The results on the efficacy for threetimes or four-times weekly therapy are
inconsistent: one publication reported
clearance of lesions in all patients within
seven weeks [197] and hence greater
effectiveness, the second publication reported 60 % clearance and thus relatively
comparable efficacy, although this was
based on only ten weeks of treatment
[193]. For 3 weekly treatment, response
rates vary between 38-100 % (EL 2).
UVA
Only one study examined conventional
UVA phototherapy with wavelengths of
275 380 nm [198]. All 16 patients had
complete clearance within four weeks
(EL 4).
Selective UV therapy (SUP)

Studies on selective UV therapy investigated the effectiveness of three exposures
per week [190] or once daily [189]. A
75 % improvement or better was achieved in 29 % of patients treated three
times weekly and in 86 % who were
treated daily (within four weeks in this
group). The latter study [189] also directly compared SUP with broadband UVB
therapy and found SUP to be more
effective (EL 3).
UVB 308 nm (excimer laser)

Nine studies on laser monotherapy met
the criteria for inclusion in the guidelines. Six of these were grade B studies and
three were grade C studies. Due to technical reasons, excimer laser can only be
used to treat solitary psoriatic plaques,
and thus usually only target lesions are
treated. In several small studies [195,
199-201], and in one larger non-randomized study [202], after several weeks of
therapy there was a good response rate at
treated sites, ranging from partial remission in five out of seven patients [200] to
complete clearance of skin lesions in all
treated patients who completed the
eight-week long study [201] (EL 3).
UVB 311 nm
In the studies included, therapy was
either once [191], twice [192-194], three
Balneo phototherapy
Brockow et al. [182, 183] (EG B) reported an increased PASI 75 response rate to
Table 21: UVB phototherapy: example of a dosage scheme [180].

Schritt 1
Determine MED. Reading after 24 hrs.
Schritt 2
Therapy commences with the initial dosage based on skin type or 70 % of MED
Schritt 3
Therapy 3 - 5x
weekly
No erythema
Increase by around 30 %
Minimal erythema
Increase by around 20 %
Persistent asymp-tomatic erythema No increase

Painful erythema
Schritt 4
Discontinue therapy until symptoms resolve
Atop therapy if painful erythema occurs. Treatment may be re-sumed after symptoms resolve, beginning
with a dosage of about 50 % less than the last dosage and increasing the dose in incre-ments of 10 %.
JDDG; 2011 9 (Suppl. 2): S1S95

Phototherapy
Table 22: PUVA: Commonly-used photosensitizers and dosages [180].

Modality
Photosensitizer
Dosage or concentration
Oral PUVA
8-Methoxypsoralen (8-MOP) 0.6 mg/kg body weight

5-Methoxypsoralen (5-MOP) 1.2 mg/kg body weight
Bath PUVA
8-MOP
0.5 1.0 mg/l

0.0006 0.005 % in Unguentum Cordes with
30 % H2O (German
Pharmacopoeia [DAB] 9)
Cream PUVA 8-MOP
Table 23: PUVA: Examples of initial dosages [180].

Oral PUVA
(8-MOP)
[J/cm2]
Oral PUVA
(5-MOP)
[J/cm2]
Bath PUVA
(1.0 mg/l 8-MOP)
[J/cm2]
0.3
0.4
0.2
II
0.5
1.0
0.3
III
0.8
1.5
0.4
IV
1.0
2.0
0.6
Skin type
UV therapy given 3 times weekly if it

was preceded by a mineral salt water bath
or high-concentration mineral salt water
bath. After six weeks of treatment, UVB
therapy alone led to a PASI 75 response
in 50 % (or 54 %) of patients, and
among those who were given a mineral
salt water bath (or high-concentration
mineral salt water bath) the rates were 73
% (or 83 %). In a study comparing treatment with MOP bath / 311 nm UVB
therapy versus salt water bath/311 nm
UVB therapy, complete clearance was

seen in 38 or 50 % of patients within
eight weeks [203]. Schiener et al. compared the efficacy of bath PUVA combined
with UVB versus a tap water bath followed by UVB therapy or a 25 % mineral
salt water bath followed by UVB phototherapy. Each was performed 4 weekly. Based on PASI 50 score, there was a
much better response for bath PUVA (78
%) and for a mineral salt water bath plus
UVB therapy (75 %) compared with a
plain water bath plus UV (61 %) or UV

therapy alone (43 %) [204]. On the
whole, there is an additive benefit of
combining a mineral salt water bath with
phototherapy (EL 2).
PUVA (monotherapy)
A total of 40 studies on PUVA therapy
met the criteria for inclusion in the guidelines. Four grade A2 studies on monotherapy, 33 grade B studies, and three
grade C studies were evaluated.
There are 20 studies on oral PUVA
therapy. In one, 5-MOP 1.2 mg per kg
of body weight was used as the photosensitizer, and in the others 8-MOP
0.6 mg per kg of body weight was given.
The treatment frequency was two to four
exposures per week. The dosage was increased according to minimum phototoxic dosage or based on skin type. In the
majority of studies, more than 75 100
% of patients achieved a score of 75 %
improvement, even at only two exposures per week [205]. Two studies directly
compared increasing the dosage based on
skin type versus an MPD-based dosage
increase. In one study, the MPD-based
method was slightly superior [206],
while in the other, the skin type-based
method was clearly more effective [205].
In the only comparative study on 5MOP versus 8-MOP, 8-MOP was found
to be the superior photosensitizer [207]
(EL 2).
Five studies examined the efficacy of
bath PUVA, administered in two [208],
three [209], or four [204, 210, 211] sessions per week. Three studies compared
bath PUVA with oral PUVA therapy
Table 24: PUVA: Example of a dosage scheme [180].

Modality
Oral PUVA
Bath PUVA
Read after 72 96 hrs.
Read after 96 120 hrs.
Step 1
Determine minimal phototoxic

dosage (MPD)
Step 2
Therapy begins with initial dos-age Based on skin type or 75 % of MPD Based on skin type or 30 % of MPD
Step 3
Step 4
Therapy
2 - 4 weekly
No erythema, good response
Increase 30 % maximum 2 weekly
Minimal erythema
No increase
Persistent asymptomatic erythema
No increase
Painful erythema
Discontinue therapy until

symptoms resolve
Resume therapy after symptoms resolve
JDDG; 2011 9 (Suppl. 2): S1S95

Reduction of last dosage by around

50 %; increase in in-crements of
around 10 %
S31
S32
Phototherapy
(same number of treatments). There was

concurrence among all studies that oral
therapy was at least as effective as bath
PUVA. The lowest rate, with only 64 %
of patients reporting at least a 75 % improvement in skin lesions, was reported
by the study with three treatment sessions per week [209]. In the other two studies, there was complete clearance in all
patients, which occurred within ten
weeks for twice weekly therapy [208] or
within four weeks for four times weekly
treatment [210].
In regard to cream PUVA, one included
study compared it with oral PUVA [212]
and three studies compared it with UVB
311 nm [191, 197, 213]. In the first
study, three times weekly use of cream
PUVA therapy led to complete clearance
in 88 % of treated patients. This level of
efficacy is lower than in the comparison
group which was given oral PUVA, although in the latter study patients were
treated four times weekly. In one study
comparing cream PUVA versus UVB
phototherapy (four times weekly treatment), all patients had complete clearance within five to seven weeks and thus
the effectiveness was the same as with
311 nm therapy (EL 2).
Other modalities
Data on the efficacy of psoralen and
UVB are available from two studies, each
comparing this method with classic oral
PUVA therapy. Both studies report oral
PUVA to be superior to PUVB, which
led to complete clearance in 86 % or
84 % of patients compared with PUVB
which achieved the same result in 77 %
or 63 % depending on the study [192,
214]. The length of time to treatment
success was six to twelve weeks.
In one study, the combination of oral
PUVA and UVB phototherapy led to
complete clearance in all patients within
15 18 sessions and hence this method
was superior to oral PUVA monotherapy
in the comparison group (clearance in
73 % of patients within 20 treatments)
[153]. A similar study reported that
these modalities were equally effective.
In both cases, all patients had complete
clearance within nine treatment sessions
[215].
A limited number of publications, the
majority of which do not meet the basic
criteria of EBM, discuss additional variables including various accompanying
treatments such as balneo therapy, bath
therapy, or climatotherapy. Studies

included in the guidelines reported an
increase in the efficacy of UVB or PUVA
therapy as a result of accompanying meditation-based stress-reduction interventions during treatment [216], 8-MOP
therapy with sunlight [217], and solarium use [218] (EL 4).
Phototherapy plus topical retinoids

UVB phototherapy may also be combined with tazarotene. In one study, this
method achieved at least 75 % improvement in 82 % of treated patients after 81
days, while only 68 % of those in the
UVB group achieved the same level of
improvement [222] (EG B).
Combination therapy
Phototherapy plus systemic therapy
See under the relevant systemic therapy
Phototherapy plus dithranol

One study on the combination of three
or five doses of dithranol and broadband
UVB phototherapy showed comparable
response rates of 40 % and 44 % (minimum 75 % improvement of skin lesion
after eight weeks) for five time weekly
therapy [223] (EG B).
The Ingram scheme combines a tar bath,
UVB phototherapy, and dithranol. The
only study that was included in the guidelines on this treatment method reported complete clearance of skin lesions in
82 % of patient within 20 days; in the
comparison group, which was given oral
PUVA, this same was true for 91 % within 34 days [224] (EG B).
Phototherapy plus topical therapy

Several of the vast number of possible
combinations of phototherapy and
topical therapies have been evaluated in
controlled clinical trials.
Phototherapy plus vitamin D3 derivatives
Two studies compared the efficacy of
UVB phototherapy with vitamin D3
derivatives. One study reported on the
combination of calcitriol and three times
weekly UVB treatments. According to
the results, 45 % of treated patients had
at least a 75 % improvement within
eight weeks, and thus combination
therapy was twice as effective as UVB
alone [185] (EG A2). In the second
study, the combination of calcipotriol
and UVB phototherapy 2 weekly yielded a response rate of 72.5 % within 12
weeks and hence was not superior to
phototherapy alone [181] (EG B).
The combination of calcipotriol with
oral PUVA therapy increases its effectiveness, unlike the combination with
UVB phototherapy. In one study 87 %
of treated patients achieved at least a
75 % improvement in skin lesions within
22 days compared with 63 % after 34
days in the PUVA group [219] (EG A2).
Phototherapy plus topical steroids
Another option is combination therapy
with steroids. In two studies on the combination of fluocinolone with UVB phototherapy, complete clearance of skin lesions occurred in 54 % [220] (EG A2)
and 42 % [187] (EG B) of patients.
These were both comparable to the
response rates for UVB monotherapy.
Yet, another study on the combination of
betamethasone with oral PUVA showed
a synergistic effect. In all treated patients,
skin lesions healed after an average of
13.6 days compared with an average of
20.25 days in the oral PUVA group
[221] (EG B).
Phototherapy plus coal tar

Six studies looked at the combination of
phototherapy and coal tar [145-150].
There were significant methodological
flaws, and none of the studies could convincingly show an additional usefulness
of coal tar.
UVB (broad spectrum, SUP, 311 nm,
308 nm)
Publications on UVB phototherapy contain only limited data on undesirable adverse effects. Erythema is the most commonly reported undesirable side effect of
all UVB modalities, except for excimer
laser (308 nm). The rate of its occurrence
is only sometimes mentioned and varies
between 33 % for broad spectrum UVB
2 weekly [181], 65 % for SUP [190],
and 73 % for 311 nm phototherapy
[192].
Symptoms related to severe dermatitis
solaris are more common with excimer
laser therapy. Typical undesirable effects
are blistering, a burning sensation during
therapy, as well as areas of brown discoloration and hyperpigmentation [199201].
PUVA
The most common side effects of oral
PUVA are erythema, pruritus, and nausea.
JDDG; 2011 9 (Suppl. 2): S1S95

Phototherapy
They are not reported in all studies, however, and when they are included the
information is often incomplete. Two
studies reported erythema in 9 % [219]
and 80 % [225] of patients. Both of
these used similar therapy schemes with
three times weekly treatment. Most studies report erythema in about 50 % of
patients. Only one publication [224]
reported that pruritus was the most
common side effect, occurring in 83 %,
while most other studies reported pruritus in 25 % [225] to 46 % [226]. Nausea
is the third most commonly reported
side effect, affecting around 35 % of
patients [224, 225]. Dizziness is often
reported as a relevant adverse effect, but
only one study gave an exact figure
(60 %) [207]. A correlation between the
frequency of undesirable adverse effects
and treatment frequency is not evident
based on the studies mentioned here.
Studies on bath PUVA all report that
erythema and pruritus are the most common side effects of therapy [208-210].
Compared with oral PUVA given at the
same frequency, the results for these two
side effects favor bath PUVA. Erythema
and pruritus were much less common
with bath PUVA, and nausea did not occur at all.
Erythema is also the most common side
effect of cream PUVA [197, 212], but it
only occurs in about 5 % and hence is
rather seldom [197]. Blistering is also reported [197, 212].
Other modalities
In two studies comparing oral PUVA
with PUVB, the former involved fewer
side effects, seen in the lower rates of
dizziness and nausea [214] as well as
erythema [192].
The combination of MOP bath and
311 nm phototherapy as well as mineral
salt bath plus 311 nm phototherapy led
to erythema with blistering in 10 % of
patients each [203].
Long-term safety (cf. Hlzle E et al. [180])
None of the chosen studies which met
the inclusion criteria contained data on
the long-term safety of various phototherapies. The current discussion is summarized as follows, taking into account the
Dutch guidelines on psoriasis therapy:
Long-term use of UVB phototherapy results in sun damage and premature aging
of the skin. Controversy exist about the
potential carcinogenic effects of UVB
JDDG; 2011 9 (Suppl. 2): S1S95


Erythema, pruritus, hyperpigmentation
Very common Only oral PUVA: nausea
Only excimer laser: blistering
Common
Occasionally
Blistering
Rarely
Oral PUVA: squamous cell carcinoma, basal cell carcinoma
Very rarely
phototherapy. Animal experiments have

demonstrated the carcinogenic effects of
UVB phototherapy. These appear to be
less pronounced, however, in narrow
spectrum therapy than in broad spectrum UVB. There are still only insufficient data available on the use of UVB
therapy in humans.
The carcinogenic effects of oral PUVA,
on the other hand, are undisputed. There
is associated with an increased risk of
developing spinocellular and basal cell
cancer, which increases depending on
cumulative UVA dose. Although there
are reports on an increased risk of melanoma following long-term therapy, the
actual risk is still unclear. Oral PUVA
therapy can also lead to disorders of
pigmentation, brown spots (PUVA lentigines), and cataracts.
Undesirable adverse effects / safety of
combination therapy
In general the combination of topical
therapies with phototherapy does not
increase the rate of adverse effects. For
combination use of vitamin D derivatives with UVB or PUVA, up to onefourth of patients experience adverse
effects, usually erythema [181, 185,
219]; similar rates are reported for the
combination of fluocinolone and UVB
phototherapy [187]. For therapy according to the Ingram scheme, pruritus was
the most common side effect, occurring
in 83 % of patients [224].
Clinically relevant adverse effects are almost always due to an overdose and consist of varying degrees of dermatitis solaris. There are isolated reports of fatalities
related to the use of oral PUVA. Careful
clinical monitoring of the patient during
phototherapy must be ensured. Special
attention should be paid to the therapeu-
tically desirable level of erythema. If

clinical signs of dermatitis solaris appear,
treatment must be stopped.
Given the kinetics of delayed erythema
as a result of PUVA therapy, the reaction
cannot be influenced by symptomatic
therapies such as steroids. Caution must
be exercised during PUVA therapy.
Many therapists give PUVA therapy 4
a week on Monday, Tuesday, Thursday
and Friday (PUVA days). Thus there are
breaks in therapy that allow for the detection of initial erythema, even with a
delay, and to wait before continuing
further therapy if necessary.
Additional side effects of oral PUVA
therapy can be limited (carcinoma) or
even avoided (nausea) with application
of a topical photosensitizer (bath or
cream PUVA).
Given that the risk of development of
skin cancer is correlated with the cumulative UVA dose, the cumulative dose
should be documented. A record should
be made of all treatment sessions with
ultraviolet light exposure.
for use
Gene defects with increased sensitivity to light or an increased risk of
skin cancer
For PUVA:
Use of cyclosporine*
Pregnant or nursing women
*[180]
Epilepsy
Necessary use of photosensitizing
agents
Skin type I
Dysplastic nevus cell nevi
S33
S34
Phototherapy
History of skin cancer

Lacking compliance / adherence
Physical or psychological inability to
participate in therapy such as cardiac
insufficiency (New York Heart Association [NYHA III IV], claustrophobia)
Photodermatosis, photosensitive diseases
Along with these, the following relative
contraindications should be taken into
account for oral PUVA therapy:
High cumulative UVA dose (more
than 150 200 individual sessions)
Prior therapy with arsenic or ionizing
radiation
Severe liver damage [180]
Drug interactions
The use of drugs that can cause phototoxic or photoallergic reactions (Table 26)
during phototherapy can lead to adverse
effects. Before beginning treatment,
information should be elicited from
the patient on the use of such medications and whether discontinuing them is
possible.
Notes on use
Performing phototherapy is generally
not a problem for dermatologists given
that it is part of specialist training, unlike
for doctors in other specialties.
For cream or bath PUVA, adequate
topical application of the photosensitizer should be ensured. For optimal
efficacy, one should adhere to the exact
amount of time required between
application of the sensitizer and
subsequent phototherapy (see also
Feasibility).
The treating physician should conduct a thorough inspection of the entire body surface, especially for signs of
cancerous lesions, precancerous lesions, and dysplastic nevus cell nevi.
The patient should be informed about
the course of therapy, possible side effects, and potential long-term risks in
particular the increased risk of cancer
as a result of therapy. He or she should
be made aware of synergistic effects resulting from additional UV exposure
during leisure time or self-treatment.
Before beginning oral PUVA therapy,
the patient should be examined by an
ophthalmologist. Protective goggles
should also be obtained.
The UV dose must be precisely
recorded (J/cm2 or mJ/cm2).
Erythema development must be
controlled regularly before increasing the dosage.
Regular monitoring of therapy also
includes documentation of the success of therapy, side effects, and any
concomitant therapy use.
Protective goggles should be worn
during UV light therapy.
Unless they are the focus of therapy,
chronic sun exposed areas (face,
neck, backs of the hands) and genital
regions should be protected from
exposure to UV light.
Adequate protective measures against
exposure to sunlight are necessary
during therapy.
Table 26: Selected medications that can cause phototoxic or photoallergic reactions.
Drugs causing phototoxic
reactions
Drugs causing photoallergic

reactions
Tetracycline
Phenothiazine
Griseofulvin
Nalidixic acid
Furosemide
Amiodarone
Piroxicam
Tiaprofenic acid
Dimethyl triazeno imidazole
carboxamide
St. Johns wort
Tiaprofenic acid
Promethazine
Chlorpromazine
Hydrochlorothiazide
Clinidine
Sunscreen (para aminobenzoic acid,
etc.)
Disinfectants (e.g., hexachlorophene)
After completing a treatment series,
the cumulative UV dosage and the
number of treatment sessions must
be recorded and given to the patient.
Patients with a high cumulative UV
dose should undergo lifelong regular
skin cancer screening.
The symptoms of an overdose of phototherapy correspond largely to the adverse
effects related to therapy, involving either
acute symptoms of dermatitis solaris or,
with a chronic overdose, an increased
risk of cancer or symptoms of (premature) aging of the skin.
If there are signs of dermatitis solaris,
therapy must be discontinued (see
dose and dosage scheme). Symptomatic
therapy consists of cooling, bland topical
agents, and antihistamines or steroids.
PUVA-induced erythema does not respond to steroids. Special care must be taken during therapy. Due to the reaction
kinetics, suitable treatment-free intervals
should be included in therapy planning
(e.g., therapy on Monday, Tuesday,
Thursday, Friday).
There have been isolated reports of deaths due to an overdose of oral PUVA
therapy.
Phototherapy involves long-term allocation of resources for any institution.
First, a suitable room must be available.
In addition to the necessary space for
phototherapy equipment, one must take
into consideration the heat generated by
it. There must also be adequate space for
the patient to change and for performing
a physical examination. Funds must also
be available for investing in equipment
and for further technical developments.
Phototherapy also requires physician and
non-physician personnel.
Although the therapy itself is often perceived as rather pleasant, it is time-consuming for the patient and frequent sessions
are difficult for employed persons. For fragile or disabled patients, phototherapy
while standing is not feasible. For oral
PUVA therapy, patients must undergo an
additional ophthalmological examination
before initiating treatment, and protective
goggles should be worn (and must first be
obtained). Sun exposure must be avoided
during leisure time.
JDDG; 2011 9 (Suppl. 2): S1S95

Phototherapy/Adalimumab
Especially for cream and bath PUVA, the

strict requirements for the treatment
procedures may require that patient to
check into a day clinic or clinic.
Costs
The direct costs of UV therapy are 300
500 per treatment cycle (treatment cycle = therapy until clearance of skin lesions). Indirect costs are not included, but
can be considerable due to frequent visits
to the doctor (including transportation
costs). For outpatient balneo phototherapy, on 01.10.2010 a supplemental
fee rate of 1125 points was established in
Germany. At 3.5 cents per points, this is
about 39.38 per session or 1,378.13
for a cycle consisting of 35 sessions (max.
number in six months).
There is currently no approved commercially-available preparation for cream
PUVA therapy. Close cooperation with a
pharmacist is needed to ensure that consistent quality of the formulation.
Summary evaluation
For monotherapy, 35 studies on UV
phototherapy, 40 on PUVA therapy,
and nine studies on laser therapy met
the inclusion criteria of the guidelines.
50 - 75 % of patients treated with
UVB phototherapy achieved at least a
75 % improvement in PASI score after
four to six weeks and often there was
complete clearance of lesions (EL 2).
Some 75 - 100 % of all patients treated
with PUVA therapy achieve at least a
75 % improvement in PASI score after
four to six weeks, and complete clearance of lesions is common (EL 2).
Dermatitis solaris, as a result of overdose, is by far the most commonly reported adverse effect, and is also frequently reported. For repeated or
long-term therapy, the consequences
of high cumulative UV dosages, such
as premature aging of the skin, must be
taken into account. There is also a risk
of developing cancer which has been
shown for oral PUVA and is considered likely for local PUVA and UVB.
The feasibility of therapy for the doctor is considerably limited by the need
for space, financial considerations, and
personnel/time. For the patient, feasibility it is significantly limited by the
amount of time involved.
JDDG; 2011 9 (Suppl. 2): S1S95

The cost-to-benefit ratio for phototherapy is good from the perspective of

health insurers. Yet the cost and time
involved for the patient are potentially
considerable.
UVB and PUVA are recommended for induction therapy for
moderate to severe psoriasis vul-
garis, especially if there is involvement of a large body surface
area.
Despite the superior efficacy of
PUVA compared with UVB
therapy alone, narrow band
UVB therapy may be conside-
red as the first choice for phototherapy. Feasibility is better and
there is a lower risk of malignancy,
The use of excimer laser may be
recommended for targeted
therapy of individual psoriatic
plaques.
The combination with topical
vitamin D3 derivatives may be
recommended for improving
the response rate.
The customary combination
with dithranol and steroids may
be recommended based on
clinical experience, but not on
the basis of the available data.
Given low feasibility and an

association with long-term
adverse effects due to the cumulative UV dose, long-term phototherapy is not advisable.
7 Systemic Therapy
7.1 Adalimumab
Ulrich Mrowietz, Thomas Rosenbach
Introduction
Adalimumab (Humira) is a fully human therapeutic monoclonal antibody
(Table 27). It corresponds to the human
immunoglobulin IgG1 and has heavy
and light chain variable regions with specificity for human TNF-.
Adalimumab is approved for use in
adults with moderate to severe plaque
psoriasis who did not tolerate or failed to
respond to systemic therapies including
MTX, cyclosporine, and PUVA therapy,
or who have contraindications to these
treatments. There are as yet no controlled studies available on the use of adalimumab in children with psoriasis.
Mechanism of action
Adalimumab binds with high affinity
and specificity to soluble and membrane-bound TNF-. This prevents binding to the TNF- receptor (p55 and
p75) and blocks the biological effect of
TNF-.
Adalimumab is administered by subcutaneous injection. According to the dosing
scheme a one-time dose of 80 mg (loading dose) is given at the beginning of
treatment, 40 mg one week later, and
then 40 mg every other week. The dosage is not adjusted for obese patients
(>100 kg).
Efficacy
Monotherapy
A total of seven studies on adalimumab
fulfilled the criteria for inclusion in the
guidelines. Three of these are grade A2
studies [227-230] and four are grade C
studies [231-234]. The resulting level of
evidence is 1.
Two of the studies included compare the
efficacy of adalimumab with methotrexate. A comparison study by Lingen
et al. with eight patients showed that after 12 weeks adalimumab was superior
with an average reduction in PASI score
of 84.5 % compared with 48.4 % in the
MTX group [233] (EG C, lower rating
due to small sample size: n = 8). A study
by Saurat et al. [229, 230] (A2; n = 271)
reported that after administering 80 mg/
week initially and then 40 mg every
S35
S36
Adalimumab

Adalimumab
Approval in Germany
2005 (psoriatic arthritis)

2007 (plaque psoriasis)
Exclude tuberculosis before treatment

initiation; during therapy: blood count,
liver values, clinical signs of infection
80 mg subcutaneously
Recommended maintenance dosage 40 mg subcutaneously every 2 weeks

Four to eight weeks; maximum efficacy

at 16 weeks
Response rate
PASI 75 achieved in 71 - 80 %
of patients with moderate to severe
psoriasis (EL 1)
Chronic infections, tuberculosis, cardiac

insufficiency (NYHA class III/IV)
Important UAEs
Reactions at the injection site, serious

infections, hair loss, autoimmune
phenomena
Anakinra, abatacept
Misc.
other week, a reduction in PASI score of

around 75 % was achieved after
16 weeks in 79.6 % of patients and a
reduction in PASI score of around 90 %
in 51.9 % of patients. In the comparison
group, which was treated with a
gradually increasing dosage of MTX
7.5 25 mg / weekly, 35.5 % of patients
achieved PASI 75 and 13.6 % of patients PASI 90 after 16 weeks. Although
the effectiveness of adalimumab was
similarly impressive after 12 and 16
weeks, patients treated with MTX had
an increase in efficacy between weeks
12 and 16.
Similar results on the efficacy of adalimumab were reported in the studies by
Menter et al. [228] (A2, n = 1212) and
Gordon et al. [227] (A2, n = 147). Menter et al. showed that with an initial dose
of 80 mg and then 40 mg every two
weeks, 71 % of patients achieved a reduction in PASI score of at least 75 %
while 20 % of patients achieved PASI 90
after 16 weeks. Gordon et al. reported
PASI 75 after 12 weeks in 80 % of patients given the same dosage.
Combination therapy
There are no controlled studies on combination therapy.
Undesirable adverse effects/safety

In placebo-controlled studies, reactions
at the injection site were the most commonly reported adverse effect (adalimumab: 20 % of patients; placebo: 14 %
of patients). Adalimumab therapy is
associated with an increased rate of infections. These include infections of the
upper respiratory passages, bronchitis,
and infections of the urinary passages.
Severe infections can also occur, such as
pneumonia, septic arthritis, post-operative infections, erysipelas, phlegmonous
infections, diverticulitis, and pyelonephritis. Rarely reported hematological
effects include thrombocytopenia and
leukopenia. Rare severe allergic reactions
include exanthem, urticaria, pruritus,
respiratory distress, tightness in the
chest, as well as swelling of the mouth,
face, lips, or tongue.
Adalimumab therapy can induce
auto-antibodies (ANA, anti-dsDNA
antibodies) and in rare cases lupuslike-syndrome.
Very rare side effects include malignancy,
especially lymphoma.
Adverse effects are more common in
older patients after use of adalimumab.
Infections, in particular, are often more
serious.
Adalimumab is contraindicated in pregnant women given lacking information

on its effects. After stopping treatment,
women should continue to use contraception for up to five months. If pregnancy occurs during therapy, treatment
must be stopped. There are no toxic effects on the embryo or fetus, and thus
normal development of the fetus may be
expected (FDA classification: B). Adalimumab can enter breast milk and should
not be used by breastfeeding women.
Women should avoid breastfeeding for at
least five months after discontinuing
adalimumab therapy.
Prevention/management of UAEs
In the event of a serious reaction to the
drug or infection, the use of adalimumab
should be discontinued and symptoms
treated.
Main contraindications/Limitations
for use
Cardiac insufficiency (NYHA grade
III IV)
History of tuberculosis or other
serious infection
Pregnancy or nursing
Severe liver disease
Demyelinating diseases
Malignancy (with the exception of
basal cell carcinoma) and lymphoproliferative diseases or history of such
disease
Vaccine with live vaccine
Drug interactions
Studies on combination therapy with
etanercept and anakinra (IL1-R antagonist) have reported the occurrence of
serious infections, without any added
clinical benefit. Thus the combination
use of adalimumab and anakinra or
abatacept is not recommended (increased risk of infection).
Notes on use
Rule out acute infection
Definitive exclusion of tuberculosis
as per current recommendations of
the Paul Ehrlich Institute [235], see
Appendix 2
JDDG; 2011 9 (Suppl. 2): S1S95

Adalimumab/Cyclosporine
costs are 22,907.83 . The drug costs

for 12-week long induction therapy are
5,172.94 .
If warranted by patient history or

clinical or laboratory chemical tests,
HIV and viral hepatitis should be
excluded.
Contraception must be ensured and
pregnancy ruled out in women of
childbearing age
Patients should be informed that
serious infections have occurred
with use of the drug and that
prompt medical attention is required if infection is suspected.
Up to 9 % of patients develop antibodies
to adalimumab during therapy. Antibodies to the drug may weaken its effects.
Summary evaluation
Seven of the nine evaluated met the
criteria for inclusion in the guidelines.
This includes two studies from the
research conducted for the European
S3 psoriasis guideline. Some 71 - 80 %
of patients with moderate to severe
psoriasis who are treated with adalimumab (initial dose of 80 mg given
subcutaneously, followed by 40 mg
every other week) achieve at least PASI
75 after 12-16 weeks (EL 1).
During the induction phase, adalimumab is one of the most highly effective
medications for the treatment of psoriasis vulgaris. Adalimumab is suitable
for long-term therapy.
In patients with concomitant psoriatic
arthritis, administration of TNF- antagonists is especially useful. Various
safety aspects related to the use of
should be recalled. Foremost among
these is the risk of serious infection.
This requires careful assessment of the
indications for therapy, as well as education and monitoring of the patient.

Surveillance for infection; if there
is suspected infection, therapy
should be discontinued, at least
temporarily.
None
Adalimumab therapy is straightforward
and rather simple for the patient to use.
Either the patient or a family member
may perform the necessary injections.
The drug must be stored in a cool place
(2 8C). This may limit feasibility in
terms of travel.
Costs
The daily drug costs for a treatment
regime consisting of 40 mg every two
weeks are 62.76 and the annual
Table 28: Monitoring.

Months
Diagnosis
Before
Every 2 3 months
Blood differential
ASAT, ALAT, GT
Pregnancy test (urine)
For suspected infection, see pre-treatment procedures
Given the vast numbers of patients

who have been treated with adalimumab (including for diseases other than
psoriasis), the risk of adverse effects is
readily evaluated.
Therapy is feasible for the doctor and
patient. Combination therapy with
MTX and adalimumab could also
counteract the formation of antibodies
to the drug, as has been seen with the
use of MTX and infliximab.
Adalimumab is recommended
for induction therapy in patients with moderate to severe
plaque psoriasis, especially if
other forms of therapy have failed, are not tolerated, or are contraindicated.
7.2 Cyclosporine
(based on Kristian Reich, Thomas
Rosenbach, Johannes Mohr)
Introduction
Cyclosporine (Table 30), originally
known as cyclosporine A, is a neutral,
strongly hydrophobic, cyclical peptide
composed of 11 amino acids (hence cyclo-), which was first discovered in the
early 1970s in the spores (thus the ending -sporin) of the fungus Tolypocladium inflatum (discovered by Gams).
The 1975 description of the chemical
and crystal complex was followed by
numerous studies on its selective immunosuppressive effects. The first cyclosporine, Sandimmun, manufactured by
Novartis, was initially used successfully
in transplantation patients. Based on experience from transplantation medicine,
the effects of cyclosporine in other immunological disorders were then studied
[236]. Since the early 1990s, the use of
cyclosporine in the treatment of plaque

Very common Reactions at the injection site, infections (upper airways)
Common
Occasionally
Infections (pneumonia, bronchitis); viral infections (herpes, zoster); lymphopenia, anemia; headache;
exanthem, psoriasis, hair loss; ar-thritis; increased liver values
Serious infections including sepsis, cutaneous and soft-tissue infections; depression, fatigue, neuralgia;
ocular inflammation; dizziness; tachycardia; dyspnea; gastrointestinal complaints
JDDG; 2011 9 (Suppl. 2): S1S95

S37
S38
Cyclosporine

Cyclosporine
Approval in Germany
1983 (transplantation medicine)

See below
2.5 3 (max. 5) mg/kg body weight
Interval therapy (8 - 16 weeks) with a dosage reduction at the end of induction

therapy (e.g., 0.5 mg/kg body weight every 14 days) or
Continuous long-term therapy with dosage reduction, e.g., 50 mg every four
weeks after week 12 and increasing the dosage by 50 mg if relapse occurs
Maximum two years treatment duration
After about four weeks
Response rate
Dose-dependent, after eight to 16 weeks at 3 mg/kg body weight, PASI 75 in

50 - 70 % (EL 1)
Absolute contraindications:
Relevant kidney dysfunction
Uncontrolled arterial hypertension
Uncontrolled infection
Relevant malignancy (current or past, especially hematological diseases
and cutaneous malignancies with the exception of basal cell carcinoma)
Relative contraindications:
Relevant liver dysfunction
Pregnancy and lactation
Concomitant use of substances that interact with cyclosporine
Simultaneous light therapy or PUVA pre-therapy with a cumulative
dose >1000 J/cm
Concomitant use of other immunosuppressants, retinoids, or long-term
pre-therapy with MTX
Important UAEs
Renal dysfunction, Increased blood pressure, Liver dysfunction, Nausea,

Loss of appetite, Vomiting, Diarrhea, Hypertrichosis, Gingival hyperplasia,
Tremors, Fatigue, Paresthesia
The possibility of multiple interactions should be taken into account (see text)
Misc.
In transplant patients, increased risk of lymphoproliferative diseases

In psoriasis patients excessive light therapy can lead to increased risk
of squamous cell cancer
Only moderately effective against psoriatic arthritis and not approved
Also been used successfully in children with chronic inflammatory diseases
psoriasis has become an established

method. It was approved for use in psoriasis vulgaris in 1993.
In the original preparation, Sandimmun, drug absorption was gradual, incomplete, unpredictable, and strongly
dependent on enteral concentrations of
bile acid. Today, cyclosporine is usually
given as a microemulsion (Sandimmun
Optoral or Neoral). Absorption of the
drug is more consistent and less

dependent on bile acid production and
thus there is also improved drug exposure [237].
The use of Sandimmun solution may
be advisable in certain patients. Sandimmun Optoral has been commercially
available in Germany since 1 January
2004 as Immunosporin. The package
insert has been updated and is now
focused on dermatological indications

for its use. In Germany cyclosporine
capsules are available in strengths
of 25, 50, and 100 mg. There is also
cyclosporine drink (100 mg/ml). Other
preparations available in Germany,
which are comparable to the original
Sandimmun, include Cicloral Hexal,
and cyclosporine from 1A-Pharma and
TEVA Generics.
JDDG; 2011 9 (Suppl. 2): S1S95

Cyclosporine
The specific wording of the current

approval of cyclosporine in Germany indicates that cyclosporine may be used in
patients with extreme, therapy-resistant
forms of psoriasis, especially plaque
psoriasis, which cannot be adequately
managed with conventional systemic
therapies. This formulation suggests
rather limited use of the drug in a subgroup of patients in whom other, older
therapy forms have not been adequately
successful. Yet it seems that in the age of
biological therapies, cyclosporine should
really be included among the conventional substances. This is indeed suggested
by the approval text for Enbrel. It is
neither medically nor ethically wise to
follow a treatment procedure in which
patients are first given phototherapy and
the oldest preparations such as retinoids
and MTX, then fumaric acid esters and
cyclosporine, and finally biologicals. In
actual practice, the most suitable therapy
should be chosen on an individual basis,
taking into account various factors such
as age, sex, disease course and activity,
prior therapies, accompanying disease
and treatments, the burden of disease,
and the presence of psoriatic arthritis
[238].
The results of the clinical studies presented in the following show that cyclosporine is among the most highly effective
therapies for such patients. Cyclosporine
is usually given as continuous long-term
therapy for up to two years, and is less often given as short-term therapy, for a few
months, with the option of repeating
therapy in intervals.
In addition to psoriasis vulgaris, cyclosporine is also approved in Germany for
use in adults with severe atopic dermatitis. It has also been successfully used in
other chronic inflammatory diseases
such as pyoderma gangraenosum, Behet
disease, and autoimmune bullous skin
diseases [239].
Mechanism of action
Basic principles of pharmacology
Cyclosporine has a molecular weight of
about 1.2 kDa. Topically applied cyclosporine can barely penetrate intact skin,
while intralesional administration has a
favorable effect on psoriasis lesions [240,
241]. After oral administration of the
microemulsion, the highest exposure occurs during the absorption phase after
about two hours. There is relatively wide
variation from one person to the next,
JDDG; 2011 9 (Suppl. 2): S1S95

although it is less variable than it was in

earlier preparations. The availability of
cyclosporine (peak concentration, clearance of oral cyclosporine) depends primarily on the activity of the intestinal
transporter protein P-glycoprotein (PGp) and hepatic activity of the 3A family
of the cytochrome P450 system (CYP3A
family). The expression of P-Gp can vary
due to genetic factors. CYP3A4 activity
also exhibits up to a 50-fold variability in
the general population. In addition, the
CYP3A family is responsible for phase I
biotransformation of the largest group of
medications. Many drugs are substrates
or modulators of CYP3A or P-Gp, and
thus potentially influence the breakdown
of cyclosporine. Especially given the fact
that cyclosporine has a narrow therapeutic spectrum, knowledge of possible interactions is paramount for all doctors
who treat patients with cyclosporine or
who plan to use it.
Generic forms of cyclosporine have on
average 20 % lower bioavailability. This
may occasionally result in an unsatisfactory level of effectiveness.
Basic principles of pharmacodynamics
An important mechanism in the activation of T cells is nuclear translocation of
factors that cause increased expression of
pro-inflammatory cytokines. Such transcription factors include nuclear factors
of activated T cells (NFATs). Following
stimulation by the T-cell receptor, the
enzyme phospholipase C releases inositol-triphosphate (IP3) from membranebound phospholipids which leads to an
increase in intracellular calcium concentrations. After binding to calmodulin,
calcium activates a calcineurin phosphatase which catalyzes dephosphorylation
of NFAT. NFAT then migrates into the
cell nucleus where, together with other
transcription factors, it binds to the regulatory segments of various target genes
and induces their transcription. The factors induced by NFAT include various
pro-inflammatory cytokines such as IL1, IL-2, IL-4, IL-8, TNF-, and IFN-.
Increased production of these cytokines,
especially IL-8, TNF-, and IFN-, is
detectable in psoriatic skin lesions and
joint involvement and is believed to be
responsible for various inflammatory
processes observed in psoriasis. These include increased activation and migration
of T cells and neutrophilic granulocytes
as well as the induction of epidermal
changes. After binding to cyclophilin, a

cytoplasmic immunophilin, the cyclosporine-immunophilin complex inhibits
phosphatase activity of the calciumcalmodulin-calcineurin complex and
thus the translocation of NFAT and subsequent NFAT-dependent cytokine production. Due to its inhibiting effect on
the production of important communication molecules of the immune system,
especially in T cells, cyclosporine is considered a selective immunosuppressant.
Its effect is reversible and it has no related
myelotoxic or mutagenic properties
[242].
A standard dosage for treatment initiation is 2.5 3 mg/kg of body weight.
A study on dosages based on weight
(1.25 5 mg/kg of body weight per day)
compared with dosages that were
independent of body weight (100
300 mg/daily) reported that a strict
weight-adjusted dosing was superior
[243]. The daily dose is generally divided
in half and taken mornings and
evenings. The microemulsion should be
taken before meals [244]. If there is an
inadequate response to the initial dosage
of 2.5 3 mg/kg of body weight after
four to six weeks, the dose may be increased to a maximum of 5 mg/kg of
body weight. If after another four to six
weeks, healing is still insufficient, cyclosporine should be discontinued. Especially for patients with severe disease in
whom a more rapid effect is desired, treatment may begin with an initial dosage
of 5 mg/kg of body weight. One study
compared the use of a 12-week-long
step-up protocol was compared with a
step-down protocol of the same length
[245]. In the step-up protocol, patients
started therapy with 2.5 mg/kg of body
weight and if there was an inadequate response to therapy after two to three
weeks were given 4 mg/kg of body
weight. If the response after another two
to three weeks was still inadequate, the
dosage was further increased to 5 mg/kg
of body weight. Patients in the stepdown group were given 5 mg/kg of body
weight at the beginning of therapy,
which was reduced if after two to three
weeks they responded well to therapy.
The dosage was reduced to 4 mg/kg of
body weight and if after another two to
three weeks the response was still
good, the dosage was further decreased
S39
S40
Cyclosporine
to 2.5 mg/kg of body weight. Despite

the higher cumulative dosage in the
step-down group, tolerability for the two
protocols was comparable. In addition,
patients treated with the step-down method also achieved more rapid healing
and had a better treatment response than
patients who started with a lower dosage.
Maximum treatment success is achieved
after about eight to 16 weeks. After signs
of improvement are seen, an attempt
may be made at slowly tapering cyclosporine, possibly also with the use of
topical therapy.
Short-term therapy
In short-term (induction) therapy, the
patient is treated until an adequate level
of success is reached, usually 10-16
weeks. After this time, cyclosporine is
stopped. A few studies have indicated
that abruptly stopping therapy leads to a
higher relapse rate (defined as loss of
50 % of improvement initially achieved
by therapy) and more rapid relapse compared with a gradual reduction of the
drug [246, 247]. Tapering chemes include reducing the dosage by 1 mg/kg of
body weight each week for four weeks or
a reducing the drug by 0.5 1 mg/kg of
body weight every two weeks. A study on
the first gradual reduction scheme reported that in 30 patients, after an initial
treatment duration of 12 weeks, the median time to relapse was 119.5 days
[246]. After treatment lasting several
months, in 30 40 % of patients the
condition worsens again about four
weeks after ending therapy (see also under Efficacy).
Long-term therapy
Long-term cyclosporine use for the treatment of psoriasis should only be considered in exceptional circumstances and
only after considering other options due
to the potential side effects of the drug,
including an increased risk of cutaneous
malignancy (especially in patients with
high cumulative dosages of past PUVA
therapies (>1.000 J/cm2)) and also due
to the possibility of an increased risk of
lymphoma, as reported in case studies.
In one 2-year study on intermittent use
of cyclosporine after relapse following
the initial induction phase, the average
percentage of time during the two years
in which patients were treated with
cyclosporine was about 43 % and the
average percentage of time in which
patients were in remission was about

60 % [246]. The greater the number of
cycles, the shorter the time to relapse.
One study on nine to 12 months of
therapy compared intermittent treatment with continuous low-dose cyclosporine for maintenance of remission and
found a lower relapse rate in patients
who received continuous therapy [248].
Another study reported that continuous
therapy with the lowest individual maintenance dose was more effective after one
year than intermittent therapy with 12week cycles given after relapse, although
the cumulative annual dose was significantly higher [249].
The S1 guidelines on the use of cyclosporine in dermatology have suggested
that after 12 weeks the effective dosage
should be reduced in increments of
50 mg in roughly 4-week intervals. If relapse occurs, or if existing lesions worsen,
the dosage should be increased again by
50 mg and therapy continued with this
maintenance dosage for up to two years.
Afterward, an attempt should be made at
discontinuing therapy.
Efficacy
Twenty-eight studies met the criteria
for inclusion in the guidelines. Two
grade A2 studies on cyclosporine monotherapy were included [237, 250], 14
grade B studies [243-245, 247, 251260], and seven grade C studies [249,
261-266]. The resulting evidence level
was 1. In regard to combination therapy,
seven grade A2 studies [260], three grade
B studies [173, 262, 267], and three
grade C studies [177, 268, 269], were
included.
Monotherapy
Studies on Sandimmun and Sandimmun Optoral (Neoral) monotherapy
were evaluated. The majority of studies
reported a clinically relevant response
four to six weeks after treatment initiation.
Ellis et al. (EG A2) reported in their
study with 85 patients that 65 % of those
who were treated with 5 mg/kg of body
weight and 36 % of those who were
given 3 mg/kg of body weight had complete remission after eight weeks (healed or nearly healed) [250]. In a study
by Koo et al. (EG A2) with 309 patients,
after eight weeks 51.1 % and after 16
weeks 87.3 % of patients who were given
2.5 5 mg/kg of body weight Neoral
had at least a 75 % reduction in PASI

score compared with baseline [237].
In the majority of 14 grade B studies,
with a total of 1,377 patients, the initial
dosages were generally between 2.5
3 mg/kg of body weight with possible
adjustments (e.g., increase to 5 mg/kg of
body weight; dosage reduction if remission) were given for a period of 12-24
weeks [243-245, 247, 251-260]. Engst
and Huber (EG B) reported than in 12
patients, after four weeks of therapy with
5 mg/kg of body weight, there was complete remission in 33.3 % and partial remission in 50 % [252]. In a larger study
by Laburte et al. (EG B) with 251 patients, there was partial remission after 12
weeks in 47.9 % of patients who were
consistently given 2.5 mg/kg of body
weight and in 88.6 % who were consistently given 5 mg/kg of body weight
[257]. In the other studies, after eight to
16 weeks there was complete remission
in 20 88 % of patients and partial remission in 30 97 %. A study by Heydendael et al. (EG B) compared 88 patients who were given MTX 15 22.5 mg
per week with patients who were given
cyclosporine 3 5 mg/kg of body
weight, and found that after 16 weeks of
therapy 33 % of patients given cyclosporine achieved complete remission (MTX
40 %) and 71 % achieved partial remission (MTX 60 %) [256]. In another
comparative study, with 84 patients
(EG B), who were given 7.5 15 mg
MTX/weekly, 58 % of patients treated
with cyclosporine 3 5 mg/kg of body
weight achieved PASI 75 after 12 weeks
and 29 % achieved PASI 90 [254]. In a
study by Reitamo et al. (EG B) comparing cyclosporine to sirolimus, with eight
treatment arms, after eight weeks partial
remission was reported in five of 19
(26 %) patients treated with 1.25 mg
cyclosporine/kg of body weight and in
10 out of 15 (67 %) treated with 5 mg
cyclosporine/kg of body weight [260]. In
a 24-week study, with 61 obese patients
(BMI >30 kg/m2), 66.7 % of those given
2.5 mg/kg of body weight achieved a
PASI 75 response with concomitant
weight loss of 5 10 % on a low-calorie
diet compared with 29.0 % who were
given the same dosage but not placed on
a diet [255].
In two older studies by von Finzi et al.
(EG C) and Higgins et al. (EG C), a
total of 30 patients were treated with
cyclosporine 3 5 mg/kg of body weight
JDDG; 2011 9 (Suppl. 2): S1S95

Cyclosporine
for nine to 12 weeks [261, 263]. In the

open study by Finzi et al. with 13
patients, partial remission occurred in
92.3 % of patients after three
weeks[261]. In another study, by Grossman et al. (EG C), four out of 34
(12 %) patients who were given 2 mg/kg
of body weight, achieved complete
remission after six weeks [262]. In two
Japanese studies, in which some patients
had only mild psoriasis, after 12 weeks
45 out of 47 (95.7 %) patients who were
treated with 3 mg/kg of body weight
[265] and 10 out of 19 (52.6 %) who
were given 2.5 mg/kg of body weight
[177] achieved PASI 75.
Out of the 22 studies on induction
therapy five included data on relapse rates several months after ending therapy.
Relapse rates after six months were
50 60 % and after eight months about
70 % [243, 253, 258, 261, 263]. Clinical studies on induction therapy did not
report severe tachyphylaxis or rebound
phenomena. In about one-third of
patients, clinical exacerbation may be
expected about three to four weeks after
ending induction therapy, depending on
whether therapy was tapered or stopped
abruptly. An average of three months
after ending therapy, only about 50 % of
the originally achieved clinical success
remains. In a longitudinal study on
2-year long intermittent administration
of cyclosporine, the median times to
relapse were increasingly shorter, from
about 116 days after the first treatment
cycle to about 40 days after the second
[246].
time depends, among other things, on

whether treatment was ended abruptly
or gradually. On average, three months
after ending therapy, only about 50 %
of the original clinical improvement remains. The response to renewed cyclosporine therapy appears not to differ from
the originally observed response, but
there are indications that the effect of
therapy decreases steadily after consecutive attempts.
Conclusions on clinical efficacy

Cyclosporine is a fast-acting, highly effective substance that may be used for
induction therapy in adult patients with
moderate to severe plaque psoriasis.
Depending on the dose, 50 70 % of patients given cyclosporine 2.5 to 5 mg/kg
of body weight achieve partial remission
(defined here as PASI 75) after an average of 12 weeks and 30 50 % achieve
complete remission (defined here as
PASI 90) (EL 1). Clinically significant
improvement is generally seen after about four weeks after treatment initiation.
Severe rebound phenomena were not
reported in the included clinical studies.
Nevertheless, in about one-third of patients, the clinical condition of disease
worsens about three or four weeks after
ending induction therapy. The length of
Combination therapy with cyclosporine

and UV phototherapy
Two studies by Franchi et al. (EG C) and
Petzelbauer et al. (EG B) showed that the
combination of cyclosporine therapy with
systemic PUVA and UVB therapy is effective [267, 268]. Given the increased risk
of UV-induced skin tumors with the use
of cyclosporine such treatment strategies
are rarely used these days. The combination with other systemic agents has not
been as intensely studied. Due to the potential for the exacerbation of side effects,
they are generally not recommended. This
applies in particular to retinoids.
JDDG; 2011 9 (Suppl. 2): S1S95

Combination therapy
Three studies were included on the combination of cyclosporine with other systemic agents or phototherapy: one grade
A2 [260], grade B [267], and grade C
[268] study each. An additional grade B
study was also included on the combination with topical therapies [262].
and sirolimus
In a study by Reitamo et al. (EG A2),
three different dosages of sirolimus
(0.5 mg/m2, 1.5 mg/m2 and 3 mg/m2)
were combined with cyclosporine
1.25 mg/kg of body weight [260]. Combination therapy with the highest dosage
of sirolimus resulted in partial remission
(PASI 75) in 61 % of patients after eight
weeks compared with 26 % of those treated with cyclosporine 1.25 mg/kg of
body weight and 67 % of patients who
were given cyclosporine 5 mg/kg of body
weight. Sirolimus is not approved for the
treatment of psoriasis vulgaris. Combination therapy involves a risk of increased immunosuppression.
Ciclosporin in combination with other

systemic therapies
Smaller open studies by Armeen et al.,
Balasubramaniam et al., and Clark et al.
have indicated that combination therapy

with MTX, mycophenolate mofetil
(CellCept), or fumaric acid esters can
enhance clinical effectiveness in patients
with severe disease [270-272].
and vitamin D3 derivatives
There have been reports of synergistic
clinical effects of topical calcipotriol
therapy combined with cyclosporine,
allowing for potential dosage reduction
of cyclosporine. In a study by Grossman
et al. (EG B), in which 69 patients were
treated for six weeks with cyclosporine
2 mg/kg of body weight and also given
calcipotriol ointment or placebo, 50 %
of those who were given combination
therapy had at least a 90 % reduction in
skin symptoms (PASI 90) compared
with 12 % in the placebo group. In a
study with 20 patients, which did not
meet the inclusion criteria for the guidelines, patients were given cyclosporine
4.5 mg/kg of body weight. The dosage
was reduced by 0.5 mg/kg of body
weight every 15 days if there was a clinical response. There was also open application of calcipotriol ointment for four
weeks on selected lesions on the right
half of the body, while a symmetrical lesion on the left side was not treated. In
17 out of 18 patients, the plaques treated
with calcipotriol demonstrated a better
response to therapy 15 days after treatment initiation [273].
The included studies, most of which
were on short-term therapy (induction
therapy), also reported various adverse
effects related to cyclosporine use. Whenever various dosages were studied, the
rate of side effects was clearly dosedependent [250].
The most commonly reported adverse
effects included:
Renal effects / blood pressure
Increase in serum creatinine (on
average by 5 30 %, in up to 20 % of
patients by around >30 %),
Drop in creatinine clearance (on
average up to 20 %)
Increased urea (in up to 50 % of
patients)
Mg decrease (by an average of 5 15 %)
Increased uric acid (in about 5 % of
patients)
S41
S42
Cyclosporine
Arterial hypertension (in about 2 15 %

of patients)
Liver / gastrointestinal tract
Gastrointestinal symptoms (nausea,
diarrhea, flatulence etc., in 10 30 %
of patients)
Increased bilirubin (in 10 80 % of
patients)
Increased transglutaminase (up to
about 30 % of patients)
Gingival hyperplasia (up to 15 % of
patients)
Other
Paresthesia (up to 40 % of patients)
Muscle pain (in 10 40 % of patients)
Headache (in 10 30 % of patients)
Tremors (in 2 20 % of patients)
Hypertrichosis (in <5 % of patients)
Long-term studies (up to two years) have
also reported undesirable adverse effects.
In one study with 251 randomized patients on use of cyclosporine 2.5 and
5 mg/kg of body weight for up to 21
months, 54 % experienced side effects
related to the use of the drug, of which 8
% were classified as serious [257]. In about one in five patients (18 %) the study
had to be prematurely discontinued due
to side effects. In 10 % the drug was discontinued due to increased serum creatinine values around >30 % compared
with baseline and in 6 % due to arterial
hypertension. While the latter was independent of the dosage, the former was
dose-dependent in 46 % of the patients
in this long-term study (compared with
up to around 20 % in short-term studies) [246].
Package insert: warnings and adverse effects
The package insert lists various specific
warnings:
The alcohol content of the capsules
(12.7 vol. % alcohol; for 100 mg capsules ca. 0.1 g alcohol). This poses a
health risk for patients with liver disease, alcohol problems, epilepsy and
brain damage as well as for pregnant
women and children.
Possible various drug interactions,
especially with statins (increased risk
of myopathy).
Occasionally reported increased intracranial pressure. If neurological
symptoms are diagnosed as benign intracranial hypertension (pseudotumor
cerebri), the use of cyclosporine
should be discontinued as continued

use may lead to permanent vision impairment.
Undesirable adverse effects are summarized in Table 31 by organ system.
Specific safety aspects for the use of
cyclosporine
Malignancy
As is the case with other immunosuppressant drugs, cyclosporine is associated
with an increased risk of lymphoproliferative disorders and other malignant
tumors, especially skin tumors. The
frequency appears to depend primarily
on the extent and duration of immunosuppression and other prior or concomitant therapies such as light therapy or
combination therapy with MTX. It is
important to keep all relevant patient
medical data, especially after long-term
cyclosporine therapy.
Patients with psoriasis vulgaris who have
received numerous phototherapy treatments (especially higher cumulative dosages of PUVA, e.g., >1.000 J/cm2) have
an increased risk of skin cancer, in particular squamous cell carcinoma. In one
study, in patients who had previously
been given PUVA, after adjusting for
PUVA and MTX exposure, after the first
administration of cyclosporine therapy
was about a 7-fold increase in the risk of
squamous cell carcinoma compared with
the previous five years [274]. The risk associated with cyclosporine in the entire
cohort, with a value of about three, was
comparable with that associated with at
least 200 PUVA treatments. In a 5-year
long cohort study (average use of cyclosporine was 1.9 years), the rate of cancer
was twice as high as in the general population [275]. This was related to a sixfold increase in skin cancer risk, usually
squamous cell carcinoma. Significant effects on the incidence of non-melanocytic skin cancer were reported by this
study in relation to duration of therapy
with cyclosporine as well as earlier PUVA
treatments or MTX therapy or the use of
other immunosuppressants. Given that
squamous cell carcinoma is not always
readily diagnosed in active psoriasis, if
there is suspicion, a biopsy should be
performed. There have been case reports
on effective therapy with acitretin in psoriasis patients who developed multiple
squamous cell carcinomas after immunosuppressant therapy (e.g., cyclosporine)
[276, 277].
In a few psoriasis patients who were treated with cyclosporine, benign lymphoproliferative changes as well as B-cell and
T-cell lymphoma were reported. These
resolved after immediately discontinuing
the drug. In the literature there are at
least 20 case reports on malignancy associated with cyclosporine use in patients
with psoriasis vulgaris. This includes at
least seven cases with nodal or cutaneous
lymphoma and several cases of HPVassociated carcinomas.
Infection
Similar to other immunosuppressant
therapies, cyclosporine use is related to
an increased risk of various bacterial,
parasitic, viral, and fungal infections,
as well as opportunistic pathogens. In
general, the increased risk of infection in
psoriasis vulgaris patients who are taking
cyclosporine does not play a major role.
Yet if infection occurs, it can trigger an
exacerbation of the skin condition. If
infection is suspected in an exacerbation
of psoriasis vulgaris, the infection should
be treated first and then cyclosporine
continued if indicated. Patients with
psoriatic arthritis, who may be given
various immunosuppressants, have an
increased risk of infection.
The data available on the safety of
cyclosporine use in pregnant women are
scarce, but there seems to be no indication
of any association with birth defects. Nor
have animal studies shown a relationship
between cyclosporine and birth defects.
Preliminary experience in patients who
have undergone transplantation suggests
that cyclosporine increases the probability
of pregnancy-related complications such
as pre-eclampsia and premature birth
with low birth weight. Thus cyclosporine
should only be used during pregnancy if
the benefits outweigh the potential risks,
which is usually not the case in psoriasis
vulgaris. Pregnant women who take the
drug should be carefully monitored. Women of childbearing age who have psoriasis should only be given cyclosporine after
a negative pregnancy test. Adequate contraception must be ensured during
therapy. It should be recalled that cyclosporine can reduce the efficacy of progesterone-containing contraceptives. In psoriasis patients who become pregnant
while taking cyclosporine, the risks and
benefits of continuing therapy should be
carefully weighed.
JDDG; 2011 9 (Suppl. 2): S1S95

Cyclosporine
Table 31: UAEs according to organ system.

Organ system
Kidney/
cardiovascular
Liver/
intestine
Nervous
system/muscle
Metabolism/
electrolytes
Skin
Gingival
hyper-plasia,
dosedependent
reversible
hepatogastric
complaints
Tremors,
fatigue, headache,
burning sensation
in hands and feet
Reversible
increase in blood
lip-ids (especially
with steroid use)
Hypertrichosis
Stomach
ulcers
Convulsions
Weight gain,
hyperglycemia,
hyperuricemia,
Acne
hyperkalemia,
hypomag-nesemia
Pancreatitis
Motor polyneuropathy, vision impairment, hearing

impairment, central
motor disturbances,
myopathy
Blood
differential
Very common
None
( 10 %)
Common
(1 %,
<10 %)
Dose-dependent,
reversible kidney
dysfunction,
risk of irreversible
kidney damage with
long-term use,
hypertension
Occasionally
(0.1 %,
<1 %)
Rarely
(0.01 %,
<0.1 %)
Ischemic heart
dis-ease
Leukopenia,
thrombocytopenia
Microangiopathic hemolytic anemia,

hemolytic
uremia
syndrome
Very rarely
(<0.01 %)
Occasionally
Skin
redness,
pruritus
Anemia
Colitis
Cyclosporine and alcohol (capsules contain 12.7 vol. % alcohol) enter breast
milk. Breastfeeding should be avoided
while using cyclosporine. Nursing mothers with psoriasis vulgaris should be
given an alternative therapy.
Cyclosporine in older patients
The data on the use of cyclosporine
in older patients are limited. There
are no specific problems related to its
use at the recommended dosages. Yet
the risk of kidney dysfunction sharply
after age 50 in patients who take cyclosporine. When treating older patients,
careful monitoring of the respective laboratory parameters is essential. The
presence / appearance of (UV-related)
skin tumors should also be given special
attention.
JDDG; 2011 9 (Suppl. 2): S1S95

Papillary edema,
pseudo-tumor
cerebri
Management of undesirable adverse

effects
Adverse effects related to cyclosporine
therapy are generally dose-dependent
and thus respond to a dosage reduction.
For certain side effects, special procedures / measures are recommended.
For an increase in serum creatinine values of around 30 % compared with
baseline, adequate fluid intake should be
ensured. For increases of serum creatinine values around 30 50 % (even within normal ranges), a dosage reduction
of at least 25 % and control within 30
days are recommended. If an increase of
30 % persists, treatment must be discontinued. If an increase of serum creatinine of 50 % occurs, the dosage
should be reduced by at least 50 %.
Follow-up should be performed within
30 days and if there is still an increase

in creatinine of 30 % compared
with baseline, cyclosporine should be
discontinued.
In patients with hypertension, defined as
systolic 160 mmHg or diastolic 90
mmHg, on two consecutive blood pressure measurements, blood pressure medication should be prescribed or increased. Possible treatments include calcium
antagonists such as amlodipine (5 10 mg/
daily), nifedipine (important note: gingival
hyperplasia), and isradipine (2.5 5 mg/
daily). Calcium antagonists, especially
diltiazem, nicardipine, and verapamil,
may also lead to an increase in cyclosporine levels, however. Beta blockers are
known to potentially trigger psoriasis.
Patients using ACE inhibitors or AT2
antagonists have an increased risk of
S43
S44
Cyclosporine
hyperkalemia. If blood pressure levels

continue to exceed those named above,
despite medication, the cyclosporine dosage should be reduced by 25 %. If blood
pressure still does not normalize, cyclosporine should be discontinued.
In hypomagnesemia, substitution with
magnesium preparations is recommended. An initial dose of, for instance,
200 mg magnesium/daily may be given
and increased if necessary. With otherwise good tolerability and efficacy of
cyclosporine and isolated laboratory
changes in Mg levels (without any neurological symptoms), no further measures are needed.
In patients with hyperkalemia, the patient should be advised to follow a lowpotassium diet and ensure sufficient
fluid intake (2 3 l/day). If there is no
improvement, the cyclosporine dosage
should be reduced by around 25 %. The
potential onset of cardia arrhythmia in
hyperkaliemia and the necessity of further, or if necessary, acute measures,
should be recalled. Changes in serum
potassium and serum magnesium levels
are reported particularly in patients with
severe renal dysfunction.
In hyperuricemia, a low purine diet and
sufficient fluid intake are recommended
(2 3 l/day). If hyperuricemia persists,
and there appears to be a threat to the
patients health, cyclosporine should be
reduced by 25 %. If there is no improvement, the drug may need to be discontinued. For information on co-medication
with allopurinol see drug interactions. If
there is an increase in transaminase or total bilirubin to more than double normal
values, the dosage should be reduced
by 25 % and follow-up tests within 30
days. If laboratory tests continue to be
abnormal, cyclosporine should be
discontinued.
If there is an increase in blood lipids
(empty stomach lipid profile: cholesterol
and / or triglycerides), a low-fat, lowcholesterol diet is advised. If the patient
fails to improve, depending on the severity of hyperlipidemia and the risk profile of the patient, a dosage reduction or
discontinuation of cyclosporine therapy
should be considered. Co-medication
with HMG-CoA reductase inhibitors or
fibrates should be avoided due to potential drug interactions. In some patients
who have undergone organ transplant,
concomitant use of fibrate drugs (bezafibrate, fenofibrate) has caused significant,
but reversible renal dysfunction either a

corresponding increase in serum. Cyclosporine may diminish the clearance of
certain HMG-CoA reductase inhibitors
(e.g., lovastatin), leading to an increase
in their plasma levels and enhancing
drug toxicity (e.g., muscle pain, muscle
weakness, myositis, and rhabdomyolysis). The package insert recommends
that for simultaneous use of cyclosporine
and statins, laboratory values should be
closely monitored and any physical
changes noted (e.g., by evaluating serum
creatinine phosphokinase values) in
order to promptly identify myopathy.
If this occurs, the drug dosage should
be reduced or treatment possibly stopped. Co-medication with ezetimibe
(Ezetrol) is possible, but here too drug
interactions have been reported (increased average area under the curve [AUC]
of total ezetimibe).
If gingival hyperplasia occurs, optimal
dental hygiene should be ensured. Depending on the severity and progression
of the disorder, cyclosporine should be
reduced or discontinued.
for use
Relevant kidney dysfunction
Insufficient regulation of blood
pressure
Serious infection
Past or current malignancy (possible
exception: prior, adequately treated
basal cell carcinoma, squamous cell
carcinoma in situ)
Prior potentially carcinogenic therapies
(e.g., arsenic, PUVA >1.000 J/cm2)
Infection-related or drug-induced
psoriasis (e.g., beta blockers, lithium,
antimalarial drugs)
Relevant liver disease
Hyperuricemia
Hyperkalemia
Simultaneous therapy with nephrotoxic drugs (see drug interactions)
Concomitant light therapy (SUP,
PUVA)
Concomitant use of other immunosuppressants (except for topical
therapy)
Concomitant use of retinoids or
therapy with retinoids in the last four
weeks before planned treatment initiation with cyclosporine

Drug or alchohol abuse/misuse
Prior long-term MTX therapy
Pregnancy
Nursing
Vaccination with live vaccines
Epilepsy
Current therapy with ricinus oil-based
preparations
Note: The lack of data from studies on

erythrodermic or pustular psoriasis limits the use of cyclosporine in these
forms of disease (as generally applies to
other systemica therapies for psoriasis).
However, in such instances, cyclosporine
may be given, often successfully, if there
are lacking alternatives.
Drug interactions
The availability of cyclosporine primarily
depends on the activity of two molecules
the liver enzyme cytochrome P450 3A4
(CYP3A4), which is involved in the metabolism of cyclosporine, and the intestinal P-glycoprotein, an ATP-dependent
transporter protein that pushes various
drugs, including cyclosporine, out of the
enterocytes back into the bowel lumen.
The activities of these molecules vary due
to genetic factors as well as under the influence of medications or herbal ingredients [239]. For treatment purposes, the
modulators and substrates of CYP3A are
mainly relevant. Powerful inhibitors of
CYP3A, associated with a risk of cyclosporine overdose, include the calcium antagonist diltiazem, the antifungal drugs
ketoconazole and itraconazole, macrolide
antibiotics (with the exception of azithromycin), as well as grapefruit juice. St.
Johns wort, on the other hand, induces
CYP3A, and hence increases the risk of
subtherapeutic cyclosporine levels. Furthermore, interactions that may enhance
side effects must also be taken into
account (e.g., nephrotoxicity).
Increased cyclosporine levels (inhibition
of CYP3A) due to:
Calcium antagonists (diltiazem, nicardipine, nifedipine, verapamil, mibefradil),
amiodarone,
macrolide
antibiotics
(erythromycin, clarithromycin, josamycin,
posinomycin, pristinamycin), doxycycline, gentamicin, tobramycin, ticarcillin,
quinolone (e.g., ciprofloxacin), ketoconazole, and to a lesser extent fluconazole
and itraconazole, oral contraceptives,
JDDG; 2011 9 (Suppl. 2): S1S95

Cyclosporine
androgenic steroids (norethisterone, levonorgestrel, methyltestosterone, ethinylestradiol), danazol, allopurinol, bromocriptine, methyl prednisolone (high doses),
ranitidine, cimetidine, metoclopramide,
propafenone, protease inhibitors (e.g., saquinavir), acetazolamide, amikacin, statins
(mainly atorvastin and simvastatin), cholic
acid and its derivatives (e.g., ursodeoxycholic acid), grapefruit juice
Reduced cyclosporine levels (induction
CYP3A) due to:
Carbamazepine, phenytoin, barbiturates, metamizole, rifampicin, octreotide,
ticlopidine, nafcillin, probucol, troglitazone, intravenous sulfadimidine and trimethoprim, St. Johns wort preparations
Potential enhancement of nephrotoxic
effects due to:
Aminoglycosides (e.g., gentamycin, tobramycin), amphotericin B, trimethoprim
and sulfamethoxazole, vancomycin, ciprofloxacin, acyclovir, melphalan, nonsteroidal anti-inflammatory drugs (e.g.,
diclofenac, naproxen, sulindac). Creatinine levels should be measured more frequently and the dosage of accompanying
medication reduced if necessary. Significant (reversible) impairment of kidney
function is possible with the use of fibrates (e.g., bezafibrate and fenofibrate).
Possible worsening of myopathy due to:
Concomitant use of HMG-CoA reductase inhibitors (statins). The related risk
must be carefully assessed.
Increased plasma levels of drugs can occur during cyclosporine use as a result of
diminished clearance. This especially applies to digoxin, colchicine, prednisolone,
certain HMG-CoA reductase inhibitors
(e.g., lovastatin), and diclofenac. The
cause is probably a diminished first-pass
effect (increased risk of kidney damage).
Other drug interactions
Increased risk of gingival hyperplasia
with concomitant use of nifedipine;
increased immunosuppression / tumor
formation with simultaneous treatment
with other immunosuppressants or
tumor-inducing substances; vaccinations
may be less effective; cyclosporine can diminish the effects of progesterone-based
contraceptives; at higher dosages of prednisone, prednisolone, and methylprednisolone there is an increased risk of seizures. Due to the disulfiram-like effect
JDDG; 2011 9 (Suppl. 2): S1S95

which has been observed after administration of N-methyl thiotetrazolecephalosporin, caution must be exercised
with concomitant use of cyclosporine
(alcohol-containing drug).
Notes on use
Laboratory tests: see Table 32
General measures
Patient history including past and
current diseases (e.g., severe infections, malignancy, kidney or liver
diseases), accompanying medication
(see drug interactions).
Specific measures
With corresponding patient history
or clinical or laboratory signs, HIV
infection and viral hepatitis should
be excluded.
Inspection for potentially malignant
skin lesions.
Signs of existing infection
Take blood pressure measurements
at two different times
Patient education:
Patients should be made aware that
any infection may be more severe or
have atypical symptoms and course
and they must therefore seek prompt
medical attention.
Drug interactions (also inform other
treating physicians of therapy)
Ensure contraception and rule out
pregnancy in women of childbearing
age (important note: diminished efficacy of progesterone-based contraceptive drugs)
Avoid excessive exposure to sunlight,
use of sun protection
Interview / examination
Status of skin and mucous membranes (e.g., increased body hair, swollen gums, rule out skin cancer)
Signs of existing infection
Gastrointestinal symptoms and neurological symptoms
Repeat recommendation to protect
against exposure to sunlight
Check co-medication
Measure blood pressure
In uncomplicated low-dose longterm therapy (2.5 - 3 mg/kg body
weight daily) later 2-month control
intervals may be used
Shorter intervals, e.g., in patients

with risk factors, when increasing
dosage, with the use of metabolic
drugs or drugs with potential interactions
Creatinine clearance if the creatinine
plasma levels appear abnormal
In certain patients undergoing intermittent or short-term therapy, a
smaller number of controls (e.g., regular control of blood pressure and
creatinine values) may be sufficient
Assessment of cyclosporine levels
may occasionally be wise especially
with suspected non-compliance or
toxicity due to drug interactions
None
Procedure if overdose is suspected
Determine cyclosporine serum levels
Discontinue cyclosporine
Assess vital signs, liver values, kidney
values, electrolytes
Initiate other treatments if necessary
(in cooperation with specialized physicians)
Measurement of cyclosporine levels
For the treatment of patients with dermatological disorders, the measurement
of cyclosporine levels in the blood is
usually unnecessary.
Tests may be performed to obtain information about medication use (compliance) (e.g., discrepancy between (high)
dosage and clinical or a discrepancy
between a (low) dose and UAEs) or
with concomitant use of drugs that may
influence cyclosporine levels.
Specific aspects of switching therapy
(see under Combination Therapy)
When switching between cyclosporine
preparations produced by different manufacturers, differences in bioavailability
must be taken into account and the
dosage adjusted as necessary.
There are no hard and fast rules on rotational therapy with cyclosporine. Longterm use of MTX should not be followed
by cyclosporine.
Cyclosporine therapy is possible following retinoid therapy, after an interval of
four weeks.
Switching to fumaric acid ester preparations, the simultaneous use of which is
S45
S46
Cyclosporine/Etanercept

Weeks
Diagnosis
Before
12
16
Blood count*
Liver values**
Electrolytes***
Serum creatinine
Uric acid
Cholesterol, triglycerides****
Magnesium*****
*
**
***
****
Erythrocytes, leukocytes, thrombocytes + blood differential

Transaminase, GT, bilirubin
Sodium, potassium
Assess twice if possible (empty stomach) and additionally at week -2 and
week 0
***** Only if indicated (e.g., muscle cramps)
relatively contraindicated, is associated

with the problem that these drugs are
slow to take action and there is a risk of
exacerbation. In principle, when switching therapy due to inadequate efficacy,
(even overlapping) therapy with biologics is possible, taking into consideration
any potential synergistic toxicity (e.g.,
infection, liver values).
week induction therapy are 1,240.68

and corresponding annual costs
5,389.37 . For 12-week long induction
therapy followed by reducing the drug
by 50 mg every four weeks until a dosage
of about 1 mg/kg of body weight is
achieved (treatment duration of six
months total), the related drug costs are
1,791.54 .

The feasibility for the treating physician
is restricted by the various drug interactions and the need for rather extensive
and time-consuming monitoring. Given
its low therapeutic spectrum and its
pharmacokinetic variability cyclosporine
is classified as a critical dose drug. This
reflects the necessity of increased attention by doctors to risk factors and undesirable adverse effects.
For the patient, the use of oral cyclosporine is unproblematic. Possible limitations result from the need to undergo regular testing, potential concerns about
side effects, and the generally limited use
of the drug, lasting only a few months.
The treating physician should ensure
patient compliance by discussing these
aspects before and during treatment.
Compared with other antipsoriatic
systemic therapies, drug interactions
in particular must be taken into consideration.
Costs
The daily drug costs for therapy with cyclosporine 300 mg/daily are 14.77
[23] (fixed price). The drug costs for 12-
Summary evaluation
Of the studies evaluated on cyclosporine therapy in psoriasis patients, 28
meet the criteria for inclusion in the
guidelines. This includes 15 studies
from the research for the European S3
psoriasis guidelines.
After 12-16 weeks, 50 - 70 % patients
achieve PASI 75 (EL 1).
Cyclosporine is especially suitable for
induction therapy.
In long-term therapy, after one to two
years maximum, continuation of
therapy should be carefully considered
given potential side effects, especially
nephrotoxicity and increased blood
pressure as well as the increased risk of
cancer.
Given the large number of patients

who have been treated with cyclosporine (for other diseases as well), the risk
of undesirable adverse effects is predictable.
Various drug interactions can occur
with the use of cyclosporine, on the
one hand leading to altered availability
of cyclosporine or the concomitant
drug and on the other hand increasing
the risk of adverse effects.
Combination use with topical preparations is helpful in the treatment of plaque psoriasis, especially since it appears
that concomitant local therapy with
vitamin D3-analogues or steroids can
help reduce cyclosporine dosage without diminishing its effectiveness.
Cyclosporine may be recommended, especially for induction

therapy, in patients with moderate to severe psoriasis vulgaris.
Combination therapy with cyclosporine and topical preparati-
ons in the treatment of psoriasis
vulgaris may be recommended.
7.3 Etanercept
Volker Streit, Wolfram Sterry
(based on Volker Streit, Jrg Prinz)
Introduction
Psoriasis vulgaris is characterized by infiltration of the skin by activated T cells and
an increased proliferation of keratinocytes. In psoriatic lesions, activation of
T cells leads to increased concentrations
of the pro-inflammatory cytokine TNF [278, 279]. Etanercept (Table 33) is a
TNF- antagonist. As a soluble receptor,
etanercept binds free TNF- and has
been used successfully in the treatment of
rheumatoid arthritis, psoriatic arthritis,
and other forms of arthritis [280, 281].
The approved indications for use of
etanercept in dermatology are as follows:
treatment of adult patients with moderate
to severe psoriasis vulgaris (plaque psoriasis) in whom other systemic therapies including cyclosporine, MTX, and PUVA
have failed, are contraindicated, or are
not tolerated; treatment of chronic severe
plaque psoriasis in children and adolescents from age eight onward who do not
tolerate or have not responded adequately
JDDG; 2011 9 (Suppl. 2): S1S95

Etanercept

Etanercept
Approval in Germany
2002 (psoriatic arthritis)/

2004 (psoriasis vulgaris)/
2008 (psoriasis vulgaris in children)

Blood count, liver values

2 25, 1 50 or 2 50 mg/weekly
2 25 mg/weekly, 1 50 mg/weekly
After 6-12 weeks; maximum efficacy

after 24 weeks
Response rate
PASI 75 in 34 % (2 25 mg), 38 %
(1 50 mg) and 49 % (2 50 mg)
after 12 weeks (EL 1)
Important UAEs
Infections, pregnancy, nursing

Local reaction, infections
Anakinra (IL-1 receptor antagonist),

Abatacept (co-stimulation inhibitor
Misc.
to other systemic therapies or phototherapy; treatment of active and progressive psoriatic arthritis in adults if the response to prior basic therapy is inadequate.
adult or pediatric patients. For children,

multiple doses may be prepared after
dissolving the powder.
The recommended adult dosage for the
treatment of plaque psoriasis is etanercept
25 mg 2 /weekly or 1 50 mg/weekly.
If there is high disease activity, or the patient is overweight, an initial dose of
50 mg 2 /weekly may be given for up to
12 weeks, followed by 25 mg 2 /weekly
or 1 50 mg/weekly. The original
restriction, which limiting continuous
therapy in Germany to a maximum of
24 weeks, was lifted in June 2009.
Mechanism of action
Etanercept is a human tumor necrosis
factor receptor (p75) Fc fusion protein.
Its terminal elimination half-life is about
four to five days.
TNF- is a pro-inflammatory cytokine
which plays a central role in the producing and sustaining the inflammatory reaction. It can be produced by almost all
cells that are involved in the underlying
inflammatory process in psoriasis. TNF induces the expression of adhesion
molecules and the production of chemokines and cytokines such as IL-1, IL-6,
IL-8, MCP-1 and VEGF.
As a soluble receptor, etanercept binds free
(but not membrane-bound) TNF- and
blocks the inflammatory cascade triggered
by TNF-. It thus has anti-inflammatory
and immunosuppressant properties.
Efficacy
inclusion in the guidelines. Of these,
there were five grade A2 studies on
etanercept monotherapy [282-286], six
grade B studies [287-292], and three
grade C studies [293-295]. The resulting
level of evidence is 1. In regard to combination therapies, one grade B and grade
C study each were assessed [296, 297].

Etanercept is available as a pre-filled
syringe containing 25 mg or 50 mg of
the active ingredient. It is also available
as an autoinjector pen with a 50 mg dose
of the drug. Etanercept is also available
in powder form in a vial containing
25 mg of the drug which is suitable for
Monotherapy
In a phase II study Gottlieb et al. (EG A2)
reported that in 57 patients (out 112) a
dosage of 25 mg 2 /weekly achieved a
reduction in PASI score of at least 75 %
in 30 % of patients int the verum group
and in 2 % in the placebo group after
12 weeks. After 24 weeks, 56 % of pati-
JDDG; 2011 9 (Suppl. 2): S1S95

ents given etanercept had an improvement in the PASI score in compared with
5 % in the placebo group [282].
In a study with 672 patients, Leonardi
et al. (EG A2) reported a PASI 75 improvement after 12 weeks in 14 % (25 mg
1 /weekly), 34 % (25 mg 2 /weekly)
and 49 % (50 mg 2 /weekly) of patients who were given etanercept compared with an improvement in only 4 % of
those in the placebo group. After 24
weeks, the proportion of patients with a
PASI 75 improvement increased by
25 %, 44 % and 59 %. The significant
improvement in PASI score was also
associated with an improvement in physician global assessment. In patients who
were treated with etanercept the Dermatology Life Quality Index improved by
around 50.8 % (25 mg 2 /weekly) and
61 % (50 mg 2 /weekly) compared
with the placebo group [283].
In a study with 142 patients, Van de
Kerkhof et al. (EG A2) showed that in
week 12, patients who were given 1
50 mg/weekly etanercept had a higher
PASI 75 response rate (38 %) compared
with the placebo group (2 %). 72 % of
patients who were treated with 1
50 mg/weekly etanercept up to week 24
achieved PASI 75 by that time [286].
In regard to drug efficacy, it is important
to note that there is a further increase in
the effectiveness of the drug after the induction phase of 16 weeks as defined in
the present guidelines. The maximum efficacy of the drug appears to be reached
after 18 24 weeks. Berends et al., Gottlieb et al., Van de Kerkhof and Leonardi
et al. [282, 283, 286, 287] reported that
2 25 mg etanercept resulted in PASI
75 after 12 weeks in 34 % of patients
and after 24 weeks in 44 % of patients.
For a dosage of 2 50 mg the PASI 75
response rates were 49 % after 12 weeks
and 59 % after 24 weeks.
Combination therapy
There are only a few controlled studies
on combination therapy with etanercept.
The combination use with topical
antipsoriatic therapies (topical steroids,
vitamin D3 derivatives, tazarotene,
dithranol) appears feasible and advisable.
There are as yet no validated data on
combination therapy with fumaric acid
esters or cyclosporine.
The combination of etanercept with
MTX is an established therapy in the
treatment of psoriatic arthritis and
S47
S48
Etanercept

Very common
Reactions at the injection site, infections

(upper respiratory tract, bronchitis, skin infections)
Common
Pruritus
Occasionally
Thrombocytopenia, urticaria, angioedema,

severe infections (pneumonia, phlegmon, sepsis)
Rarely
Anemia, leukopenia, neutropenia, pancytopenia,

vasculitis, subacute lupus erythematosus (LE),
discoid LE, tuberculosis, demyelinating processes
Very rarely
Aplastic syndrome
rheumatoid arthritis. Zachariae et al. showed in a study with 59 psoriasis patients

that continuous combination therapy
with etanercept plus MTX for 24 weeks
was superior to therapy with etanercept
and a reduction in MTX therapy (in the
first four weeks) [297] (EG B).
In regard to the potential benefit of retinoids, Gisondi et al. reported in a study
with 60 patients that 15 % of patients
who were given etanercept (1 25 mg/
weekly) plus acitretin (0.4 mg/kg of
body weight) achieved PASI 75 in week
12. 20 % of patients who were given a
standard dosage of etanercept (2 25 mg/
weekly) achieved PASI 75, while only
8 % who were treated with acitretin
alone did so. A reduction in the weekly
dose of etanercept could potentially help
reduce therapy costs [290] (EG B).
The combination of etanercept (2 50 mg/
weekly) with a 12-week regimen of UVB 311 nm phototherapy has been shown
to lead to more rapid healing of psoriasis
as reported by Kircik et al. in a study on
86 patients. In that study, 85 % of patients achieved PASI 75 and 58 % achieved PASI 90 [296] (EG C).
There are data on the use of etanercept in
other diseases (rheumatoid arthritis, etc.)
add up to over 2 million patient years on
more than 600,000 patients. The most
commonly reported side effects are local
reactions at the injection site. Placebocontrolled studies report this side effect
in 14 % of psoriasis patients treated with
etanercept (11 17 %) compared with
7 % in the placebo group [283]. In patients taking anti-TNF- therapy there is
an elevated risk of serious infection, including sepsis, which may be fatal in rare
cases. The use of TNF- blockers should
be avoided in patients with clinically

relevant infections.
In placebo-controlled studies on psoriatic arthritis and psoriasis vulgaris, there
are no differences in the infection rates in
patients who are given etanercept versus
placebo. An analysis of 1,960 patients
with rheumatoid arthritis who took etanercept for up to five years reported the
same frequency of infections (requiring
hospitalization or intravenous antibiotics) as in the placebo group during the
double-blind phase of the study or in the
patients who were given MTX [298]. In
another study the rate of infections was
just as frequent in patients who were
treated for a longer period of time with
etanercept as in a placebo group [299].
In a retrospective study of 117,000 patients, 13 patients who were given etanercept developed tuberculosis [300].
The incidence of malignancy in patients
given etanercept versus a comparison
group was similar to the expected rates
and incidences in the study population.
In 4,114 patients with rheumatoid
arthritis who were given etanercept for
up to six years there were 129 new malignancies. In 2,711 patients with psoriasis
vulgaris who were given etanercept for
up to 2.5 years in the framework of
various studies, there were 30 reports of
malignant diseases and 43 reports of
non-melanocytic skin cancer; regular
skin examinations for patients with an
increased risk of skin canter, e.g., after
PUVA therapy, are recommended [301].
One study reported that there was no
difference in 2,054 patients with rheumatoid arthritis who were given longterm etanercept therapy (7,777 patient
years) in regard to severe infections or the
development of cancer compared with
comparison groups [302].
Among patients taking anti-TNF-, the

number of patients who developed lymphoma was marginally higher than in the
control group. It is not certain whether
etanercept use can increase the incidence
of lymphoma.
Undesirable hematological effects,
demyelinating diseases, and autoimmune processes are effects of all TNFblockers and hence occur with etanercept as in other TNF- blockers.
Due to the pharmacokinetics of etanercept, there is no need for dosage modification in patients with impaired renal
and liver function. There have been no
reports of increased etanercept concentrations in patients who experienced
acute kidney or liver failure during treatment. Etanercept should be used with
caution in patients with moderate to
severe alcohol-induced hepatitis.
Etanercept should be discontinued if
adverse effects or infection occur.
for use
Cardiac insufficiency NYHA grade
III - IV
History of tuberculosis or other
severe infections
Pregnant and nursing women
Malignancy (except for basal cell carcinoma) and lymphoproliferative diseases, also in the patient medical history
Vaccination with a live vaccine
Drug interactions
Clinical studies have found no evidence of
drug interactions with concomitant use of
steroids, salicylates, non-steroidal anti-inflammatory drugs, analgesics or MTX.
Patients who have taken anakinra (IL-1
receptor antagonist) together with
etanercept r have an increased number
of serious infections and neutropenia.
The use of etanercept is not advised in
patients who are taking anakinra or
abatacept (co-stimulation inhibitor).
A statistically significant decrease in leukocytes has been reported with concomitant use of sulfasalazine.
JDDG; 2011 9 (Suppl. 2): S1S95

Etanercept
Notes on use
See Table 34.
General measures
Exclude TB based on current recommendations by the Paul Ehrlich
Institute [235], see Appendix 2
If warranted by the patient history
or the results of clinical or laboratory
tests, rule out HIV infection and
viral hepatitis.
Specific measures
Patients must ensure adequate contraception / rule out pregnancy in
women of childbearing age
Patients should be informed of the
potential for severe and atypical infections and should seek prompt medical attention if symptoms occur.
Monitoring for infections; if an infection is detected or suspected, stop
therapy at least temporarily
Discontinue therapy if pregnancy
occurs
None
Clinical studies on patients with rheumatoid arthritis have not found any dose
limiting toxicity [301]. There is no
known antidote for etanercept.
Treatment with etanercept is simple and
straightforward. The injection may be
self-administered or may be performed
by a family member. The drug should be
stored in a cool place (2 8C). This
may be inconvenient in terms of travel.
Costs
The daily costs of the drug for 12-weeklong induction therapy 2 50 mg/weekly, followed by 1 50 mg/weekly or
2 25 mg/weekly for another 40 weeks
are 75.96 [23]. For continuous use
1 50 mg/weekly for 12 months, the
daily drug costs are 62.76 . The resulting annual costs of treatment are
27,724.76 or 22,907.83 .
The drug costs for 12-week-long induction therapy 2 25 mg/weekly are
5,271.94 or, for 2 50 mg/weekly,
10,543.88 .
JDDG; 2011 9 (Suppl. 2): S1S95


Before
Blood differential
X
X
X
X
X
X
ALAT, ASAT, GT
X
If there is suspicion of infection, see pre-treatment procedures.
X
X
X
X
Antibodies to the drug are detected in up
to 6 % of patients who take etanercept.
The antibodies are not neutralizing and
in most patients are only transitory.
There appears to be no association
between antibody formation and clinical
response or side effects. In one study,
antinucleated antibodies were reported
in up to 11 % of patients who were treated with etanercept versus 5 % in the
placebo group [301].
Summary evaluation
Out of 20 studies assessed in regard to
the efficacy of etanercept monotherapy
in patients with psoriasis, 16 met the
criteria for inclusion. This includes
eight studies from the research for the
European S3 psoriasis guideline.
In treatment with etanercept 2
25 mg or 1 50 mg given subcutaneously once a week, about 35 % or
38 % of patients achieve PASI 75 after
12 weeks. For therapy with 2 50 mg
given subcutaneously every week for
12 weeks, about 50 % of patients
achieve PASI 75 (EL 1). The maximum efficacy of etanercept is not reached until after the induction phase.
Etanercept is suitable for long-term
use. Based on the data from available
studies, an increase in effectiveness in
long-term therapy of psoriasis vulgaris
may be expected in some patients.
The use of TNF- antagonists is especially beneficial for patients with psoriatic arthritis. The efficacy and safety
of etanercept are not influenced by the
formation of antibodies to the drug.
Various safety aspects should be considered when administering etanercept.
One of the most important is the risk
of infection. Careful evaluation of the
indications for use of the drug as well
as education and monitoring of the
patient are essential.
Given the widespread use of etanercept

(for other diseases as well), the risk
of side effects related to its use is
readily assessed.
patient.
Combination use of etanercept with
MTX or acitretin can have synergistic
effects.
Treatment recommendations
Etanercept 2x50 mg is recommended for induction therapy
in patients with moderate to
severe psoriasis vulgaris, especi-
ally if other treatment forms
have been unsuccessful, are
not tolerated, or are contraindicated.
Etanercept 1 50 mg or 2
25 mg may be recommended
for induction therapy.
Comment: In the framework of
the consensus conference, there
was no strong consensus (>
75 %) on the therapy recommendations for etanercept. The
recommendation was based on a
majority vote of 62 % of the
guidelines experts.
Alternative formulations were
may be recommended (2
50 mg) or may be considered
(1 50 or 2 25). This was
due to the initially comparatively lower efficacy of etanercept
versus other biological agents,
given that etanercept reaches
maximum efficacy only after the
induction phase.
S49
S50
Fumaric acid esters

Fumaric acid esters
1995 (psoriasis vulgaris, moderate to
severe disease)
Recommended control
Serum creatinine, transaminase /
parameters
GT, blood differential, urine status
Based on recommended dosage scheme
Recommended maintenance dosage Individual dosage modification
After about six weeks
PASI 75 in 50 - 70 % of patients
Response rate
at the end of the induction phase
after 16 weeks (EL 2)
Chronic diseases of the gastrointestinal
tract and/or kidneys as well as chronic
diseases that are associated with dimiMain contraindications
nished leuko-cyte count or function
Patients with malignant diseases
Pregnant or nursing women
Gastrointestinal complaints, flush,
Important UAEs
lym-phopenia, eosinophilia
No known drug interactions
Misc.
Approval in Germany
7.4 Fumaric acid esters

Ockenfels
Introduction
The use of fumaric acid esters was
approved for use in Germany in1995 in
systemic therapy of severe psoriasis vulgaris (Table 36). In 2008 the indications
were expanded to include moderate psoriasis vulgaris. The preparations Fumaderm and Fumaderm initial are sold
as standard commercially-available products. Both preparations contain a mixture of dimethyl fumarate (DMF) and
three salts of ethyl hydrogen fumarate.
DMF is considered to be the actual active ingredient. Fumaderm is the only
approved preparation. Fumaderm and
Fumaderm initial differ only in terms
of the amount of DMF. The effects of
fumaric acid ester on psoriasis vulgaris
were first reported in 1959. At that time,
the drug was mainly given as an individual formulation. Most of the reports on
the clinical effects of psoriasis are from
open studies. Only a handful of studies
have been performed using evidencebased criteria.
Systemic therapy with Fumaderm is based on an established dosing scheme for
severe psoriasis vulgaris. A significant

improvement in the condition of the
skin is reached over a period of about
three months of treatment.
Mechanism of action
The main ingredient in Fumaderm, dimethyl fumarate, is rapidly hydrolyzed
by the body and broken down into its
metabolite, methyl hydrogen fumarate
(MHF). MHF is further broken down
into free fumaric acid and ultimately carbon dioxide and water.
At the molecular level, our current understanding of the mechanism of action
is based on the results of numerous scientific studies. DMF interacts with intracellular thiols, which are present in every
cell for stabilization of the redox balance.
DMF leads to a long-term increase in the
already reduced glutathione. The now
increased glutathione level causes inhibition of redox-sensitive kinases that as a
result inhibit the phosphorylation and
ubiquitination of the inhibitor of the
nuclear factor kappa B (I B). The translocation of the nuclear factor kappa B
(NF B) is regulated by cytosol in the cell
nucleus. NF B plays an important role in
the transcription of the genes that code
for pro-inflammatory mediators such as
TNF- and IL-8 and adhesion molecules such as E-selectin and ICAM1/
VCAM-1. This results in a strong antiinflammatory effect [303]. The influence
of the intracellular redox potential via
glutathione explains the number of previously reported immunological effects
seen in different cell types. Earlier papers
reported reduced expression of the
above-named adhesion molecules on
human endothelial cells after exposure to
DMF [304]. The ability of DMF to
strongly inhibit the production of
pro-inflammatory cytokines was also
previously reported [305]. Interestingly,
DMF and MHF also inhibit the maturation of dendritic cells which are believed
to have an important role in the development and maintenance of the immune
reaction in psoriasis vulgaris [306]. Earlier articles on the effect of in vitro
MHF on activated T cells reported that
it stimulated a change from secretion of
Th1-like cytokines to Th2-like cytokines
[307-309]. Another important effect of
DMF, which has been shown for all cell
types studied, is that at higher concentrations it induces apoptosis in vitro.
Activated cells seem to be especially
sensitive [310].
Dosage and dosing scheme (Table 37)
Standard clinical procedure consists of
slowly increasing the dosage based on an
established dosing scheme. The gradual
increase is intended to improve tolerability, especially in regard to gastrointestinal complaints.
The dosage is adjusted on an individual
basis according to the response to
therapy and the occurrence of any side
effects. The recommended maximum
dose is 1.2 g/daily = six tablets Fumaderm, although this is not always
necessary for effective therapy. In most
patients, between two and four Fumaderm tablets are sufficient. The dosage
is increased until an adequate clinical
response is achieved. Next it is slowly
tapered until the individual maintenance
dosage is reached.
Fumaric acid ester therapy may be
discontinued spontaneously without
any re-bound effects or pustular exacerbation.
Efficacy
Nine studies on fumaric acid ester monotherapy met the criteria for inclusion
in the guidelines. Two were grade A2
JDDG; 2011 9 (Suppl. 2): S1S95

Fumaric acid esters
Table 37: Dosing scheme for Fumaderm therapy.

Fumaderm initial
Week 1
1-0-0
Week 2
1-0-1
Week 3
1-1-1
Fumaderm
Week 4
1-0-0
Week 5
1-0-1
Week 6
1-1-1
Week 7
2-1-1
Week 8
2-1-2
Week 9
2-2-2
studies [311, 312], two grade B studies

[313, 314], and five grade C studies[305,
315-318]. The resulting level of evidence
was 2.
Based on the results of these studies, a
16-week regime of Fumaderm therapy
leads to a reduction in PASI score
between 50 and 80 %. In a study by
Altmeyer et al. (EG A2), in which
Fumaderm was tested on a larger sample (n = 50) there was a reduction in
PASI score after 16 weeks of around
50.2 % in patients with severe psoriasis
vulgaris [311]. Gollnick et al. (EG A2)
reported in a comparison study on
Fumaderm monotherapy and Fumaderm with topical application of a calcipotriol-based ointment in the placebo
arm, a reduction in PASI score of around
51.9 % after 13 weeks [312].
In a long-term treatment study by Altmeyer et al. (EG C), after ending induction therapy of 16 weeks there was a reduction in PASI score of around 79.1 %
[315]. In a small study, with 13 patients
with psoriasis vulgaris, Bayard et al. (EG
C) reported that after 12 weeks of
therapy 45 % of patients had a significant improvement or clearance [316]. In
a study published by Nugteren-Huying
et al. (EG B), 75 % of patients achieved

a reduction in the proportion of affected
skin of more than 70 % [314]. In a comparative study by Kolbach et al. (EG B)
on Fumaderm versus dimethyl fumarate monotherapy, 53 % of patients had
are more than 75 % improvement in
skin symptoms [313]. These data were
confirmed by a study by Litjens et al.
(EG C) with 20 patients who were given
a 20-month regime of Fumaderm. After 12 weeks of therapy there was a reduction in PASI score of 53.3 % [305].
In an Italian clinical application study by
Carboni et al. (EG C), among 40 patients who were treated with Fumaderm
a total of 71 % had significant improvement of skin symptoms or clearance after
12 weeks [317].
In an open study by Mrowietz et al.
(EG C), a 16-week treatment regimen
led an even greater reduction in PASI
score of an average of 80 % in patients
with severe psoriasis vulgaris [318].
Fumaric acid esters thus exhibit good
efficacy after six to eight weeks of
therapy in patients with psoriasis vulgaris.
The effectiveness of the drug increases
as therapy continues. The dosage is
easily adjusted and the dose is modified

Very common
Gastrointestinal complaints, flush
Common
Lymphopenia
Occasionally
Eosinophilia, proteinuria
Rarely
Increased ALAT or bilirubin
Very rarely
JDDG; 2011 9 (Suppl. 2): S1S95

on an individual basis to ensure the use

of the lowest possible dose. Depending
on individual disease activity, psoriasis
vulgaris may recur in a matter of weeks
or months after discontinuation of
therapy. There are no reports of tachyphylaxis occurring.
Gastrointestinal complaints (in up to
60 % of patients especially in the initial
weeks of therapy) and flush are the most
common side effects of fumaric acid
esters. Taking the tablets with milk can
help improve gastrointestinal tolerability.
Acetyl salicylic acid may be taken to help
reduce symptoms of flush.
Gastrointestinal tract symptoms include
diarrhea, increased frequency of stools,
nausea, and abdominal cramps. The
symptoms of flush are highly varied and
range from a brief feeling of warmth to
reddening of the face lasting for several
hours.
Leukocytopenia, lymphocytopenia, and
eosinophilia are common side effects of
fumaric acid esters. If lymphocyte levels
drop below 700/l, the dosage should be
cut in half. If at follow-up after 2-4
weeks there is no increase in lymphocyte
count, the dosage should be cut in half
again. If 1 tablet of Fumaderm/daily
does not lead to an increase in lymphocyte count, or if the levels drop below 500/l, therapy must be discontinued. An increase in eosinophilic
granulocytes is always transient and is
usually observed between weeks four
and ten.
There are very rare reports of isolated increases in ALAT, especially during treatment initiation. Increased bilirubin has
also been reported.
There are occasional reports effects related to kidney function (proteinuria).
Normal functioning is restored after reducing the dosage or stopping the drug.
There are no reports of opportunistic infections occurring or an increased tendency toward infection.
A number of open studies have been conducted on patients with psoriasis vulgaris
who were treated with Fumaderm for
more than one year [315, 319]. In addition to very good efficacy, no side effects
were associated with longer-term therapy
that led to discontinuation of treatment.
In a case report long-term use of the drug
in psoriasis patients, some had undergone
14 years of continuous therapy with
S51
S52
Fumaric acid esters/Infliximab
Fumaderm. None of the patients developed a malignancy nor was there an increased susceptibility to infection [320].
There is no need for dosage adjustment
in older patients or in patients with impaired liver function since fumarates are
not primarily metabolized by the liver.
Patients with kidney dysfunction should
not be treated with fumaric acid esters.
In a retrospective study on patients who
were given continuous Fumaderm for at
least two years, or who were given therapy
for at least three years with a maximum
treatment-free interval of six months, patients evidently tolerated long-term therapy
and there was significant improvement or
clearance (based on PGA) in 80 % after
more than two years of therapy. These data
indicate that Fumaderm is suitable for
long-term therapy [321].
There are no studies on the use of fumaric acid esters during pregnancy or in
nursing women. Toxicology studies have
shown that fumaric acid esters have neither teratogenic nor mutagenic potential.
If side effects occur, the dosage should be
reduced. If adverse effects persist, the
drug must be stopped.
of use
Pregnancy and breastfeeding
Kidney and severe gastrointestinal
disease
Co-medication with MTX, retinoids,
psoralens, cyclosporine, immunosup-
pressants, cytostatics, and drugs with a

known harmful effect on the kidneys.
Drug interactions
Fumaric acid esters can impair kidney
function. Increased toxicity with concomitant use of nephrotoxic substances can
occur. The manufacturers information
warns against an interaction with
nephrotoxic drugs.
Notes on use
Laboratory controls see Table 39
Laboratory controls see Table 39
None
Treatment with Fumaderm is straightforward. The tablets are taken up to
3 /daily. Only routine examinations are
needed. Use of the drug is limited by gastrointestinal intolerance. The specific dosing scheme and the specific UAEs (including gastrointestinal symptoms and flush)
require thorough education of the patient.
Costs
The daily drug costs during the induction phase (three weeks Fumaderm initial followed by nine weeks of Fumaderm tablets 3 1) are 7.51 [23].
If the dosage is increased to Fumaderm
tablets 6 1, the costs of the drug are
7.81 . The drug costs for 12-week induction therapy are 630.72 , and the
annual treatment costs are 3,200.86 .
None.

Weeks
Diagnosis
Blood differential*
Liver values**
Serum creatinine
Urine status
Before
Up to 4th month
every 4 weeks
After 4th month

every 8 weeks
X
X
X
X
X
X
X
X
X
X
X
X
* Erythrocytes, leukocytes, thrombocytes, blood differential

** Transaminase, GT
Combination therapy
Combination therapy with systemic
drugs for the treatment of psoriasis is not
advised at this time. However, case
studies have reported successful use of
combination therapies with MTX and
cyclosporine [271].
Fumaric acid esters may be combined
with any topical drug for the treatment
of psoriasis vulgaris. The combination
with calcipotriol-based ointment has
been studied in a double-blind, placebocontrolled study. This study reported a
significantly improved effect of combination therapy compared with Fumaderm treatment plus vehicle in the control group [312].
The combination with UV light (UVB,
PUVA) may be used in the first three weeks
of treatment with Fumaderm initial.
Summary evaluation
Out of 13 evaluated studies, nine met
the criteria for inclusion in the guidelines. After 16 weeks, 50 - 70 % of
patients achieved PASI 75 (EL 2).
Fumaric acid esters are suitable for
long-term therapy.
The clinical experience with fumaric
acid esters is much greater than the
documentation of efficacy and safety
of their use in clinical studies.
Clinical use of the drug is limited by
gastrointestinal effects and symptoms
of flush.
The feasibility for the doctor and patient is good.
An advantage of fumaric acid esters is
their low rate of drug interactions.
Fumaric acid esters may be recommended for induction therapy in
adult patients with moderate to
severe psoriasis vulgaris.
7.5 Infliximab
Wolfram Sterry, Volker Streit
(based on Jrg Prinz, Volker Streit)
Introduction
Infliximab (Table 40) is a chimeric
(mouse / human) monoclonal antibody
against TNF-. It is an IgG1 immunoglobulin with human sequences in the
constant regions and murine sequences
in the complementarity determining
regions of the light and heavy chains.
JDDG; 2011 9 (Suppl. 2): S1S95

Infliximab

Infliximab
Approval in Germany
2004 (psoriatic arthritis)/

Recommended control
parameters
Before therapy rule out tuberculosis,

during therapy: leukocyte and
thrombocyte counts, liver values,
clinical signs of infection

dosage
Response rate
Important UAEs
Misc.
5 mg/kg of body weight

5 mg/kg of body weight (initially:
infusions on day zero, week two and week
six; maintenance therapy: every eight weeks)
After one to two weeks
PASI 75 in 80 % in patients with moderate to severe psoriasis vulgaris (EL 1)
Acute or chronic infections, tuberculosis,
cardiac insufficiency NYHA III - IV
Infusion reactions, severe infections,
autoimmune phenomena
Anakinra
-
Infliximab belongs to the group of selective immunosuppressants.

In dermatological diseases, infliximab is
approved for use in adults with moderate
to severe plaque psoriasis who have not
responded to other systemic therapies
(incl. cyclosporine, MTX, and PUVA) or
in whom these treatments are contraindicated or are not tolerated. Infliximab is
also approved for use in patients with active and progressive psoriatic arthritis
that has not responded adequately to
disease-modifying antirheumatic drugs.
Mechanism of action
Infliximab binds specifically to soluble,
transmembranous and receptor-bound
TNF-. Binding blocks soluble TNF-
and its proinflammatory activity is neutralized. Binding to membrane cellbound TNF- causes elimination of
affected cells, possibly as a result of
complement activation and / or antibodydependent cellular cytotoxicity, or due to
induction of apoptosis.
Infliximab has a serum half-life of 8-9.5
days. The elimination time is up to six
months.
The dosage used for the treatment of
psoriasis vulgaris is weight-dependent.
JDDG; 2011 9 (Suppl. 2): S1S95

Individual doses 5 mg/kg of body weight

are given at weeks zero, two, and six, and
then every eight weeks.
The long interval between infusions increases the likelihood of antibody formation to infliximab.
Infliximab is infused intravenously. The
infusion is administered over a period of
two hours. If there is no infusion reaction, it may also be administered in one
hour. During the infusion, and for
one hour after, the patient should be
monitored with the potential for emergency intervention if an infusion reaction occurs.
Efficacy
Nine studies met the criteria for inclusion in the guidelines. Four grade A2
studies on infliximab monotherapy
[322-325], one grade B study [326], and
three grade C studies [327-329] were
included. This resulting evidence level is
1. One grade C study on combination
therapy was evaluated [269].
Monotherapy
The studies by Chaudhari et al. (EG B)
and Gottlieb et al. (EG A2) examined the
efficacy of infliximab by dosage
(3 mg, 5 mg or 10 mg/kg of body
weight), with the same treatment inter-
vals as described above [323, 326]. The

results showed that in the majority of patients infliximab achieved complete or
nearly complete clearance of psoriasis
vulgaris lesions. At a dosage of 3 mg (or
5 mg/kg of body weight), 72 % (88 %)
of patients achieved PASI 75 and 45.5 %
(57.6 %) achieved PASI 90. After
stopping therapy, it took an average 14
16 weeks until 50 % of baseline findings
were reached again [323]. The study by
Chaudhari et al. (EG B) [326] did not
show any additional increase in efficacy
for a dosage of 10 mg/kg of body weight
1 /weekly compared with 5 mg/kg of
body weight.
Studies by Reich et al. [325] and Menter
et al. [330] confirmed that infliximab demonstrates a good level of efficacy. Reich
et al. (EG A2, n = 378 U88) reported a
PASI 75 response in 80 % of patients,
and Menter et al. reported the same in
75.5 % of patients after ten weeks of infliximab 5mg/kg of body weight.
A study by Antoni et al. (EG A2) on the
treatment of psoriatic arthritis with
5 mg/kg of body weight at weeks zero,
two, six, 14, and 22, an improvement in
accompanying psoriasis vulgaris was also
noted [322]. The analysis included patients with mild to moderate psoriasis and
with body surface area involvement 3
% (baseline PASI score 11.4 12.7). In
the framework of this study, 64 % of patients with psoriatic arthritis achieved
PASI 75 and 41 % achieved PASI 90 after 14 weeks [322]. This level of improvement is much lower than for the treatment of patients with moderate to severe
psoriasis vulgaris (PASI 75 %: 88 % of
patients; PASI 90: 57.6 % of patients
after 10 weeks, Gottlieb et al. [323]).
Whether this difference is specific for
the patient sample with psoriatic arthritis or a result of the low baseline PASI, is
uncertain.
The study by Reich et al. also generated
additional data on long-term therapy.
After 10 weeks or 24 weeks, there was a
very good response both in the per
protocol analysis as well as in the ITT
analysis; PASI 75 in 80 % after 10 weeks
and in 82 % after 24 weeks. After
50 weeks, 61 % of patients in the ITT
group achieved PASI 75 as did 71 % in
the per protocol analysis [324].
Combination therapy
A study by Vena et al. (EG C, n = 10) investigated the sequential use of infliximab
S53
S54
Infliximab
and cyclosporine. Patients who had not

responded sufficiently to conventional
therapy with cyclosporine were given
two infusions two weeks apart. Afterward, beginning at week two, therapy
with cyclosporine 3 mg / kg of body
weight was given. After two weeks of
therapy there was an average reduction
in PASI score of about 56 %. After six
weeks of therapy (two infusions of infliximab, four weeks of cyclosporine)
there was an average reduction in PASI
score of around 82 %. Over the course
of treatment there was a reduction in
PASI score of 75 % after 12 weeks
and 63 % after 24 weeks. The reported
values for PASI 75 in sequential therapy
with infliximab / cyclosporine after
12 weeks is around 60 % and hence
lower than in continuous infliximab
therapy [269].
Undesirable drug interactions / Safety
There is a large amount of data on the
safety of infliximab in chronic inflammatory bowel diseases and in arthritis.
These safety data are roughly applicable
to psoriasis vulgaris. Yet prior treatments of psoriasis patients (UVB,
PUVA), which may lead to as yet
unidentified undesirable adverse effects
or risks, should still be taken into
account.
Infusion reactions
Acute infusion reactions are a commonly
reported side effect of infliximab.
Usually these reactions are mild with
chills, headache, flush, nausea, dyspnea,
or infiltration at the infusion site. The
probability of an infusion reaction is
increased in patients with infliximabspecific antibodies. Anaphylactoid reactions, irrespective of infliximab-specific
antibodies, are also possible. Thus patient monitoring with the possibility of
emergency care during infusion and for
one hour afterward is required. Serum
sickness may occur three to 12 days
following infusion.
After a long treatment-free interval,
renewed treatment initiation may lead
to arthralgia, myalgia, Quincke edema,
or other acute reactions.
Administration of an antihistamine can
help reduce or prevent a moderate infusion reaction [331]. The use of low-dose
MTX (5 10 mg/weekly), in addition to
infliximab, can reduce the formation of
infliximab antibodies [332, 333].
Infections
Infliximab therapy has been associated
with serious infections including sometimes even fatal sepsis. The use of infliximab is not advised in any patient with a
clinically relevant infection. There are
also rare reports of opportunistic infections such as listeriosis, histoplasmosis,
cryptococcosis, and pneumocystis
carinii pneumonia. The use of infliximab carries a risk of re-activation and
generalization of pre-existing latent
tuberculosis.
Cardiac effects
Infliximab has been associated with
exacerbation of existing cardiac insufficiency. The use of infliximab is not
advised in patients with pre-existing
cardiac insufficiency NYHA III I.
As with other TNF- blockers, there are
also occasional reports of an association
between infliximab and demyelinating
diseases of the central nervous system.
Multiple sclerosis may be exacerbated by
infliximab. In patients with multiple
sclerosis, infliximab should only be
administered after carefully weighing the
potential benefits and drawbacks.
Hepatotoxicity
There are isolated reports of liver damage
related to infliximab including liver failure and death. All patients had hepatitis
B infection and damage occurred from
two weeks to more than one year after
starting therapy. In psoriasis patients,

studies so far have only reported elevated
transaminase levels severe liver damage
has not yet been reported. If icterus occurs or if there is a significant increase in
serum liver enzymes, infliximab should
be discontinued.
Hematological changes
Leukopenia, neutropenia, thrombopenia,
pancytopenia, and related deaths, have
been reported in patients who have rheumatoid arthritis or Crohn disease and are
taking infliximab. If the results of a blood
count are abnormal, the patient should
be placed under clinical surveillance and
infliximab stopped if necessary.
The number of cases of lymphoma in
patients treated with anti-TNF- antibodies is reportedly minimally higher
than in control groups. The risk of other
malignancies is no greater than the risk
reported for controls. It is unclear
whether exposure to infliximab could
increase the incidence of these diseases.
Lupus erythematosus-like syndrome
Some patients who take infliximab develop antinuclear antibodies in serum and
some also develop dsDNA-antibodies.
The reversible onset of lupus erythematosus-like syndrome is occasionally reported.
A few patients taking anti-TNF-
therapy develop drug-induced lupus
erythematosus or lupus erythematosuslike syndrome. Unlike drug-induced
lupus erythematosus due to other drugs,
there are almost always anti-DNA

Very common Infections, including severe or opportunistic infections,
Common
infusion reactions, exanthem, pruritus, urticaria,
hyperhidrosis, sebostasis, increased liver transaminase
Occasionally
Anemia, leukopenia, lymphadenopathy, lymphocytosis,

lymphopenia, neutropenia, thrombopenia, lupus-like
syndrome, allergic reactions of the respiratory tract,
anaphylactic reactions, antinuclear antibodies, syncope,
bradycardia, heart palpitations, cyanosis, and arrhythmia
Rarely
Demyelinating diseases, anaphylactic shock, serum sickness;

onset or exacerbation of psoriasis, including pustular forms
of the disease (primarily palmar/plantar)
Very rarely
Liver cell damage, hemolytic anemia, thrombopenia,

agranulocytosis
JDDG; 2011 9 (Suppl. 2): S1S95

Infliximab

Before
Blood differential
Before each additional infusion
ASAT, ALAT, GT
Before each additional infusion
For suspected infections, see pre-treatment procedures
antibodies in anti-TNF- lupus erythematosus. The most important measure

in drug-induced lupus erythematosus is
to discontinue use of the TNF blocker.
The disease usually heals fully [334].
Pregnancy / teratogenicity / nursing
Immunoglobulins can pass the placental
barrier and can also be secreted in breast
milk. The use of infliximab is therefore
not advised in pregnant or breastfeeding
women. Women of childbearing age
should use adequate contraception.
For the administration of the drug,
emergency equipment should be set up
and ready to use.
If a severe infection occurs, the immunosuppressant effect of infliximab should
be recalled. Given the six-month long
elimination time, the effect can last several weeks after administration of the
last dose. Simultaneous administration
of methotrexate can help reduce the
formation of antibodies to infliximab
[332, 333].
of use
Drug interactions
Based on the results of studies with etanercept, in which combination therapy with
anakinra (an IL-1 R antagonist) led to serious infections without any added clinical
benefit, the combination of infliximab and
anakinra is not advised. Based on the manufacturer information, there are no targeted studies on the use of infliximab and
drug interactions with other medications.
Notes on use
See Table 42.
Exclude acute infection
Certain exclusion of tuberculosis
based on current recommendations
of the Paul Ehrlich Institute [235],
see Appendix 2
If warranted by the patient history
or clinical or laboratory chemical
signs, rule out HIV infection or viral
hepatitis.
Reliable contraception / rule out pregnancy in women of childbearing age
potential for severe and atypical
infections and should seek prompt
medical attention if symptoms occur.
Cardiac insufficiency NYHA grade
III - IV
Known hypersensitivity to mouse
proteins
Pre-existing tuberculosis or other
severe infections

Monitoring of the patient up to one
hour after infusion
Monitoring of the patient for infections; if infection is suspected, treatment should be interrupted

Malignancy (except for basal cell cancer) and lymphoproliferative diseases,
also in the patient history
Live vaccines
Autoimmune diseases
Demyelinating processes

Individual dosages up to 20 mg/kg of
body weight are tolerated without any
toxic effects. In the event of an overdose,
the patient should be closely monitored
and any symptoms quickly and adequately treated.
JDDG; 2011 9 (Suppl. 2): S1S95

None

Infusion therapy with infliximab requires
surveillance for several hours and specific
infusion management. Yet the interval
between infusions is long and thus allows
for unlimited participation in social life.
The drug should be stored in a cool
(2 8C) place. This limits feasibility, for
instance in terms of travel.
Costs
The daily costs of the drug for the treatment of an 80 kg patient with infliximab
(5 mg/kg of body weight) at weeks zero,
two, six, 14, 22, 30, 38, 46, and 54 are
92.13 [23]. This corresponds to annual
therapy costs of 33,627.36 . At the same
dosage, the drug costs for infliximab
therapy, per infusion, are 3,835.30 . The
drug costs of 12-week induction therapy
(three infusions) are 11,505.90 .
Clinical studies have shown a good level
of efficacy in patients with nail involvement [324, 335-337].
There are indications that infliximab is
not only effective in psoriasis vulgaris,
but also in erythrodermic psoriasis and
pustular psoriasis. Antibodies to infliximab develop in 10 30 % of patients
[338]. Affected patients have an increased risk of infusion reactions and the effectiveness of the drug is diminished.
Summary evaluation
Out of 15 evaluated studies, nine met
the criteria for inclusion in the guidelines. This includes six studies from the
research for the European S3 Psoriasis
guideline.
After 10 weeks of infliximab therapy
(5 mg/kg of body weight at the usual
intervals), 75 - 88 % of patients with
moderate to severe psoriasis achieve
PASI 75 (EL 1). Infliximab is one of
the most effective treatments available
for induction therapy in psoriasis
vulgaris. Infliximab is also suitable for
long-term therapy. Based on data from
available studies, the efficacy of longterm therapy may diminish in some
psoriasis patients after 24 weeks of treatment. The use of TNF- antagonists
can be especially useful in patients
with psoriatic arthritis. There are also
indications that infliximab may be suitable for the treatment of severe, rare
forms of psoriasis.
S55
S56
Infliximab/Methotrexate
Several safety aspects must be taken

into consideration for the use of infliximab. The most important are infusion
reactions and the risk of serious infection. This requires a careful assessment
of the indications for its use, and
thorough education and monitoring of
the patient.
Given the vast number of patients
who have been treated with infliximab
(for other diseases as well), the risk of
adverse effects is readily assessed.
The feasibility for the patient is good.
For the doctor, the effort involved is
increased by the need for infusion
management.
Therapy should be given continuously
every eight weeks in order to prevent
more frequent infusion reactions as
can occur with episodic administration.
Combination therapy with infliximab
and MTX may help prevent the formation of antibodies.
Infliximab is recommended for
induction therapy in patients
with moderate to severe psoriasis vulgaris, especially if other
forms of therapy have failed to
achieve sufficient treatment success or are contraindicated or
not tolerated.
7.6 Methotrexate
Hans-Michael Ockenfels, Wolfram Sterry
(based on Jrg Prinz, Volker Streit)
Introduction
The efficacy of folic acid antagonists in
psoriasis vulgaris was first reported in
1951 [339]. In 1971 MTX (Table 43)
was approved by the American Food and
Drug Administration (FDA) for the treatment of severe psoriasis vulgaris. MTX
is primarily given for severe, treatmentrefractory chronic plaque psoriasis as
well as pustular psoriasis and erythrodermic psoriasis [340].
Mechanism of action
Methotrexate
(4-deoxy-4-amino-10methyl folic acid) is an analogue of folic
acid. It acts as a folic acid antagonist,
competitively inhibiting the enzyme
dihydrofolate reductase. MTX has a

Methotrexate
Approval in Germany
Lantarel
Metex 7.5 / 10 mg
Metex 2.5 mg
1991 (Psoriasis vulgaris)

Blood differential (Hb, Hct, blood

differential, thrombocytes), kidney
function (serum creatinine, urea,
urine sediment), liver values (serum
transaminase), amino-terminal
propeptide of type III pro-collagen
7.5 15 mg/weekly
Recommended maintenance dosage 5 22.5 mg/weekly depending on effect

After four to eight weeks
Response rate
PASI 75 in 25 50 % of patients at the

end of the induction phase of 16 weeks
(EL 2)
Liver dysfunction, pregnancy
Important UAEs
Liver fibrosis/cirrhosis, pneumonia /

alveolitis, bone marrow suppression,
kidney damage
Multiple drug interactions (see text)
Misc.
Strict avoidance of alcohol, chest x-ray

before treatment initiation
105-fold greater affinity for dihydrofolate reductase than the natural substrate
dihydrofolic acid. It thus blocks the
transformation of dihydrofolic acid to tetrahydrofolic acid. This inhibits C1 metabolism which is important for biosynthesis of thymidine and purines and thus
DNA synthesis; at higher doses, protein
synthesis is also inhibited. The inhibition
of C1 metabolism can be reversed by giving tetrahydrofolic acid (calcium folinate, citrovorum factor) (Leucovorin).
The precise mechanism of action of
MTX in psoriasis vulgaris is still unknown. Along with antiproliferative effects, MTX also has immunomodulatory
properties. MTX is primarily eliminated
through the kidneys. The dosage must be
modified in patients with renal dysfunction.
Dosing and dosage scheme
MTX is administered in psoriasis vulgaris 1 /weekly orally or parenterally. For
oral administration, the weekly dose
should be divided into three individual
dosages to be taken 12 hours apart within 24 hours. This is intended to help reduce drug toxicity (Weinstein scheme)
[341], although the evidence on whether
this is better than once weekly administration is still insufficient. There is almost no difference between oral versus
parenteral (intramuscular, i.v., or subcutaneous) administration in terms of effectiveness and toxicity [342].
Recent studies have reported administration of an initial dose of MTX 7.5
mg/weekly which may be increased up to
22.5 mg/weekly depending on treatment
response. This maximum dosage for the
treatment of psoriasis vulgaris is based on
general recommendations and should
not be exceeded [229, 230, 254]. Some
studies report starting therapy at a higher
dose of 15 mg/weekly [229, 230] or
more.
After onset of remission, long-term
therapy may be continued with as low as
possible a dose of MTX. There are no reports in the literature on rebound effects
if MTX is abruptly discontinued [343].
JDDG; 2011 9 (Suppl. 2): S1S95

Methotrexate
There is inadequate data from studies on

whether it is necessary to taper the drug.
In patients with rheumatoid arthritis,
combination therapy with MTX and 2.5
mg folinic acid /weekly (12- 24 hours after taking MTX) or 1 mg folic acid/daily
can reduce the likelihood of side effects
requiring treatment discontinuation
(e.g., liver toxicity). A small, significant
increase in MTX is needed to maintain
the same clinical effect. In psoriasis patients there are indications that taking
daily folic acid (1 5 mg) on the days
that MTX is not administered can reduce the rate of gastrointestinal side effects [344-346]. Yet recent studies have
reported that concomitant use of folates
20 mg/week reduces the effectiveness of
MTX. Salim et al. reported an increase
in PASI score with concomitant use of
MTX plus folate compared with patients
who were given MTX alone [347]. In a
randomized cross-over study, Chldek et
al. reported a 50 % decrease in efficacy if
during the induction phase MTX plus
20 mg folate/weekly is taken compared
with patients who first received MTX
monotherapy and then 16 weeks of folates in addition [348]. These data perhaps
suggest that at least in the induction
phase, folate supplements should be
avoided.
Efficacy
inclusion in the guidelines. This included one grade A2 study on methotrexate
monotherapy [229, 230], six grade B
studies [233, 254, 256, 347-349], and
three grade C studies [341, 350, 351].
The resulting level of evidence is 2.
For combination therapy with UVB, one
grade B and one grade C study each were
included [352, 353], and for combination therapy with PUVA one grade C
study [354] and one study on the combination of etanercept and MTX (EG B)
were included [297].
Monotherapy
Many of the studies on treatment with
MTX were published in the 1960s and
1970s. The amount of clinical experience with MTX is much greater than the
documentation of its efficacy in clinical
studies.
In one monotherapy study by Heydendael (EG B) with 88 patients, after 16
weeks 40 % of patients had a 90 % improvement in PASI score and 60 % of
JDDG; 2011 9 (Suppl. 2): S1S95

patients had a 75 % improvement in

PASI score [256]. In a study by Nyfors
with 50 patients (EG C), 62 %of patients had a 95 % improvement in the
PASI score over the course of the study
and 77 % had at least a 75 % improvement in the PASI score [351].
Such good PASI scores are no longer
achievable in newer monotherapy studies. In a study by Flytstrm et al., after
12 weeks only 24 % of patients had
achieved PASI 75 [254]. A large comparison study by Revicki and Saurat compared monotherapy arms with methotrexate, adalimumab, and placebo [229,
230]. In the methotrexate arm, 35.5 %
of patients had achieved PASI 75 after 16
weeks. These studies used a lower dosage
of 7.5 mg/weekly, however. Better response rates may have been seen with higher dosages or over longer follow-up periods. In a study by Ranjan et al., PASI
75 was reported in 67 % of patients
[349]. Yet this study evaluated small
groups of patients (15 per arm) who were
given a higher MTX dosage of 15 mg per
week from the beginning.
The only study that reported length of
remission after stopping treatment was
the monotherapy study by Nyfors and
Brodthagen (EG C) [351]. Nineteen patients with complete remission were followed-up after stopping MTX. Relapse
(which was not precisely defined) was reported in nine out of 19 patients (47 %)
within three months, and in three out of
19 patients each (16 %) within six or
nine months. Four out of 19 (21 %) patients remained free of symptoms after
one year. A long-term therapy study by
van Dooren-Greebe, in which patients
were given topical therapy in addition to
MTX, there was a relapse rate of 47 %
after three months and 80 % within 12
months after discontinuing therapy
[355]. A long-term treatment study on
MTX monotherapy for one to nine years
reported that 128 out of 248 patients
had complete clearance of lesions (53 %)
and 94 out of 248 patients (38 %) had
nearly complete healing, so that in total
roughly 90 % of patients had complete
or nearly complete clearance [356]. Thus
is seems that longer-term MTX monotherapy can increase response rates. Due
to lacking data on the induction phase,
these long-term therapy studies were not
included in the systematic evaluation of
the efficacy of induction therapy with
MTX.
Combination therapy
MTX plus phototherapy
Combination therapy with UVB phototherapy or PUVA can enhance the effectiveness of MTX. In an open combination study by Morison et al. (EG C) with
MTX / PUVA in 30 patients, 93 % of
patients experienced complete remission
after an average of 5.7 weeks [354].
The side effects specifically related to the
combination of MTX with UV therapy
are not yet defined and require longterm study. One potential side effect of
combined MTX / PUVA therapy is increased phototoxicity. There was no observable increase in phototoxicity, however, in a MTX / UVB combination
therapy study by Paul et al. (EG C)
[353]. Nevertheless, there are preliminary indications that MTX could mediate increased phototoxicity of UVB radiation.
Combination therapy with MTX and
etanercept
Especially in patients who have not responded adequately to MTX, the effectiveness of the drug may be significantly
enhanced by the addition of 50 mg etanercept twice weekly for 12 weeks followed by 25 mg 2 /weekly for another
12 weeks. In a study by Zachariae, 55 %
of patients who were given combination
therapy with MTX and etanercept over
the entire course of the study achieved
PASI 75 after 12 weeks. The same was
true for only 25 % of patients who were
given MTX monotherapy for the first
four weeks [297]. In the 25 patients studied, the use of combination therapy
with etanercept and MTX did not lead
to any notable difference in terms of side
effects compared with the results for each
drug given as monotherapy.
Undesirable drug interactions / safety
Liver toxicity is the most important adverse effect limiting the use of MTX. In
general the risk of liver fibrosis or cirrhosis occurring with a cumulative dosage of
1 1.5 g is very low. Yet some authors
have reported that these side effects can
occur independently of the dose or
length of therapy [351, 355, 357, 358].
In terms of long-term safety, most studies focus on pathological liver changes
(liver fibrosis and liver cirrhosis). The results of the studies vary considerably
with fibrosis rates of 1 50 % and
cirrhosis rates of 0 25 %. Alcohol
S57
S58
Methotrexate
consumption, obesity, hepatitis, a positive family history for hereditary liver disease, and diabetes mellitus increase the
risk of liver toxicity [359, 360]. It is generally agreed that the probability of liver damage can be reduced by strictly
avoiding additional toxic influences
[342, 361-367].
The assessment of the risk of severe liver
damage due to MTX and the resulting
recommendations are clearer and simpler
than previously as a result of the use of
imaging techniques and also the measurement of serum levels of amino-terminal propeptide type III procollagen
(PIIINP). National medical societies as
well as the authors of the guidelines have
distanced themselves from the recommendation of a liver biopsy at cumulative doses of 1.5 g MTX or more. Highresolution ultrasound and measurement
of amino-terminal propeptide type III
procollagen (PIIINP) are non-invasive
diagnostic techniques that provide a
good indication of liver fibrosis in patients taking MTX. If high-dose MTX
therapy is planned, before beginning
therapy PIIINP should be measured as it
is not the absolute values but rather the
change in values that is important. It
should be recalled that test reliability
may be reduced by factors such as smoking, taking NSAIDs or other drugs, as
well as joint involvement.
Myelosuppression, acute pneumonitis,
alveolitis and pulmonary fibrosis can result in death. Myelosuppression has been
frequently reported, especially in patients with kidney insufficiency. Acute
pneumonitis and alveolitis are uncommon. A discussion with the patient about earlier symptoms (e.g., dry cough,
nausea, fever, dyspnea, and cyanosis) can
aid early detection. Progressive lung fibrosis is a rare and serious side effect of
the drug. In patients with acute dyspnea
and unproductive cough, further diagnostic studies are needed.
Hypoalbuminemia and impaired kidney
function increase the risk of undesirable
side effects. The risk of malignant tumors and lymphoma in patients taking
MTX for psoriasis vulgaris has only been
studied on smaller sample sizes. In a
study on 248 psoriasis patients who were
given MTX therapy for an average of seven (four to 14) years, Nyfors and Jensen
reported that the rate of malignant neoplasms tended to be lower than expected
[368]. A follow-up study that followed

Very common Hair loss (reversible)
Common
Nausea, fatigue, vomiting, transaminase increase
Occasionally
Fever, headache, depression, infections
Rarely
Bone marrow suppression with leukopenia, thrombocytopenia,

agranulocytosis, pancytopenia, liver fibrosis and liver cirrhosis,
gastrointestinal ulcerations, nephrotoxicity
Very rarely
Interstitial pneumonia, alveolitis
patients for up to 25 years after therapy,

and included 554 women with chorionic
carcinoma who underwent MTX monotherapy (with comparable total dosages,
but a different dosing scheme than in
psoriasis vulgaris) reported that there was
no increase in the incidence of second
tumors [369]. Thus MTX does not appear to increase the risk of malignancy.
There are no reports of increased rate of
infection or opportunistic infections.
Management of undesirable adverse effects
Indications for interrupting therapy include elevated transaminases (more than
three times normal levels), anemia, reduced leukocyte or thrombocyte counts in
peripheral blood, increased creatinine levels, acute dyspnea, cough, and serious
infections.
Decreased leukocytes or thrombocyte
counts usually occur seven to ten days after the last dose. Treatment should be
stopped if any of the following occur: severe leukocytopenia, diarrhea (dehydration), ulcerative stomatitis, nephrotoxicity or pulmonary toxicity. Increased
MCH (mean corpuscular haemoglobin)
is common side effect and is a sign of developing megaloblastic anemia. Folic
acid substitution (5 mg) on the day after
MTX is administered can help prevent
mild side effects of the drug.
for use
Patients who plan to have children
(men and women)
Pregnancy and breastfeeding
Inadequate contraception
Known hypersensitivity to methotrexate (e.g., pulmonary toxicity)
Kidney insufficiency
Prior Tbc or other serious infection
Active peptic ulcer
Hematological changes (leukocytopenia, thrombocytopenia, anemia)

Renal dysfunction
Liver dysfunction
Chronic congestive cardiomyopathy
Diabetes mellitus
History of hepatitis
Lacking patient compliance
Ulcerative colitis
Diarrhea
Gastritis
Drug interactions (Table 45)
Antibiotics can influence the intestinal
flora and impair (re)absorption of MTX.
Folic acid can diminish the effectiveness
of MTX.
Caution should be exercised when administering MTX along with other potentially hepatotoxic drugs or alcohol as well
as concomitant vaccination with a live
virus.
Notes on use
In women, MTX treatment should be
initiated immediately after the last
menstrual cycle. Women of childbearing age, as well as men undergoing
therapy, must ensure adequate contraception during therapy and for three
months afterward.
General measures
If warranted based on patient history or clinical or laboratory signs,
rule out HIV infection and viral
hepatitis.
JDDG; 2011 9 (Suppl. 2): S1S95

Methotrexate
Table 45: Drug interactions.

Mechanism
Medication
Diminished renal elimination of MTX
Cyclosporine
Salicylates
Sulfonamides
Probenecid
Penicillins
Colchicine
Cyclo oxygenase inhibitors = COX
inhibitors
Increased bone marrow and

gastrointestinal toxicity
Ethanol
Co-trimoxazole
Pyrimethamine
Chloramphenicol
Sulfonamides
COX inhibitors
Cytostatics
Displacement of MTX from plasma

protein binding
COX inhibitors
Probenecid
Barbiturates
Phenytoin
Retinoids
Sulfonamides
Sulfonylurea medications
Tetracycline
Co-trimoxazole
Chloramphenicol
Intracellular accumulation of MTX
Dipyridamole
Liver toxicity
Retinoids
Ethanol
Leflunomide
Specific measures
Inform the patient on how to take
the drug (only one day a week) and
about early symptoms of potential
adverse effects
Physical examination, detection of
skin changes typical of cirrhosis
Liver ultrasound if needed, i.e., if
there is a positive history or with detection of pathology during physical
inspection
Chest x-ray (for comparison later if
any pulmonary changes occur during therapy)
Measure serum levels of aminoterminal propeptide type III procollagen (PIIINP) before beginning
treatment.
JDDG; 2011 9 (Suppl. 2): S1S95


Contraception (women as well as
men undergoing treatment)
Laboratory controls, see Table 46
More frequent laboratory tests are
needed when increasing dosage and in
patients with an increased risk of elevated MTX levels (dehydration, diminished renal function, new drugs)
Chest x-ray: with symptoms of acute
fever, cough, dyspnea, and cyanosis;
important: MTX alveolitis
MTX may be given with supplemental folates to reduce drug toxicity. A
common treatment scheme is folate
5 mg the day after taking MTX.
Strict contraception for at least three
months after therapy (men and women)

The cumulative MTX dose should be
documented. Toxic MTX serum levels
are >10 8 mol/liter for bone marrow
and 5 10 9 mol/liter for the gastrointestinal epithelium.
If there is the slightest suspicion of an
overdose, prompt administration of calcium folinate / folic acid (Leucovorin)
is needed: 20 mg (10 mg/m2), given parenterally (intramuscular, i.v. route) or
orally. The absorption of orally administered calcium folinate depends on a saturation mechanism. At dosages exceeding 40 mg the oral bioavailability is
diminished. At these levels parenteral administration is necessary. Therapy
should be given as quickly as possible
(within four hours); the longer the time
since administration of MTX the lower
the effect of folic acid. Serum creatinine
and MTX levels should be measured as
soon as possible and over the course of
therapy after 12 to 24 hours. The folinic
acid dose (calcium folinate) should be
adjusted according to MTX level and
kidney function. Hydration and alkylation of urine may be necessary to prevent
precipitation of MTX and its metabolites in the kidneys. Careful monitoring of
toxic effects should continue as needed,
taking into consideration hematological
effects. If the overdose is due to kidney
dysfunction, hemodialysis should be performed if necessary.
Treatment with MTX therapy requires
thoroughly educating and closely monitoring the patient, especially in the initial
treatment stages when frequent clinical
controls and laboratory tests are needed.
Patients must be made aware of early
symptoms of side effects and followedup. After the first three months, the effort involved in treatment is minimal. It
is not very time-consuming for the physician or the patient as long as the patient
responds to therapy and tolerates it well.
Costs
The daily costs of treatment with MTX
15 mg/weekly are 0.27 (fixed price)
[23]. The drug costs of 12-week induction therapy are on average 22.96 , and
the annual costs are 99.75 (costs do
not include folic acid). The additional administration of folic acid (e.g., 3 /weekly Folsan 5 mg) costs an additional 0.07
per day or 24.00 per annum.
S59
S60
Methotrexate/Retinoids

Weeks
Diagnosis
2nd
From 4th month
onward:
Before
1 month: 3rd month:
every 2 3
treatment 1 /weekly 1 every
months
4 weeks
st
Blood differential*
Liver values**
Creatinine
Pregnancy test
(urine)
Liver ultrasound
Chest x-ray
Amino-terminal
propeptide type
III pro-collagen
*
**
***
****
***
****
Hb, Hct, erythrocytes, leukocytes, blood differential, thrombocytes

ALAT, ASAT; AP, GT, albumin, bilirubin, LDH
Once yearly for dosages 15 mg/week
Before treatment and every three months in 1st year, then 1x a year if available
None.
Summary evaluation
In regard to the efficacy of methotrexate therapy in patients with psoriasis
vulgaris 14 studies met the criteria for
inclusion in the guidelines. This includes six studies from the research for
the European S3 psoriasis guideline.
After 16 weeks of treatment with
MTX 25 - 50 % of patients achieve
PASI 75 (EL 2).
The maximum efficacy of MTX is not
reached until after the induction
phase, regardless of dosing scheme.
MTX is suitable for long-term therapy.
The clinical experience with methotrexate is much greater than the documentation of its effectiveness and
safety in clinical studies.
Clinical use of the drug is limited by
severe adverse effects associated with
its use as well as very rare, but serious
idiosyncrasies.
Careful patient selection, thorough
education of the patient, strict monitoring, use of the lowest possible effective
dose (max. 22.5 mg/week), and
additional use of folic acid or folinic
acid allows for an acceptable safety
profile for MTX.
Feasibility for the doctor and patient is

limited by the need for careful monitoring of the patient during the induction
phase.
Injection therapy is preferable due to
individually variable bioavailability of
orally administered MTX. MTX is suitable for use with TNF- inhibitors.
MTX may also be used in patients with
concomitant psoriatic arthritis. Of all
systemic agents, MTX has the lowest
medication costs per day.
MTX may be recommended
for induction therapy in patients
with moderate to severe psoriasis
vulgaris.
7.7 Retinoids
Michael Sebastian, Sandra Philipp
(based on Markus Friedrich, Michael
Sebastian)
Introduction
Retinoids (Table 47) are vitamin A derivatives which have been used since the
1970s for the treatment of psoriasis vulgaris. Studies have been published on
etretinate (Tigason), acitretin (Neotigason), and isotretinoin (Roaccutan).
The first study done on etretinate was

published in 1975 and the first on acitretin in 1984. During the 1980s etretinate
fell out of favor due to its adverse effects,
the risk of birth defects, and unfavorable
pharmacokinetics. Isotretinoin is not registered for the treatment of psoriasis because it is less effective than etretinate
[370]. Because there are good studies on
acitretin, and given that etretinate is not
available in Germany, no studies on etretinate monotherapy are included. At the
same dosage, etretinate appears to be somewhat more effective than acitretin
[371-374] . Yet treatment with acitretin
involves fewer side effects, and the drug
half-life and lipophilia appear to be
much lower [375] than for etretinate.
Since 1988, of the two, only acitretin is
still sold in Germany.
Mechanism of action
The precise mechanism of retinoid action is not fully understood. Retinoids
activate receptors belonging to the
steroid receptor superfamily (RAR alpha,
beta, gamma). The ligand and receptor
complex binds to specific sites and then
modulates gene expression. Vitamin A
acid derivatives have antiproliferative
and immunomodulatory properties. In
the skin, acitretin influences mitotic activity and keratinocyte differentiation of
and slows down intraepidermal migration of neutrophilic granulocytes. Retinoids inhibit IL-6 induction of TH17
cells, which play an important role in the
pathogenesis of psoriasis and induce the
differentiation of regulatory T cells [376378].
After oral administration, 36-95 % of
the drug is absorbed in the intestine.
Acitretin is bound to albumin, is less
lipophilic, and unlike the precursor
substance it is not stored in adipose
tissue. Thus it is more rapidly excreted.
The average half-life of the drug is
two days.
Acitretin 0.3 0.5 mg/kg of body
weight/daily is initially administered for
three to four weeks. The dosage is then
adjusted according to the treatment response, usually to between 0.5 0.8 mg/
kg body weight/daily. The maximum
dose is 1 mg/kg body weight/daily. At
optimal dosages, patients have slightly
dry lips. This sign may be useful for helping to determine the optimal dosage
JDDG; 2011 9 (Suppl. 2): S1S95

Retinoids

Acitretin
Approval in Germany 1992 (Psoriasis vulgaris)
Recommended
control parameters
Blood count, liver values, kidney values, blood lipids,

glucose (initial), pregnancy test, x-ray controls of
bone status in patients undergoing long-term therapy
Recommended initial
dosage
0.3 0.5 mg/kg of body weight/daily for about

four weeks, possibly followed by 0.5 0.8 mg/kg
of body weight
Recommended
maintenance dosage
Individual dosage depending on result

and tolerability
Onset of clinical
effect
After four to eight weeks
Response rate
Highly variable and dose-dependent, partial remission

(PASI 75) in 20 - 30 % of patients (30 - 40 mg/daily)
(EL 2)
Main
contraindications
Kidney and liver damage, women of childbearing

age who plan to have children, pregnancy, nursing
Important UAEs
Hypervitaminosis A, e.g., cheilitis, xerosis, nosebleed,

alopecia, increased vulnerability of the skin
Important drug
interactions
Phenytoin, tetracycline, methotrexate, alcohol,

minipill
Misc.
Contraception up to two years after discontinuing

the drug in women of childbearing age
[379]. The duration and the dosage are

determined by disease severity and drug
tolerability. As soon as remission occurs,
one can consider stopping treatment.
Long-term therapy is generally not advised, but may be performed on a caseby-case basis.
Efficacy
inclusion in the guidelines. One grade A2
study on monotherapy [372] and seven
grade B studies [176, 277, 288, 290,
380-382] were included. The resulting
level of evidence is 2.
For combination therapy, one grade
A2 study [383], six grade B studies
[176, 277, 290, 382, 384, 385], and one
grade C study were included [386].
The efficacy of acitretin reported in the
included studies varied greatly. Evaluation was further complicated by differing
definitions of treatment success and inhomogeneous study populations.
The efficacy of low-dose ranges (20 40 mg)
should be distinguished from that of
drug dosages in higher ranges.
JDDG; 2011 9 (Suppl. 2): S1S95

Monotherapy
Gisondi et al. (EG B) treated 20 patients
with acitretin 0.4 mg/kg of body
weight/daily. After 16 weeks about 12 %
of patients achieved PASI 75 as did 30 %
of patients after 24 weeks [290]. Mittal
et al. (EG B) reported that 23 % of patients achieved PASI 75 with a dosage of
25 mg/daily for 12 weeks [382]. Caproni
et al. (EG B) achieved similar response
rates at a dosage of 0.4mg/kg body
weight/daily after 12 weeks in 27 % of
patients [288]. In a study comparing different drug dosages, Gupta et al. (EG B)
reported that none of the patients given
lower doses of 10 25 mg/kg of body
weight/daily achieved PASI 75, but in
the high-dose range of 50 75 mg/kg of
body weight/daily 25 % of patients
achieved PASI 75 after eight weeks
[381].
Kragballe (EG A2) reported marked improvement in 73 % of patients who were
given an initial dosage of 40 mg/daily increasing to up to 80 mg after four weeks;
the total duration of treatment was 12
weeks [372].
Ezquerra et al. studied 20 patients who

were given acitretin 25 mg/daily in the
first 45 days and then 25 mg every other
day and reported a PASI reduction of
47.2 % after 45 days and 50.6 % after 90
days [176]. In a study by van de Kerkhof
et al. (EG B) 59 patients were initially
treated with acitretin 20mg/daily which
was increased in 14-day intervals to 70
mg/daily. After 12 weeks, 41 % of patients had significant improvement or
complete clearance of skin lesions [277].
On the whole, the included studies showed a strong dose-dependent improvement of skin lesions. Yet the increasing
rate of adverse effects with increasing doses complicates treatment at effective
drug levels and leads to higher drop-out
rates. At lower dosages of up to 20
mg/day there were no or only mild side
effects reported, yet the therapeutic effect was insufficient [387-389].
Combination therapy
Acitretin and photo(chemo)therapy
Acitretin has synergistic effects with
photo(chemo)therapy. Clearance of psoriasis lesions occurs more rapidly at a lower dosage than with administration of
either treatment as monotherapy. For
combination therapy, oral retinoids 20
30 mg are started 10 14 days before
phototherapy. Studies have shown that
25 mg/daily of acitretin in combination
with PUVA can achieve complete remission of more than 94 % after 12 weeks
(Saurat, EG A2), and at 20 40 mg/daily
a PASI 90 score can be reached in less
than eight weeks (Lauharanta, EG B)
[383, 384]. Combination therapy with
UVB light also produces very good results. Studies have reported faster healing
of psoriatic skin lesions with the combined use of acitretin and UVB than with
UVB alone. In a study by Carlin et al.
(EG C), the combination of acitretin 25
mg/daily with daily visits to the solarium
(UVB proportion 5 %, UVA proportion
7 12 %) resulted in a PASI 75 score in
59 % and a PASI 90 score in 47 % of patients [386]. A study by zdemir et al.
with 60 patients confirmed these results.
Patients in this study were given acitretin
0.3 0.5 mg/kg of body weight/daily one
week before UV therapy. Thirty patients
each were then given either UVB phototherapy or PUVA therapy (oral PUVA).
After eight weeks of combination
therapy with acitretin and UVB or
PUVA, 56.7 % and 63.3 % of patients
S61
S62
Retinoids
achieved total remission (PASI 90)

[385].
Given that the altered stratum corneum
increases risk of dermatitis solaris due to
enhanced penetration of UV light, dosage increases should be done more carefully than with UV monotherapy. For
UVB phototherapy, exposure should begin with half the usual UVB dosage to
avoid phototoxicity.
Acitretin and calcipotriol
In a study by van de Kerkhof et al. (EG
B) 76 patients were given acitretin in
combination with calcipotriol, a vitamin
D3-analogue, and 59 control patients received only the calcipotriol base. The rates of clearance were 67 % for combination therapy and 41 % for monotherapy.
The cumulative dose of acitretin was lower in the patients who were given combination therapy and there was no difference in the rate of side effects [277].
Acitretin and etanercept
In a three-arm study by Gisondi et al.
(EG B) with 60 participants, 22 patients
were given etanercept 2 25 mg/weekly
subcutaneously, 20 were given acitretin
0.4 mg/kg of body weight/daily, and 18
patients were given a combination of etanercept 1 25 mg/weekly subcutaneously and acitretin 0.4 mg/kg of body
weight/daily. After 12 weeks of therapy,
15 % of patients who were given combination therapy achieved PASI 75 compared with 20 % who were given etanercept monotherapy and 8 % who were
given acitretin monotherapy. After 24
weeks, combination therapy with a lower
dose of the TNF inhibitor of 1 25
mg/weekly plus 0.4mg/kg of body
weight/daily acitretin yielded similar results as monotherapy with double the
dosage of the TNF inhibitor of 2 25
mg/weekly. This perhaps suggests that
combination therapy with acitretin
could potentially help reduce the dosage
of etanercept [290].
Undesirable drug interactions/safety
Clinically effective doses are often related to side effects. Most are reversible,
with the exception of hyperostoses. All
studies reported a dose-dependant
profile of undesirable adverse effects.
Cheilitis occurs in nearly 100 % of treated patients. The risk of birth defects
limits the potential for therapy in
women of childbearing age.

Very common
Hypervitaminosis A (e.g., xerosis of the skin and mucous

membranes), cheilitis
Common
Conjunctivitis (note: contact lenses), effluvium,

photosensitivity
Occasionally
Muscle, joint, and bone pain
Rarely
Gastrointestinal complaints, hepatitis, icterus,

bone changes related to long-term therapy
Ver rarely
Pseudotumor cerebri
Table 49: Prevention of UAEs.

UAE
Measure
Dry skin or mucous

membranes
Apply cream (also to nasal mucosa if needed),

eye drops, avoid wearing contact lenses
Diffuse alopecia
Inform patient of reversible nature of the side effect
Light sensitivity
Avoid exposure to sunlight, use sunscreen
Increased serum lipids

and/or liver values
Alcohol abstinence, low-fat/low-carbohydrate diet,

lipid-lowering drug (gemfibrozil or atorvastin),
if levels fluctuate: monitor frequency and
discontinue therapy if necessary
Muscle and bone pain
If symptoms persist: x-rays, NSAIDs,

avoid excessive physical activity
Generalized edema (rare) Stop treatment, order tests of kidney function
Prevention/Management of UAEs (Table 49)

If side effects occur, the dosage may be
adjusted or the drug may be divided into
two doses per day.
for use
Severe kidney or liver dysfunction
Women of childbearing age: pregnancy, nursing, desire to have children, inability to ensure adequate
contraception for up to two years
after ending treatment
Important relative contradictions
Alcohol misuse [390]
Manifest diabetes mellitus
Wearing contact lenses
Childhood
History of pancreatitis
Use of drugs to control hyperlipidemia
Arteriosclerosis
Simultaneous use of tetracyclines or
methotrexate
Drug interactions
Tetracyclines (tetracycline, doxycycline, or minocycline) and acitretin
may lead to increased intracranial
pressure (pseudotumor cerebri). The
simultaneous use of tetracyclines with
acitretin is contraindicated.
With concomitant use of phenytoin,
acitretin can displace plasma proteins
from binding sites.
Concomitant use of high-dose vitamin
A other systemic retinoids is not advised.
There is an increased risk of toxic hepatitis in patients using methotrexate.
The contraceptive effect of low-dose
progesterone pills (minipill) may
be diminished by concomitant use of
acitretin.
Notes on use
The capsules are preferably taken with
fatty meals or whole milk. In women,
therapy should commence on the second
or third day of the menstrual cycle (if the
patient had not used adequate contraception the month before) to ensure that
JDDG; 2011 9 (Suppl. 2): S1S95

Retinoids
the patient is not pregnant at the start of

treatment. In a small number of patients,
acitretin is transformed into etretinate.
This is promoted by alcohol consumption. Alcohol use must therefore be strictly avoided by women of childbearing
age while taking the drug and for two
months after discontinuing treatment.
Given the potential transformation of
acitretin to etretinate, women of childbearing age must use contraception for
up to two years after discontinuing
treatment.
Rule out alcohol misuse
Inform the patient that blood may
not be donated during therapy and
for up to one year afterward
Ask about bone and joint pain
For long-term therapy (1-2 years):
if symptoms warrant, exclude ossification by radiological examination
of the spine and joints.
For women of childbearing age: adequate contraception and avoidance
of alcohol during treatment *
Advise patients not to donate blood
for up to one year after stopping
therapy.
Women of childbearing age must
ensure effective contraception* for
up to two years after therapy
Women of childbearing age should
avoid alcohol consumption for up
to two months after ending
treatment
* The use of two contraceptive measures
is advised: e.g., condom + pill; contraceptive coil/NuvaRing + pill. Important: avoid the use of low-dose progesterone preparations (minipill) during
treatment and for two years after stopping treatment as their effectiveness is
diminished by acitretin.
Overdose / management of an overdose
An acute overdose results in the clinical
appearance of acute hypervitaminosis A
with symptoms such as headache, nausea
and/or vomiting, fatigue, irritability, and
pruritus.
Management of an overdose:
Discontinue retinoid use
JDDG; 2011 9 (Suppl. 2): S1S95


Before
treatment
Blood differential*
Liver enzymes**
Kidney values***
Triglycerides,
cholesterol, HDL****

(monthly up to 2 years
after therapy)
monthly
Glucose (empty stomach)
*
**
***
****
12
16
Simple blood count (Hb, Hct, leukocytes, thrombocytes)

ASAT, ALAT, AP, GT
Creatinine, urea
Preferably measured twice on an empty stomach (2 weeks before and on
the day of treatment initiation)
Measure vital signs, liver values, kidney values, and electrolyte levels
Further measures as needed (also consultation of physicians in other specialties if necessary)
Note: The acute toxicity of acitretin is
low. In the event of an overdose, side effects are usually reversible and resolve
once the patient stops taking the drug.
After the first four weeks routine laboratory controls are performed only once a
month. Adherence /compliance are limited by the need to undergo a monthly
pregnancy test for up to two years after
ending therapy.
Costs
The daily drug costs for retinoid therapy
(35 mg/daily) are 5.20 [23]. The drug
costs for 12-week induction therapy with
Neotigason (Hoffmann La Roche,
first month 25 mg/daily, second and
third month 50 mg/daily) are 436.62
(as of June 2005).
The evaluation of pustular psoriasis and
erythrodermic psoriasis is beyond the
scope of the guidelines, yet it should be
mentioned that the use of retinoids for
the treatment of these diseases is especially effective [388, 391].
Summary evaluation
Out of 59 studies evaluated, eight meet
the criteria for inclusion in the guidelines. This includes studies on monotherapy and combination therapy
(EL 2). Seven studies were included
from the research for the European S3
Psoriasis Guidelines. The effectiveness
of low-dose retinoids as monotherapy
in moderate to severe psoriasis vulgaris
is not satisfactory. After eight to 12
weeks, at a dosage of 0.4 mg/kg of body
weight to max. 40 mg/daily, 23 30 %
of patients achieve PASI 75 (EL 2).
Although the drug is more effective at
higher dosages, the related side effects
are also often greater, with involvement
of the skin and mucous membranes.
Use of the drug is limited in women of
childbearing age due to the risk of
birth defects, the need for monthly
pregnancy tests, and having to ensure
contraception for up to two years after
stopping therapy.
One advantage of retinoids is their
synergistic effects when used in combination with UV phototherapy. The
data from the included studies are
insufficient, however. The results of a
paper by Gisondi et al. suggest potential synergistic effects in combination
therapy with retinoids and TNF
inhibitors, but larger studies are still
needed.
S63
S64
Retinoids/Ustekinumab
Due to its lacking efficacy, acitretin cannot be recommend as low-
dose monotherapy.
Acitretin cannot be recommended
for women of childbearing age
with plaque psoriasis.
7.8 Ustekinumab
Wolf-Henning Boehncke, Sandra Philipp,
Kristian Reich, Michael Sebastian, Tobias
Weberschock
Introduction
Ustekinumab (Table 51) is a recombinant
completely human IgG1 antibody. It
binds with high specificity and affinity to
the common p40 subunit of the cytokines IL-12 and IL-23. Ustekinumab is
approved for use in the treatment of moderate to severe psoriasis vulgaris in adult
patients who did not respond to other
systemic therapies including cyclosporine
A, MTX, and PUVA, or in whom these
are contraindicated or not tolerated.
Mechanism of action
Ustekinumab binds to the p40 subunit
of IL-12 and IL-23. This prevents their
interaction with the IL-12R1 receptor
on nature killer cells and T lymphocytes.
This in turn impairs the IL-12 and IL-23
signaling-dependent maturation and expansion of Th1- and Th17-cells. At 20
days the terminal elimination half time is
about the same as natural IgG1.
Ustekinumab is available as a 45 mg/
0.5 ml or 90 mg/1.0 ml injection solution in a pre-filled syringe. It is given as a
subcutaneous injection in the abdomen
or thigh. An initial dose of 45 mg is recommended in week 0, followed by a 45 mg
dose in week four and then every 12 weeks.
In patients who weigh more than 100 kg
the dosage is 90 mg per injection.
Efficacy
Monotherapy
Three studies met the criteria for inclusion in the guidelines. Three grade A2
studies on monotherapy were included.
The level of evidence is 1. No studies on
combination therapy with ustekinumab
were included.
PHOENIX-1 [392] is a phase III trial
with 766 patients who were given either

Ustekinumab
Approval in Germany
January 2009 (psoriasis vulgaris)
Recommended control
parameters
In week four, then every 8-12 weeks:

blood count and differential, GOT, GPT, GT
Recommended Initial
dosage
45 mg (for >100 kg body weight: 90 mg)

in weeks 0 and 4
Recommended
maintenance dosage
45 mg (for >100 kg body weight: 90 mg)

every 12 weeks
Six to 12 weeks; maximum efficacy

after 24 weeks
Response rate
PASI 75 after 12 weeks 45 mg: 67 % (EL 1)

(PASI 75 after 12 weeks 45 mg in patients
100kg body weight: 73 - 74 %,
PASI 75 after 12 weeks 90 mg in patients
>100kg body weight: 68 - 71 %)
Active tuberculosis or other serious

infectious diseases
Important UAEs
Infections
Important drug interactions No known interactions
Misc.
placebo or ustekinumab 45 mg (n = 255)

or 90 mg (n = 256) as a subcutaneous injection in weeks 0 and 4 and then every
12 weeks. After 12 weeks, 67 % of patients given the low dose of the drug had a
reduction in PASI score of at least 75 %
compared with 66 % who were given the
higher dose and 3 % who received placebo. After 28 weeks, 71 % of patients
treated with 45 mg and 79 % of patients
given 90 mg had a PASI 75 response.
The 255 patients in the placebo arm
were also treated with ustekinumab from
week 12 onward. 65.9 % of patients had
a PASI 75 response after 16 weeks of
therapy. Long-term therapy with ustekinumab was effective over 40 weeks of
therapy.
PHOENIX-2 [393] is another phase III
trial. After 12 weeks, 67 % of patients
who were given 45 mg achieved PASI
75 as did 76 % of patients treated with
90 mg. After 28 weeks, the corresponding values were 70 % (45 mg) and 79 %
(90 mg).
In the analysis of the efficacy data from
the PHOENIX-1 and PHOENIX-2 trials, based on 10 kg weight classes, a significantly superior efficacy was seen at
the higher dosages of 90 mg in patients
with a body weight of > 100 kg, while in
patients < 100 kg both dosages were sufficiently effective.

In a study by Gottlieb et al. [394] (EG
A2) on the treatment of psoriatic arthritis, 124 patients were given either placebo or 63 mg or 90 mg of ustekinumab
for 12 weeks. The amount of improvement as well as other skin changes was
documented. Participants needed to
have involvement of at least 3 % of body
surface area (baseline PASI: placebo:
8.45/ verum: 9.75). After 12 weeks, 53 %
of patients who were given 63 mg or
90 mg (two injections, one each in week
0 and week 4) achieved PASI 75. Given
the varying dosages of ustekinumab and
the differences in the samples with regard
to skin lesions and prior therapy, these
results cannot be compared with those
for patients who have psoriasis.
Combination therapy
There are no controlled studies on combination therapy, although the combination with topical antipsoriatic agents appears feasible and sensible.
Undesirable adverse effects
(UAE)/safety
Ustekinumab is presently only approved
for use in psoriasis. The evaluation of its
JDDG; 2011 9 (Suppl. 2): S1S95

Ustekinumab
safety is therefore based on the above-named studies as well as on smaller phase I

and phase II trials and studies on psoriatic arthritis.
In the placebo-controlled induction phases of the PHOENIX-1 and PHOENIX2 trials, the rate of common and serious
side effects related to ustekinumab was
comparable to that of placebo. The most
common side effects were:
Infections, general: 21.5 % and 31.4
% (placebo: 20 % and 26.7 %), specifically
nasopharyngitis: 6.8 % and 10.2 %
(placebo: 7.1 % and 8.6 %)
Upper respiratory infections: 2.9 %
and 7.1 % (placebo: 3.4 % and
6.3 %)
Headache: 4.6 % and 5.5 % (placebo:
2.4 % and 4.1 %)
Arthralgia: 2.4 % and 3.4 % (placebo:
2.7 % and 2.9 %)
The rates of serious adverse events were
0.8 % and 2.0 % and thus within the same
ranges as in the placebo group (0.8 % and
2.0 %). Occasional serious side effects reported in the PHOENIX-1 trial included
two infections (bilateral erysipelas of the
legs and herpes zoster), both of which were
successfully bought under control. In the
PHOENIX-2 trial, one patient given ustekinumab developed a serious infection, in
this case also erysipelas.
The rate of severe infections was low (<1
%) in subsequent phases of the study as
well. In both studies together there were
15 malignancies, including 11 cases of
skin cancer, during the total observation
period. An analysis of all safety data from
phase II and III trials on psoriasis, which
was presented to the American Food and
Drug Administration (FDA), was based
on data from 2,266 patients, of whom
70 % were treated with at least six
months of ustekinumab. There was no
association with lymphocytopenia nor
were there any cumulative toxic effects
reported. The number of reported malignancies was low and was either comparable to that of patients who were given
placebo or similar to the incidence
among healthy subjects based on epidemiological data. The same applies to serious cardiovascular events.
The long drug half-life and sustained clinical effect during injection intervals does
not allow one to draw any conclusions on
the duration of safety-related immunological effects. Infections were no more fre-
JDDG; 2011 9 (Suppl. 2): S1S95

quent at the beginning of the injection interval, when drug levels are comparable
higher, than later when they are lower. For
information on live vaccines, see below.
Pregnancy/birth defects/nursing
There are insufficient data on the use of
ustekinumab in pregnant women. It is
also unclear whether the drug can enter
breast milk. The package insert recommends that women of childbearing age
use contraception during treatment and
for up to 15 weeks after stopping ustekinumab.
Prevention/management of UAEs
Infections are among the most important side effects occurring with use of the
drug. Patients should be informed about
all early symptoms of infection.
Although there have been no reports of
tuberculosis in patients taking ustekinumab, patients should undergo screening
based on the recommendations of the
Paul Ehrlich Institute (www.pei.de) before beginning therapy [235]. Active tuberculosis is a contraindication for use of
ustekinumab. In latent tuberculosis, accompanying prevention is necessary.
The use of ustekinumab should be discontinued at least 15 weeks prior to receiving
a live vaccine. Treatment should be resumed no sooner than two weeks afterward.
Based on the manufacturers information, it is unnecessary to perform laboratory tests during ustekinumab therapy. A
blood count and a blood differential
(GOT, GPT, GT) are recommended
during week four and then every eight to
12 weeks.
Main contraindications/Limitations
for use
Absolute contraindications:
Existing tuberculosis or
serious infections
other
Important relative contraindications:

Malignancy (except for basal cell carcinoma) and lymphoproliferative diseases, also in the patient history
Live vaccines
Drug interactions
For ustekinumab, a monoclonal antibody, no chemical interactions or interactions via the cytochrome P450 system
are expected.
Notes on use
Exclude tuberculosis based on current
recommendations of the Paul Ehrlich
Institute [235], see Appendix 2
If warranted by patient history or
clinical or laboratory signs, rule out
HIV infection and viral hepatitis.
Contraception must be ensured and
pregnancy excluded in women of
childbearing age
potential for serious and atypical
infections and that they should seek
prompt medical attention if symptoms occur.
Monitoring for infection, if there
is suspicion of infection, therapy
should be discontinued, at least temporarily
Interrupt therapy if pregnancy occurs
Therapy must be administered by
trained medical personnel
None
Overdose/management of overdose
In clinical studies on other diseases, during the first 12 weeks of therapy dosages
as much as 10 higher of ustekinumab
are given as in the studies on psoriasis.
During follow-up of at least 37 weeks,
the safety profile was comparable to that
in psoriasis studies. There is no known
antidote for ustekinumab.
Treatment with ustekinumab involves
very little effort. Although self-injection
by the patient is theoretically possible,
given the high costs of each injection
ustekinumab should be administered by
the treating physician. The long injection intervals make ustekinumab treatment especially feasible. The need to
store the drug in a cool place (2 8C) limits its use when travelling.
Costs
The daily drug cost for injections of 45
mg or 90 mg ustekinumab for 12
months are 69.27 , or 25,283.08 per
year. The real drug costs within the induction period of 12 weeks (two injections) are 9,947.44 , and proportional
costs are 7,460.58 .
S65
S66
Ustekinumab/Climatotherapy
UV light exposure by sunbathing in suitable regions is also a part of climatotherapy.

Balneotherapy and climatotherapy are
frequently used together in the treatment
of psoriasis vulgaris (Table 53). Such
measures may be performed as described
at the Dead Sea, at the North or Baltic
Seas, or in the mountains.
A distinction is made between balneotherapy/heliotherapy, using natural resources (= climatotherapy), and artificial balneo-phototherapy used with a
specific type of bath (e.g., low-concentration or high-concentration salt water)
followed by phototherapy using an artificial source of UV light. Interventions
that use artificial UV lamps and/or artifical balneotherapies are evaluated in the
chapter on balneotherapy and phototherapy. This chapter focuses on the use
of natural balneotherapy and heliotherapy.

Before 1
Blood differential
Before each injection
ASAT, ALAT, GT
Before each injection
If infection is suspected, see pre-treatment procedures
About 5 % of patients taking ustekinumab (PHOENIX 1) develop antibodies
to the drug. Observations from
the PHOENIX 2 trial show that neutralizing antibodies are more common
in patients who respond poorly to
treatment.
Summary evaluation
All three of the studies that were evaluated also met the criteria for inclusion in the guidelines. All were grade
A2 studies, resulting in an evidence level of 1.
After being treated with ustekinumab
45 mg subcutaneously in weeks 0 and
4, 67 % of patients had at least a 75 %
improvement in PASI score after 12
weeks (EL 1).
Ustekinumab is highly effective against
psoriasis vulgaris during the induction
phase. In some patients, the maximum
effectiveness of the drug is not reached
until after six months of treatment.
Ustekinumab is suitable for long-term
therapy.
At present, there are data from a few
thousand patients. Based on these
data, there is no indication of an increased risk of infection. For an assessment of long-term safety, larger patient samples are needed.
patient.
Ustekinumab is recommended
for induction therapy in adult
patients with moderate to severe
psoriasis vulgaris, especially if
other therapies have been unsuccessful, are not tolerated, or
are contraindicated.
8 Other therapies
8.1 Climatotherapy
Wolf-Henning Boehncke, Martin
Schlaeger, Tobias Weberschock
Introduction
Climatotherapy (Table 53) includes the totality of all meteorological influences on the
skin. In terms of psoriasis vulgaris treatment, climatotherapy generally consists of
staying for longer periods of time in regions
with a large amount of sunlight. Several
Scandinavian countries have centers in the
Canary Islands, for instance. Balneotherapy
in natural waters is another example of climatotherapy (e.g., at the Dead Sea).
Balneotherapy with mineral-rich water is
a centuries-long tradition in Europe. The
term natural balneotherapy refers to
bathing in mineral-rich natural waters.
Classification as such is based on the chemical composition, physical properties,
and mechanisms of action [395].
Mechanism of action
Climatotherapy alone or in combination
with balneotherapy is based mainly on
the known effects of ultraviolet light (see
Phototherapy chapter). The underling
mechanism of action of balneotherapy is
largely unknown. Chemical, thermal,
and mechanical effects which may have
an effect on the immune system are under discussion.
It is impossible to cite any standardized
schemes for climatotherapies as the various

Climatotherapy
Approval in Germany
More than 200 years of clinical

experience with climate therapy
Regular inspections of the skin
Therapy schemes vary by institution /

treatment site
dosage
Therapy schemes vary by institution /

treatment site
Onset of clinical action
Highly variable
Response rate
Highly variable (EL 3)
Depend on chosen modality
Important UAEs
Depend on chosen modality
N/A
Misc.
JDDG; 2011 9 (Suppl. 2): S1S95

Climatotherapy/Psychosocial therapy
modalities differ so greatly. Generally

speaking, therapy involves highly frequent often daily use of therapy.
Efficacy
To grade C studies [396, 397] with a total of 149 patients met the criteria for inclusion in the guidelines. The resulting
level of evidence is 3.
A prospective case series by Cohen et al.
studied climatotherapy at the Dead Sea.
Treatment consisted of two highly-concentrated salt water baths per day combined with sunbathing. After an average of
two weeks, about 55 % of patients had a
75 % reduction in PASI score and 87 %
had a 50 % reduction in PASI score
[396].
A study by Harari et al. reported that the
therapeutic effect could be further increased by a longer stay at the Dead Sea.
After four weeks, all of the patients in
this study had a 50 % reduction in PASI,
76 % had a 75 % reduction in PASI, and
63 % ended the study with a 100 % reduction in PASI [397].
Any type of UV light therapy involves
the risk of UV light-related side effects.
Especially with regard to long-term safety, the potential side effects of phototherapy must be recalled (see chapter on
Phototherapy).
for use
There are established absolute and relative contraindications for various treatment schemes that include phototherapy. These correspond to those in the
chapter on phototherapy.
Absolute contraindications*
Genetic defects with increased light
sensitivity or increased risk of skin
cancer
* cf. [180]
In regard to climatotherapy, a few risk
factors are controversially discussed. For
instance, advanced age and hypertension
are not necessarily contraindications
[398].
Drug interactions
The use of drugs that can cause phototoxic or photoallergic reactions can provoke dermatitis solaris in patients under-
JDDG; 2011 9 (Suppl. 2): S1S95

going climatotherapy. Thus before initiating phototherapy, patients should be asked about the use of such drugs and
whether they may be discontinued (see
chapter on Phototherapy).
Notes on use
Climatotherapy is generally performed
at a specialized center with trained personnel. It is thus largely unproblematic.
Climatotherapy, particularly in combination with balneotherapy, is found in
certain geographic regions at specialized
centers. Unlike in other European countries, such therapies are not widespread
in Germany (e.g., at the North Sea or
Baltic Sea). Patients often greet this treatment option positively. It is also not uncommon for patients to experience a significantly decreased psychological
burden of disease during their treatment
because they are free from the stigmatization associated with the visible disease
symptoms.
Summary evaluation
Out of 39 evaluated studies, two met
the criteria for inclusion in the guidelines (EG C). The level of evidence is 3.
During a 1-4 week treatment regime at
the Dead Sea, 55 % (two weeks) and
76 % (four weeks) of patients achieved
PASI 75 (EL 3).
For combination therapy with natural
phototherapy, the efficacy and safety of
treatment are determined by the phototherapy component.
Climatotherapy is by definition performed in certain regions at specialized
clinics.
Climatotherapy, e.g., at the Dead
Sea, may be recommended as part
of integrated therapy in patients
with a long history of psoriasis
vulgaris.
Climatotherapy is not recommended for acute or short-term
therapy.
8.2 Psychosocial therapy
Gerhard Schmid-Ott, Michael Sebastian
(based on Gerhard Schmid-Ott, Markus
Friedrich, Michael Sebastian)
Introduction
Psychosocial treatment of the somatic
symptoms of psoriasis vulgaris can only
be offered as a complementary treatment
along with topical or systemic treatments. The stress experienced due to
psoriasis vulgaris varies individually, and
not every patient stands to benefit from
additional psychosocial therapy in terms
of improved skin symptoms. Clinical experience suggests that psychosocial
therapy tends to benefit patients with
chronic recurrent disease more than
those with chronic stationary psoriasis
[399].
As yet there are no systematic studies on
the improvement of quality of life due to
additional psychosocial therapy in patients with psoriasis vulgaris.
Future studies should at least aim to assess the predictive value of different levels
of subjective stress reactivity [400].
Impaired quality of life in patients
with psoriasis vulgaris
An American study by Rapp et al. reported that the influence of psoriasis vulgaris on quality of life was as strong as that
of other chronic and even life-threatening diseases (e.g., cancer, heart attack,
and chronic lung disease) [3]. Only patients with decompensated cardiac insufficiency had a significantly stronger impairment of physical health. Mental
health was much more severely impaired
only in patients with depression [3]. Several reviews have focused on the quality
of life of psoriasis patients [401, 402].
Studies on psoriasis should strive to include quality of life as a target criterion,
along with somatic and even economic
factors [401].
In a survey by the German Psoriasis Association (Deutscher Psoriasis Bund e.
V.) the general burden of disease in everyday life was reported by about 27 % of
the total 3,753 patients as minimal, by
about 45 % as problematic, and by
some 25 % as severe [2]. The Psoriasis
Disability Index (PDI) [403] measures
psychosocial and physical limitations associated with psoriasis vulgaris which are
strongly associated with a diminished
quality of life. About 50 % of study participants had mild psoriasis vulgaris
(defined as <3 % involvement of body
surface area). The average PDI was 9 (on
a scale of 0 45 = maximum impairment), about 35 % had moderate psoriasis vulgaris (3 10 % of BSA) with an
S67
S68
Psychosocial therapy
average PDI of 14, and about 15 % of respondents had severe disease (>10 %
BSA) and an average PDI of 19.
Patient education programs for
psoriasis vulgaris
Given the considerable psychosocial burden of disease, for a large number of patients with plaque psoriasis, educational
programs are an important and economical form of additive psychosocial treatment of disease. Under the auspices of
the Working Group on Dermatological
Prevention (Arbeitsgemeinschaft Dermatologische Prvention [ADP]), educational programs have been developed
within the framework of an interdisciplinary and interprofessional consensus
conference. Details on the Education
of Patients with Chronic Inflammatory
Dermatoses are found in Table 54.
The main goal of such programs is to
help participants understand the contents and background of scientifically validated data and therapies for psoriasis
vulgaris and to evaluate these and make
use of them for themselves.
The goals of patient education, modified
after Schmid-Ott et al. [404] are:
Increase treatment motivation
Increase self-efficacy
Adequate management of disease
Emphasize the patients own resources
Increase patient competence in dealing with the disease
Promote patients sense of responsibility
Prevent progressive disease
Avoid delayed sequelae and reduce
psychosocial costs related to disease
Support acute medical care
More efficient use of healthcare resources
Education may be done on an outpatient
basis and close to the patients home,
e.g., in a doctors private practice, or in a
day clinic, or in the framework of a hospital rehabilitation program.
The need for participation in a patient
education program is determined by the
treating clinician or private practice dermatologist. The diagnosis of psoriasis
vulgaris should be confirmed and the
patient should have at least a 6-month
history of disease. Patients should be
able to attend regularly. For patients
with chronic or chronic recurrent disease, it is advisable plan to participate
in the program when symptoms are

absent or minimal.
It is very important that the program
transmits not just theoretical knowledge
of the dermatological disease, but also
that it conveys ideas on how to manage
it. Patients should learn things that are
important for their own behavior such as:
How long can I treat my symptoms alone
and when should I consult a doctor? In
addition, patients with psoriasis vulgaris
often experience the exchange with
others who have the disease as a relief as
there is usually greater understanding
than with normal or healthy people.
The behavioral and communications
training (psychological portion of patient education) is concerned with recognizing positive and negative ways of
managing the disease, that is, how to deal
with anxiety, stress, embarrassment, and
stigmatization. This involves not only discussing certain situations, but also roleplaying. In addition, participants are introduced to systematic relaxation
techniques which are a proven method of
stress reduction. Along with theoretical
knowledge, participants can also practice
progressive muscle relaxation techniques
(based on Jacobson) during the course.
Based on current clinical experience with
patient education classes for people with
chronic skin diseases, most patients seem
to consider such programs useful. The
possibility to ask questions without any
time pressure is especially welcomed by
patients. Even if such seminars cannot
heal psoriasis vulgaris, they may make
dealing with the disease easier, or help improve the condition of the skin, or even
lengthen the intervals between relapse.
Mechanism of action
As yet there are no studies on the mechanism of action of psychosocial therapy.
The significant stress-induced increase in
cytolytic CD8+/ CD16-/ CD11b+ T
lymphocytes and their significant
decrease one hour after stress, has been
detected in blood tests from psoriasis patients but not in healthy subjects [405].
This suggests a potential pathophysiologically relevant mechanism of the effects
of mental stress that could be reduced by
psychosocial treatment. Empirical evidence is still lacking, however.
Psychosocial therapy courses should take
place 1 /weekly, either in a group ses-
sion with meditation or as psoriasis symptom management [216, 406], or as an

individual discussion with hypnosis
[407] and based on treatment form it
should last six [406] or 20 [216] or a maximum of 13 weeks [407]. Patient education courses should be conducted by a
physician specialized in psychosomatic
medicine and psychotherapy or psychiatry and psychotherapy, or by a psychotherapist or a doctor who is also a qualified psychotherapist.
Efficacy
A total of three studies met the criteria
for inclusion in the guidelines, of which
two were grade B studies [216, 407] and
one was a grade C study [406]. The resulting level of evidence is 4.
The studies included one study on meditation [216], one on hypnosis and the
use of specific suggestions [407], and one
on (behavioral therapy) management of
psoriasis symptoms [406].
A clear positive effect of meditation in
combination with phototherapy has
been shown by Kabat-Zinn et al. (EG B)
[216]. In a study with 37 patients, in 50
% of patients treated with 3x/weekly
UVB therapy with additional meditation
exercises, the length of treatment until
complete clearance of skin lesions was
achieved decreased from 121 to 84 days,
and for 3x/weekly PUVA therapy from
112 to 78 days.
A study by Tausk et al. (EG B) contains a
strong bias, because out of the original
691 psoriasis patients contacted only 11
actually participated in the study [407].
In Fortune et al. (EG C) 93 out of 209
participated [406]. Study dropout rates
were 14 of 37, or about 38 % [216], two
out of 11, or about 18 % [407], and 35
out of 93, or 27 % [406]. It is impossible
to determine the onset of action of psychosocial therapy. Rather, the studies aimed to investigate the extent to which
psychosocial therapy may improve the
effect of topical or systemic dermatological therapy. One-year catamnesis studies
(Fortune et al., EG C, conducted a 6
month-long catamnesis [406]) are
lacking as are studies on the extent to
which longer educational programs for
patients with chronic recurrent psoriasis
vulgaris may increase the time between
exacerbations, as suggested by clinical experience.
Psychosocial therapy measures such as
psoriasis symptom management [406]
JDDG; 2011 9 (Suppl. 2): S1S95

Table 54: Psoriasis education based on ADP criteria.
Preparation
Hourly units
1 hr. dermatology
Topics
First discussion (individually), patient history, clinical examination
1 hr. dermatology
(optional: rheumatology)
Psoriasis/psoriatic arthritis
Definition, clinical appearance, etiology
Pathogenesis / pathophysiology compared with physiology
1 hr. psychology
Introduction to psychosomatic medicine physical and mental experience

Disease management,
interaction between psyche and skin.
What is stress, and how does it arise?
Individual stresses, eustress and distress,
introduction to systematic relaxation (e.g., progressive muscle relaxation /
autogenic training)
2 hrs. dermatology
Psoriasis vulgaris
Provocation factors, associated diseases, skin care, topical therapy
1 hr. dermatology
Psoriasis vulgaris
Systemic and UV therapy, climatotherapy, outpatient, partly inpatient
and inpatient rehabilitation
1 hr. psychology
Systematic relaxation, self assurance,

Role-playing I
Situations with friends and family members, e.g., vacation planning,
marginalization
Role-playing II
How do I explain psoriasis vulgaris to others? and
Meeting strangers, e.g. new customer at work.
1 hr. nutrition science
Diet / nutritional recommendations for patients with psoriasis vulgaris,

health-food diet,
Dietary recommendations for accompanying diseases,
The significance of alcohol, products consumed for enjoyment, spices, etc.
as individual triggers
1 hr. psychology
Systematic relaxation,
Role-playing III
Dealing with anger, anxiety, embarrassment, despair, and
other negative feelings.
1 hr. dermatology
Legal aspects,
Scientifically unproven treatments,
Self-help,
Testing learning success
1 hr. psychology
Systematic relaxation,
Doctor-patient relationship
Self-help
Day 1
Day 2
Day 3
Day 4
Day 5
and patient education programs (see below) have direct and indirect effects. Direct effects influence skin symptoms,
e.g., as a result of improved stress management, while indirect effects influence
the development of psoriasis vulgaris,
e.g., with improved adherence / compliance and a more rational use of standard
dermatological therapies as well as a greater sense of individual responsibility, e.g.,
prompt consultation of a dermatologist
JDDG; 2011 9 (Suppl. 2): S1S95

if there is an exacerbation of disease or

for more adequate interval therapy. The
goal of all psychosocial programs is to
improve the quality of life in patients
with psoriasis vulgaris.
Theoretically, it is possible that psychosocial therapy could worsen the somatic
symptoms or psychological well-being of
a patient. A causal classification based on
as yet unknown interactions between

therapy, condition of the skin, and additive psychological therapy is as yet not
possible.
To identify adverse psychological effects
of psychosocial therapy, psychological
symptoms should be regularly assessed
(before beginning therapy and then
every four weeks). One example is the
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anxiety measurement in the Hospital

Anxiety and Depression Scale (HADS)
[408], which was specifically designed
for patients with somatic disorders and is
now used internationally. A validated
German version of HADS is also available. In the event that this test would reveal a significant increase in anxiety or
depression, a psychotherapeutic or psychopharmacological intervention would
be needed, requiring a physician specialized in psychotherapeutic medicine or
psychiatry and psychotherapy, and if necessary, psychosocial therapy would have
to be interrupted or discontinued. It
should be mentioned that, compared
with topical and systemic therapies, an
advantage of additive psychosocial
therapy is that there are no adverse somatic effects related to use of the drug.
for use
Acute risk of suicide
Acute psychosis
Insufficient language ability
Other comorbid psychological disorders that are diagnosed independently
of psoriasis vulgaris such as anxiety or
depressive disorders
Current substance misuse
Drug interactions
Not applicable.
Notes on use
Psychosocial history, psychological
testing (see above)
Specific aspects of treatment discontinuation
The possibility of exacerbation of psychological symptoms should be considered.
These include anxiety and depression and
even suicidal tendencies. If needed, a physician specialized in psychosomatic medicine and psychotherapy or in psychiatry
and psychotherapy should be consulted.
For the dermatologist, the feasibility of
additional psychosocial therapy is often
limited. Dermatologists can, however,
ask about triggering factors and identify
possible psychosocial triggers. Symptoms
such as pruritus or a diminished sex life
can lead to depression and withdrawal

from social activities. Yet such topics are
seldom brought up by the patient. It is
thus the responsibility of the dermatologist to try to carefully sensitize the patient
to a more complete bio-psycho-social
view of the disease and to inform the patient of relevant options (education, selfhelp groups, psychotherapy, relaxation
techniques, psychosomatic basic care,
e.g., by the family doctor, etc.). Additive
psychosocial therapy should be done on
an interdisciplinary basis by a physician
for psychosomatic medicine and psychotherapy or for psychiatry and psychotherapy, a psychotherapist or a doctor
who also is specialized in psychotherapy.
The feasibility of an educational course
for the patient is limited by the amount
of time needed (1 /weekly for about
two hours). Many patients are also concerned about dual-stigmatization, i.e.,
psychosocial discrimination due to skin
symptoms as well as for being in psychotherapy which is often associated with
being crazy, dangerous, or incurable. The
interdisciplinary programs initiated by
ADP, DDG, and BVDD which consist
of five class hours (double-hours) either
1 /weekly or on two weekends on an
outpatient basis with a group, are less
stigmatizing, as is presumably Psoriasis
Symptom Management [406].
Costs
Education programs:
Costs may be calculated on the basis of
the Model plan for better prevention
and care of children and adolescents with
atopic eczema (neurodermatitis) a national, prospective multicenter project
for the development and testing of a
standardized patient education program. One course, consisting of six
double-hours, costs 400 /patient. The
costs of a comparable course for patients
with psoriasis vulgaris (five doublehours) would be 335 /patient.
Hypnosis therapy:
The costs per treatment hour (individual
treatment) are about 60 . For 26 weeks
of hypnosis, the costs would be 1,560 .
None.
Combination therapy
Psychosocial therapy is only complementary to other forms of psoriasis therapy.
Summary evaluation
Out of nine evaluated studies, three
met the criteria for inclusion in the
guidelines. The resulting evidence level
is 4.
The studies on the additive, psychosocial therapy of psoriasis patients were
grade B and C studies; there was a significant selection bias and significant
dropout rates. These factors make it
impossible to draw any valid conclusions at this point on the efficacy of treatment.
One advantage of psychosocial therapy
is the low number of adverse effects.
Psychosocial therapy in the form of
psoriasis symptom management or patient education programs can have direct effects on skin symptoms, e.g.,
with improved stress management, as
well as indirect effects on the development of psoriasis, e.g., with improved
adherence / compliance.
Both of these treatment forms require
further empirical study.
The potential effects of disease
on social, emotional, and psy-
chological aspects of life should
be considered in any patient
with psoriasis.
Patients should be informed of

the availability of self-help groups.
Patients should be informed about the possibility of participating in a structured education
program according to the re-
commendations of the Working
Group on Dermatological Prevention.
Patients with a severely impaired
quality of life, as well as repeated
severe exacerbations of psoriasis
vulgaris due to stress may be referred, if they wish, to a physician specialized in psychosoma
tic medicine and psychotherapy
or specialized in psychiatry and
psychotherapy, or to a psychotherapist or a physician who is
also a qualified psychotherapist.
JDDG; 2011 9 (Suppl. 2): S1S95

Implementation and evaluation/Interface definitions
9 Implementation and
evaluation
10 Interface definitions
Martin Schlaeger
Alexander Nast, Berthold Rzany

Implementation of the guidelines
Implementation is an important part of
the success of the guidelines. Implementation will be continued in the framework of BVDD and DDG events. The
guidelines will be disseminated by publication of the full version and a summary
(lab coat pocket guide), as well as an electronic version and a patient version.
Theoretical learning approaches as well
as social interaction should be used as
media.
Evaluation of the guidelines
and implementation strategy
The impact of the publication of treatment guidelines is difficult to measure
given that every treatment decision is
made on an individual basis. Determining whether the optimal therapy has
been selected or not is not feasible in
everyday clinical practice nor is it a helpful measurement of the usefulness of a
guideline.
Based on the goals outlined in the guidelines, however, various indications of the
awareness and use of the guidelines may
be measured. Further studies should determine whether there are changes in the
use of various therapy options according
to the recommendations of the guidelines.
Updates
The field of medicine is in constant flux
and pertinent guidelines must be continuously updated to reflect current knowledge. In terms of conventional therapies
for psoriasis vulgaris, there are no significant changes on the horizon in the coming years. But for biological therapies,
it is rather likely that revisions will be necessary.
The present guidelines are valid until
31.12.2014. Taking into consideration
the literature that will have been published by then, preparation of revisions is
done in advance. The necessity for revising individual chapters in the framework of a literature update is decided on
by the broader interdisciplinary group of
experts. Coordination of the update is
performed by the dEBM Berlin.
ICD-10 code: L40.0
JDDG; 2011 9 (Suppl. 2): S1S95

10.1 Outpatient Inpatient

The focus of the present guidelines is on
psoriasis vulgaris. A number of outpatient treatment options are available for
patients with psoriasis vulgaris and the
vast majority of patients can be adequately treated on an outpatient basis. A
limitation is the sometimes long travel
distance for highly frequent therapies
such as outpatient UV therapy. In
Germany, in 2000 about one million patients with psoriasis vulgaris were treated
on an outpatient basis. The ratio of outpatient to inpatient therapy is 50 : 1
[11]. There is a general trend toward a
decrease in hospitalization at the same
level of morbidity.
The goals of inpatient treatment of psoriasis vulgaris have changed over time.
Up to ten years ago, the goal of treatment was nearly complete clearance as
well as the acquisition of psoriasis-specific therapies. Yet compensation for hospital care, which is based on diagnosis, is
now forcing an often standardized procedure and a different definition of inpatient treatment goals. The average hospital
stay of about two weeks is only enough
time to allow for healing of psoriasis to
begin, especially in severe, treatment-resistant forms. In inflammatory disease,
flare-ups can often be stopped. It is therefore necessary to have the option of
subsequent additional outpatient therapy
or treatment at a specific center as well as
rehabilitation.
The following are the current indications
for hospitalization due to psoriasis:
Moderate to severe psoriasis vulgaris
(definition of severity: see introduction).
The indication for hospitalization is
best based on the extent of body surface
area involvement, disease activity, and
the intensity of symptoms (pruritus and
scaling).
Hospitalization is also justified after unsuccessful outpatient treatment attempts, which have been properly administered by a specialist.
Severe impairment of quality of life due
to psoriasis vulgaris, especially with lesions affecting visible sites, or severe functional impairment or restricted activity,
e.g., with involvement of the hands and
feet in certain occupations, are also indi-
cations for hospitalization or rehabilitation (disability insurance) if employment

is threatened.
Hospitalization may be considered in patients with complications due to comorbidity such as diabetes mellitus or other
organ diseases as well as physical disability.
In addition, all emergency events or rare
cases of psoriasis vulgaris, such as acute
erythrodermia, psoriasis vulgaris cum
pustulatione, or massive eruptive episodes, especially with generalized symptoms, are an indication for hospitalization.
10.2 Other areas of medicine
Dermatology general medicine
Care of patients with psoriasis vulgaris is
performed by dermatologists and general
practitioners. For general practitioners,
the diagnosis of psoriasis vulgaris is rather uncommon, at 1.3 %, while for private practice dermatologists it is a common diagnosis, at 9.4 % of men and 6.8
% of women [11].
Mild psoriasis vulgaris may be treated by
a dermatologist or a general practitioner.
If there is any uncertainty, or if warranted by the disease burden, the diagnosis
should be confirmed by a dermatologist.
This is especially important considering
that psoriasis vulgaris has life-long, farreaching personal, material, and insurance-related consequences. The quality
of life of the patient is usually severely
impaired. A dermatologist should therefore be involved in treatment planning.
If treatment is unsuccessful or if the disease progresses despite therapy, or if
there are complications such as severe pruritus, involvement of the scalp, anogenital region, or nails, the patient should
be referred to a dermatologist.
Moderate to severe forms of psoriasis
vulgaris should be treated by a dermatologist given the greater level of experience and the wide spectrum of therapy
options (e.g., UV phototherapy). Comorbidities should be taken into account
and treated in cooperation with the appropriate specialist.
Dermatology rheumatology
If there are joint symptoms and a confirmed diagnosis of psoriatic arthritis, the
patient should be referred for diagnosis
and treatment by an internist specialized
in rheumatology.
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Interface definitions/Responsibilities
Dermatology psychosomatic medicine

Patients with severe psychological distress
or repeated severe stress-related exacerbations may be referred, if they wish, to a
specialist in psychosomatic medicine who
is familiar with the problems associated
with psoriasis. Suitable specialists include
psychosomatic medicine physicians/psychotherapists and psychiatrist/psychotherapist. Psychosocial therapy is another option
(cf. Chapter on psychosocial therapies).
Responsibilities
Project leader:
Prof. Dr. med.

Berthold Rzany ScM
Project
coordination /
methods:
Dr. med. Alexander

Nast
Dr. med. Adel Sammain
Secretariat:
Martin Hussain
Med.
Ricardo Erdmann
documentation: Stefanie Rosumeck
Address:
Division of Evidence Based Medicine
(dEBM)
Klinik fr Dermatologie, Venerologie
und Allergologie
Charit Universittsmedizin Berlin
Charitplatz 1
10117 Berlin
E-mail: info@psoriasis-leitlinie.de
5+5 group
Clinical dermatologists (named by the DDG):
Prof. Dr. med. Wolf-Henning Boehncke*
deputy:
Dr. med. Tobias Weberschock
Zentrum der Dermatologie und Venerologie

Klinikum der Johann Wolfgang Goethe Universitt
Theodor-Stern-Kai 7, 60590 Frankfurt/Main, Germany
Prof. Dr. med. Ulrich Mrowietz*
Klinik fr Dermatologie, Venerologie, Allergologie

Universittsklinikum Schleswig-Holstein
Schittenhelmstrae 7, 24105 Kiel, Germany
Priv.-Doz. Dr. med. Hans-Michael Ockenfels*
Haut- u. Allergieklinik, Klinikum Hanau, Leimenstrae 20, 63540

Hanau, Germany
Dr. med. Sandra Philipp*
Klinik fr Dermatologie, Venerologie und Allergologie

Charit Campus Mitte
Charitplatz 1, 10117 Berlin, Germany
Prof. Dr. med. Wolfram Sterry*

Charit Campus Mitte
Private practice dermatologists (appointed by BVDD):

Prof. Dr. med. Kristian Reich*
Dermatologikum Hamburg Stephansplatz 5, 20354 Hamburg, Germany
Priv.-Doz. Dr. med. Thomas Rosenbach*
Lotter Strae 58 - 61, 49078 Osnabrck, Germany
Dr. med. Martin Schlaeger*
Gottorpstrae 12, 26122 Oldenburg, Germany
Dr. med. Michael Sebastian*
Bahnhofstrae 1, 15831 Mahlow, Germany
Dr. med. Volker Streit*
Neue Strae 9, 21244 Buchholz, Germany
Broader, multidisciplinary group

Pharmacoeconomics:
Prof. Dr. med. Matthias Augustin*
Universittsklinikum Hamburg-Eppendorf
Klinik und Poliklinik fr Dermatologie und Venerologie
Martinistrae 52, 20246 Hamburg, Germany
Pharmacology:
Priv.-Doz. Dr. med. Hans-Dieter Orzechowski*
Institut fr Klinische Pharmakologie und Toxikologie

Charit - Universittsmedizin Berlin
Hindenburgdamm 30, 12200 Berlin, Germany
Nursing care representative:

Sigrid Mller*
Sanaderm GmbH & Co. KG Fachklinik fr Hautkrankheiten, Allergologie und Lymphologie GmbH & Co. KG
Lffelstelzer Strae 36, 97980 Bad Mergentheim, Germany
JDDG; 2011 9 (Suppl. 2): S1S95

Responsibilities/Conflict of interest
Patient representatives:
Joachim Klaus*
Joachim Koza*
Deutscher Psoriasis Bund e.V.

Seewartenstrae 10, 20459 Hamburg, Germany
Psychosomatic medicine:
Saale Reha-Klinikum Bad Ksen
Klinik I
Am Rechenberg 18, 06628 Bad Ksen, Germany
Prof. Dr. med. Gerhard Schmid-Ott*

Moderation of consensus procedure:

Charit Campus Mitte
Prof. Dr. med. Berthold Rzany ScM
*Participants in consensus procedure who were eligible to vote

Review of medical societies (2+2 Commission)
Herr Dr. med. Martin Schlaeger
Oldenburg, appointed by BVDD
Herr Dr. med. Michael Reusch
Hamburg, appointed by BVDD
Herr PD Dr. med. Thomas Herzinger
Mnchen, appointed by der DDG
Herr Dr. med. Alexander Nast
Berlin, appointed by DDG
All rights, in particular the right to copy

and disseminate or translate the guidelines into other languages belong to the
psoriasis guidelines group for an unlimited length of time. Excerpts may not be
reproduced in any form (photocopy,
microfilm, etc.) without the written
consent of the psoriasis guidelines group,
nor may they be altered, copied or electronically disseminated.
Financial support for the guidelines

The update of the S3 guidelines on the
treatment of psoriasis vulgaris is a joint
project by the German Society of Dermatology (DDG) and the Professional
Association of German Dermatologists
(BVDD). The project was financed by
the Friends and Supporters of the
DDG. The expert panel received reimbursement for related travel costs only.
No additional financial assistance was

awarded.
The guidelines were independently edited without involvement of the sponsors.
All decisions of guidelines group were
made autonomously. Given that the
group consisted of a diverse mix of clinicians and private practice physicians
with very different potential conflicts of
interest, we believe any potential interests cancel each other out.
Acknowledgements
First and foremost we would like to
thank the German Society of Dermatology (DDG), represented by Professor
Luger, and the (BVDD), represented by
Dr. med. Reusch, whose financial and
conceptual support enabled the creation
of S3 Guidelines on the Treatment of
Psoriasis Vulgaris.
We would also like to thank all of the authors and co-authors who invested a considerable amount of time and energy in
the evaluation of the clinical studies and
formulated treatment recommendations
based on evidence-based data as well as
their own experience. Without their assistance, it would have been impossible to
create this updated S3 guideline.
We are also grateful to the participants in
the external review. Their critical evaluation and numerous suggestions ensured
that the present guidelines are clearly written and present an easily understood aid
for physicians and interested patients.
Finally, we would like to thank all of
those involved, who are not mentioned
by name, but who contributed to the
realization of the updated version of the
first dermatological S3 guideline.
Prof. Dr. med. B. Rzany
Dr. med. A. Nast
Conflict of interest
Matthias Augustin
Advisory capacity/consultant or paid collaboration in a scientific advisory board for

Abbott, Biogen Idec, Essex Pharma, Janssen-Cilag, and Wyeth.
Lecturing and training fees or paid authorship or co-authorship for Abbott, Biogen Idec,
Essex Pharma, Janssen-Cilag, and Wyeth.
Financial support (third-party funds) for research or direct financial support from employees of Abbott, Biogen Idec, Essex Pharma, Janssen-Cilag, and Wyeth.
Member of the German Society of Dermatology and the Professional Association of
German Dermatologists.
In the view of the author there is no conflict of interest.
JDDG; 2011 9 (Suppl. 2): S1S95

S73
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Wolf-Henning Boehncke
Member of the scientific advisory boards of Abbott, Essex Pharma, Janssen-Cilag, and Wyeth.
Lecture fees received from Abbott, Biogen Idec, Essex Pharma, Janssen-Cilag, Wyeth, and Serono.
Research funding by Abbott, Biogen Idec, Essex Pharma / Centocor and Wyeth.
Member of the German Society of Dermatology.
Ricardo Erdmann
Joachim Klaus
Joachim Koza
Ulrich Mrowietz
No conflict of interest.
Consultant for pharmaceutical companies whose products are mentioned in the guidelines.
Received support for research projects from companies whose products are mentioned in
the guidelines.
Member of the German Psoriasis Association, the German Society of Dermatology, and
the Professional Association of German Dermatologists.
Sigrid Mller
Alexander Nast
Lecture fees at independent symposia which were indirectly sponsored by Pfizer, Johnson
& Johnson, and Abbott.
Member of the German Society of Dermatology, the Working Group on Dermatology
Research (Arbeitsgemeinschaft Dermatologische Forschung), and the European Academy
of Dermatology and Venereology.
Hans-Michael Ockenfels
Lecturer on neurodermatitis for Klosterfrau Bedan.

Patent No. 10310913: Invention of a laser system for the treatment of skin diseases.
Member of the German Society of Dermatology and in the Professional Association of
German Dermatologists (Berufsverband der Deutschen Dermatologen).
Hans-Dieter Orzechowski
Sandra Philipp
Fees for clinical study activities, received from Abbott.
Consultant for Abbott, Merck Serono, Wyeth, Revotar, Essex Pharma, Biogen Idec, and
Janssen-Cilag.
Consultant for Pro Haut e.V.
Co-author contract with Thieme Publishers (Georg Thieme Verlag).
Member of the German Society of Dermatology, the Working Group on Dermatology
Research, and the European Academy of Dermatology and Venereology.
Kristian Reich
Advisory capacity/consultant or paid collaboration in a scientific advisory board for

Biogen Idec, Centocor, Wyeth, Pfizer, Merck, Leo, Norvartis, Essex Pharma, Intendis,
Abbott, Celgene, and Medac.
Lecture and training fees and paid authorships and co-authorships for Biogen Idec, Centocor,
Wyeth, Pfizer, Merck, Leo, Norvartis, Essex Pharma, Intendis, Abbott, Celgene, and Medac.
Paid participation in clinical studies: Biogen Idec, Centocor, Schering Plough, Abbott,
Norvartis, Celgene, and Leo.
Member of the German Society of Dermatology, the European Academy of Dermatology
and Venereology, the Working Group on Dermatology Research, Chair of the scientific
advisory board of PsoBest, and member of the scientific advisory board of the German
Psoriasis Association.
Thomas Rosenbach
Advisory capacity/consultant or paid collaboration in a scientific advisory board for Merck

Serono, Wyeth, Essex Pharma, Abbott, Janssen-Cilag, and Leo.
Lecture and training fees and paid authorships and co-authorships for Merck Serono,
Wyeth, Essex Pharma, Abbott, Janssen-Cilag, Leo, Biogen Idec, Intendis, Immedis, Horn
GmbH, and Medical Training.
Member of the German Society of Dermatology, the Professional Association of German
Dermatologists, and the German Psoriasis Association.
Stefanie Rosumeck
JDDG; 2011 9 (Suppl. 2): S1S95

Berthold Rzany
Adel Sammain
Martin Schlaeger
Advisory capacity/consultant or paid collaboration on a scientific advisory board for Wyeth

and Essex Pharma up until 2009.
Professorship sponsored by Wyeth and Biogen Idec from 2008-2010.
Review of maintenance therapy for psoriasis vulgaris commissioned by Wyeth in 2010.
Member of the German Society of Dermatology.
Member of the German Society of Dermatology and in the Professional Association of
Gerhard Schmid-Ott
Lecture fee from Pfizer on Somatopsychological and psychosomatic aspects of pain on

15 September 2010 in Detmold.
On the staff of the Hannover Medical School.
Michael Sebastian
Advisory capacity/consultant or paid collaboration on a scientific advisory board for

Abbott, Wyeth, and Janssen-Cilag.
Lecture and training fees or paid authorships or co-authorships for Abbott, Wyeth,
Janssen-Cilag, Biogen Idec, and Leo.
Wolfram Sterry

Abbott, Pfizer, Wyeth, Serono, Schering-Plough, and Allmiral.
Lecture and training fees or paid authorships or co-authorships for Abbott, Pfizer, Wyeth,
Serono, Schering-Plough, and Allmiral.
Deputy head of the German Society of Dermatology and deputy head of the guidelines
commission of the Professional Association of German Dermatologists.
Abbott, Wyeth, and Leo.
Lecture and training fees or paid authorships or co-authorships for Abbott, Wyeth, and Leo.
Member of the German Society of Dermatology and the Professional Association of
Volker Streit
Tobias Weberschock
Member of the German Network on Evidence-Based Medicine, the German Society of

Dermatology, and Guidelines International Network.
The documentation and disclosure of potential conflicts of interest was based on the standardized form Declaration of Conflicts of Interest provided by the AWMF. The completed forms are available online at http://www.psoriasis-leitline.de. Given the diversity of the
members of the guidelines group, it is assumed that any potential conflicts of interest balance each other out.
JDDG; 2011 9 (Suppl. 2): S1S95

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Glossary/References
Glossary
Adherence
The degree to which a patient follows the treatment plan decided on with the physician.
Biologics
Abbreviated form of biological products including any virus, therapeutic serum, toxin,
antitoxin, vaccine, blood, blood component or derivative, allergen, or analogous product
that may be used to prevent, treat, or cure human disease or injury (Section 21 C.F.R.
600.3 of the Code of Federal Regulations (C.F.R.) of the FDA).
Blinding
Not disclosing to study participants (i.e., patient, doctors, caregivers, or analysts) whether a
given patient is in the therapy or the control group.
Catamnesis
Follow-up of the patient and further observation after completion of therapy.
Clearance
Complete resolution of skin lesions.
Dermatitis solaris
Inflammatory reaction with reddening of the skin due to exposure to short-wave UV light.
Evidence
First-line
The Latin term evidencia actually means manifestness. In the context of evidence-based
medicine, the term means proof or confirmation and refers to data from clinical studies
that confirm or contradict other data.
First-choice therapy option.
Head-to-head-trial
Study which directly compares two forms of treatment.
Idiosyncrasy
Congenital or acquired, sometimes serious immediate hypersensitivity to specific external

substances, or acoustic or visual stimuli as well as people or objects. It is not caused by an
immune response but rather by defective or lacking enzymes.
Intention-to-treat analysis
(ITT)
Technique in which all patients assigned to a particular group are analyzed together, whether
or not they were underwent the full or partial treatment regime or were not treated at all.
Loading dose
The high initial dosage of a drug given in order to quickly reach an effective concentration
in tissue and fluids.
Number needed to treat

(NNT)
The number of patients who must be treated with a certain therapy in order to achieve an
additional treatment benefit compared with another therapy (often standard treatment or
placebo) or to avoid an additional negative event.
Off-label use
Use of a drug other than for its approved use by the German Federal Institute for Drugs
and Medical Devices (BfArM).
Psoriasis vulgaris
Synonym for psoriasis en plaque and plaque psoriasis.
Randomization
Assigning patients to intervention or control groups based on random allocation in order to

evenly distribute unknown individual variations.
Rebound
Rapid, more severe recurrence of a disease after ending therapy.
Relapse
Loss of 50 % of the initial improvement achieved by therapy.
Second-line
Second-choice therapy option.
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V. Focused UV-B narrowband microphototherapy (Biopsorin). A new treatment for plaque psoriasis. Dermatol
Ther. 2009; 22: 3835.
Peroni A, Gisondi P, Zanoni M, Girolomoni G. Balneotherapy for chronic
plaque psoriasis at Comano spa in
Trentino, Italy. Dermatol Ther. 2008;
21 Suppl 1: S318.
Halevy S, Giryes H, Friger M, Sukenik H. Dead sea bath salt for the treatment of psoriasis vulgaris: A
double-blind controlled study. J Eur
23742.
418. Calzavara-Pinton P. Narrow band

UVB (311 nm) phototherapy and
PUVA photochemotherapy: a combination. J Am Acad Dermatol. 1998;
38: 68790.
419. Markham T, Rogers S, Collins P.
Narrowband UV-B (TL-01) phototherapy vs oral 8-methoxypsoralen
psoralen-UV-A for the treatment of
chronic plaque psoriasis. Arch Dermatol. 2003; 139: 3258.
420. ul Bari A, Iftikhar N, ber Rahman S.
Comparison of PUVA and UVB
therapy in moderate plaque psoriasis.
J Pak Assoc Dermatol. 2005: 2631.
421. Serwin AB, Chodynicka B. Soluble
tumour necrosis factor-alpha receptor
type 1 as a biomarker of response to
phototherapy in patients with psoriasis. Biomarkers. 2007; 12: 599607.
422. Calzavara-Pinton P, Ortel B, Carlino
A, Honigsmann H, De Panfilis G. A
reappraisal of the use of 5-methoxypsoralen in the therapy of psoriasis.
Exp Dermatol. 1992; 1: 4651.
423. Henseler T, Wolff K, Honigsmann H,
Christophers E. Oral 8-methoxypsoralen photochemotherapy of psoriasis. The European PUVA study: a
cooperative study among 18 European centres. Lancet. 1981; 1: 8537.
424. Kaur J, Sharma VK, Sethuraman G,
Tejasvi T. Comparison of the efficacy
of psoralen ultraviolet A with narrowband ultraviolet B phototherapy for
the treatment of chronic plaque psoriasis in patients with skin types IV
and V. Clin Exp Dermatol. 2008; 33:
5135.
425. Torras H, Aliaga A, Lopez-Estebaranz
JL, Hernandez I, Gardeazabal J,
Quintanilla E, Mascaro JM. A combination therapy of calcipotriol cream
and PUVA reduces the UVA dose and
improves the response of psoriasis
vulgaris. J Dermatolog Treat. 2004;
15: 98103.
426. Valbuena MC, Hernandez O, Rey
M, Sanchez G, de Quintana LP.
Twice- vs. thrice-weekly MPD PUVA
in psoriasis: a randomized-controlled
efficacy study. Photodermatol Photoimmunol Photomed. 2007; 23:
1269.
427. Smith CH, Jackson K, Bashir SJ,
Perez A, Chew AL, Powell AM,
Wain M, Barker JN. Infliximab for
severe, treatment-resistant psoriasis: a
prospective, open-label study. Br J
Dermatol. 2006; 155: 1609.
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428. Vena GA, Cassano N, Agnusdei CP,

Bellini M, Calabretta S, Centofani S,
Cervadoro G, Coviello C, Curia S,
Dattola S, de Caro C, del Brocco L,
Donato L, Favero L, Ferrari A, Gianfaldoni R, Liguori G, Loconsole F,
Lopreiato R, Malara G, Massimino
SD, Nannipieri A, Pettinato M, Postiglione D, Postorioni C, Pronesti
ME, Provenzano E, Puglisi Guerra A,
Ricciuti F, Ruggiero G, Scudero A,

Spitaleri S, Trinca Armati F, Valenti
G, Vernaci R, Verrina F, Zagni GF,
Zappala F. Treatment of psoriasis vulgaris with calcipotriol betamethasone
dipropionate combination followed
by calcipotriol and assessment of the
adjuvant basic use of urea-based
emollients. Eur J Inflamm. 2005; 3:
3741.
429. Magliocco MA, Pandya K, Dombrovskiy V, Christiansen L, Wong Y,

Gottlieb AB. A randomized, doubleblind, vehicle-controlled, bilateral
comparison trial of bexarotene gel 1
% versus vehicle gel in combination
with narrowband UVB phototherapy
for moderate to severe psoriasis vulgaris. J Am Acad Dermatol. 2006; 54:
1158.
JDDG; 2011 9 (Suppl. 2): S1S95

Appendix 1
Appendix 1 Criteria for inclusion in the guidelines

Excerpt from the literature evaluation form (LEF)
A.
Article inclusion/exclusion:
This is a pre-screening step. If the article is not included, it is not evaluated for quality and results.
1.
First author + year:

.............................................................................................................................................................................................
2.
Language:
.............................................................................................................................................................................................
3.
Study type: prospective?

(No exclude study) yes no
If it is not described as a prospective study, the study is excluded.
4.
Study on maintenance therapy without interim results <16 weeks?

(yes exclude study) yes
no
induction and maintenance therapy study
4. a. Sequential therapy? (only applies to combination therapy)
yes
no
5.
Adult patients only?

(no/not reported exclude study)
6.
Form of psoriasis: 75 % chronic plaque psoriasis (psoriasis vulgaris)?

(no/not reported exclude study)
yes
no/not reported
Studies that fail to specify the type of psoriasis cannot be included.
The efficacy data for chronic plaque psoriasis (psoriasis vulgaris) must be reported in order to enable a separate analysis.
7.
Severity of skin lesions:

(Not reported
exclude study)
mild
moderate
severe not reported
The degree of severity must be specified. Because the guidelines also address topical therapies, studies on patients with mild
psoriasis may also be included.
8.
Type of therapy? (combination study is not evaluated separately as a monotherapy study but rather as a combination or
sequential therapy study)
Monotherapy
Combination therapy
Uncertain classification
This criterion must be strictly followed. If the use of co-medication is not reported, the study must be excluded.
9.
Plausible dosage?
(no exclude study) yes
no
Limits of customary dosages are as follows:
Whole-body PUVA: maximum four times weekly (only oral PUVA)
Methotrexate: maximum 25 mg per week
Cyclosporine: maximum 5 mg of body weight/daily (Sandimmun, Neoral)
yes
no/not reported
10. Number of patients reported who achieved remission of more than 75 % or total remission?
(no exclude study) yes
no
Systemic therapy:
Total remission 90 % improvement compared with baseline. If the article does not define total remission, one can assume
that remission is 75 % and this should be added. The results use two variables: remission 75 % and remission 90 %.
Topical therapy:
Is a measurable effect reported that can be used to estimate the efficacy of treatment (PASI, TSS, PGA, TLA, BSA)?
It is not an assessment of efficacy itself, but rather the fact that efficacy data are reported which is important.
11. Notes:
Type of article:
Review
Article should be quoted:
yes
Safety study
no
12. Additional comments:

............................................................................................................................................................................................
.............................................................................................................................................................................................
.............................................................................................................................................................................................
.............................................................................................................................................................................................
JDDG; 2011 9 (Suppl. 2): S1S95

S93
S94
Appendix 2
Appendix 2 Measures for excluding tuberculosis (scheme) modified after Diel et al. [235]
1) Patient history
Immunosuppression
Other risk factors for TB
Prior LTBI/TB
(Occupational) TB contact
Origin
BCG vaccine status
TST/IGRA status
Chest x-rays for comparison
2) Clinical examination
3) Chest x-ray in two If there are radiological signs of prior but inadequately or un-treated TB without signs of activity,
planes, CT of thorax regardless of results of IGRA test:
chemopreventive therapy with isoniazid (INH) for nine months
if needed
4) IGRA test
IGRA negative:
generally no chemoprevention
IGRA positive:
after ruling out the need for therapy: chemopreventive therapy with isoniazid (INH) for nine months
If previous exposure to someone with infectious pulmonary TB is plausible despite negative IGRA tests
and if BCG vaccine is un-likely given the patients native country.
Complementary TST
Or for equivocal results on repeated IGRA test.
Positive TST determines further procedures
Bacteriology if needed
LTBI = Latent tuberculosis infection, TB = tuberculosis, TST = Tuberculin skin test, IGRA = Interferon-Gamma Release Assay
The Interferon Gamma Release Assay (IGRA) is based on detection of INF-, which is secreted by T lymphocytes that are sensitized during a current or previous infection with mycobacterium tuberculosis (MTB).
The two commercially-available IGRA tests that are sold in Germany use direct measurement of IFN- concentration in whole
blood (QuantiFERON-TB Gold In-Tube, Cellestis, Australia; QFT) or measurement of the number of IFN- secreting T lymphocytes from isolated peripheral mononucleated cells (PBMC; T-SPOT.TB, Oxford Immunotec, Great Britain) [235].
Usually at least one of the tests is offered by routine diagnostic laboratories, or the samples are sent by the lab to one that does offer them. The QuantiFERON-TB Gold In-Tube (QFT) test requires three special tubes coated with antigen which may be obtained from the respective laboratory.
For the T Spot.TB test, 8 ml of fresh, heparinized whole blood are needed from adult patient and at least 2 - 4 ml from children.
Vacutainer Cell Preparation tubes or Standard Lithium Heparin tubes may be used. The sample must then be thoroughly shaken.
For both tests, the samples may be transported at room temperature (QuantiFERON-TB within 16 hours / T Spot.TB test within 8 hours).
For information on outpatient billing, see the resolution of the German Association of Physicians/ Health Insurers (Arbeitsgemeinschaft rzte/Ersatzkassen), 255th session (written resolution) from 24 September 2010 on the addition of fee number 32670
in section 32.3.7 of chapter 32 of the German Physician Fee Schedule (E-GO) (Resolution No. 930) effective as of 1 January
2011, Dtsch Arztebl 2010; 107(42): A-2069 / B-1801 / C-1773. For inpatient billing, see OPS Code 1930.0.
JDDG; 2011 9 (Suppl. 2): S1S95

Appendix 3
Appendix 3 Literature tables

Abbreviations used in the literature tables
1
2
+
BSA
CSA
CSSS
d
GSS
IGDA
ITT
J
KG
M
MOP
MPD
mR
n.a.
n.z.
NNT
PASI
PDI
PGA
pR
PR
RI
Tbl.
tR
TSS
UAW
W
Single-blind
Double-blind
Yes
No
Body Surface Area
Cyclosporine
Composite Sign Severity Score
Day
Global Severity Score
Investigator Global Dynamic Assessment
Intention To Treat
Years
Body weight
Months
Methoxypsoralen
Minimal Phototoxic Dose
Moderate remission
Not reported
Not applicable
Number Needed to Treat
Psoriasis Area and Severity Index
Patient Disability Index
Psoriasis Global Assessment
Partial remission
PASI reduction
Remission index
Tablets
Total remission
Total Severity Score
Undesirable adverse effects
Week
# Nr
Indicates reference number in reference list
JDDG; 2011 9 (Suppl. 2): S1S95

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Guidelines on the Treatment of Psoriasis Vulgaris

Guidelines on the Treatment of Psoriasis Vulgaris

S3 Guidelines on the treatment of psoriasis vulgaris

JDDG; 2011 9 (Suppl. 2): S1S95

patients with type 2 diabetes or chronic

Patient satisfaction with current therapies

There is inadequate use of systemic therapy

There is uncertainty concerning the use of

The economic costs of disease are high.

JDDG | Supplement 2 2011 (Band 9)

primarily for initial treatment as well as

JDDG | Supplement 2 2011 (Band 9)

fects. The choice of an effective therapy

contained in the guidelines, such as contraindications and drug interactions, is

JDDG; 2011 9 (Suppl. 2): S1S95

efficacy. The methodological quality of

JDDG; 2011 9 (Suppl. 2): S1S95

used if the therapeutic effect was longer

Table 1: Grades of evidence.

Meta-analysis containing at least one randomized grade A2 study.

Randomized, double-blind, high-quality clinical comparative study (e.g.,

Randomized clinical study of lesser quality or other comparative study

Table 2: Evidence levels.

Intervention is supported by grade A1 studies or mostly consistent

Intervention is supported by grade A2 studies or grade B studies with

Intervention is supported by grade B studies or grade C studies with

Little or no systematic empirical evidence

Table 3: Standardized wording for recommendation.

JDDG | Supplement 2 2011 (Band 9)

JDDG | Supplement 2 2011 (Band 9)

Ulrich Mrowietz, Kristian Reich

JDDG; 2011 9 (Suppl. 2): S1S95

JDDG; 2011 9 (Suppl. 2): S1S95

that can cover the entire surface area of

JDDG | Supplement 2 2011 (Band 9)

for milder disease (<5 10 % affected

JDDG | Supplement 2 2011 (Band 9)

The definition of treatment goals, and

sis. A DLQI score of less than 5 may be

JDDG; 2011 9 (Suppl. 2): S1S95

Nevertheless, the following study results

Table 4: Cost-effectiveness for biologics.

CE Nelson et al. [45]

JDDG; 2011 9 (Suppl. 2): S1S95

JDDG | Supplement 2 2011 (Band 9)

Basic treatment/Therapy options and treatment evaluation

4 Therapy options and

JDDG | Supplement 2 2011 (Band 9)

JDDG; 2011 9 (Suppl. 2): S1S95

Therapy options and treatment evaluation

JDDG; 2011 9 (Suppl. 2): S1S95

JDDG | Supplement 2 2011 (Band 9)

Therapy options and treatment evaluation

4.2.1 Topical monotherapy

JDDG | Supplement 2 2011 (Band 9)

JDDG; 2011 9 (Suppl. 2): S1S95

Therapy options and treatment evaluation

4.2.2 Phototherapy and systemic monotherapy

Table 7: Perccentage of patients achieving a PASI reduction

Table 6: Phototherapy and systemic therapy.

The evidence level applies to

JDDG; 2011 9 (Suppl. 2): S1S95