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ARTICLE IN PRESS JID: YMDA [mUS1Ga; July 12, 2018;14:21 ] Disease-a-Month 0 0 0 (2018) 1–40
Contents lists available at ScienceDirect
Disease-a-Month
journal homepage: www.elsevier.com/locate/disamonth
Biologics for the primary care physician: Review and treatment of psoriasis
Eric D. Schadler, BS a , b , ∗, Bernhard Ortel, MD a , b , Stephanie L. Mehlis, MD a , b
a University of Chicago Pritzker School of Medicine, Chicago, IL, United States b NorthShore University HealthSystem,
Department of Medicine, Division of Dermatology, 9933 Woods Drive, Skokie, IL, United States
a r t i c l e i n f o
Article history: Available online xxx
Keywords: Plaque psoriasis Biologic Clinical trials
a b s t r a c t
Psoriasis is a chronic, systemic, inflammatory disease that affects approximately 7.5 million people in the United States. The
disease results in significant suffering, morbidity, and economic impact. Psoriasis is considered a multifaceted disease with a
strong genetic component. Genetic data has revealed the presence of particular risk alleles found in patients with psoriasis.
Triggers of the disease have been eluci- dated and include factors such as trauma, obesity, infection, stress, and medications. At
its core, psoriasis is a result of a dysfunctional immune response with T-cells at the center of immunogenesis. Clinically, psoriasis
is characterized by discrete, erythematous scaly plaques. These lesions are often found on extensor surfaces, especially the
elbows and knees. Significant amounts of overlying scale due to rapid epidermal proliferation is typical of the condition. Patients
often complain of pinpoint bleeding when these scales are removed (Auspitz sign), a result of vascular dilation and
proliferation. Although extensor surfaces are the prototypical destination of lesions, psoriasis may
Abbreviations: AE, Adverse event; APL, Antigen presenting cell; BMI, Body mass index; BSA, Body surface area; CVD,
Cardiovascular disease; CZP, Certolizumab pegol; FDA, Food and Drug Administration; GWAS, Genome wide association
study; HLA, Human leukocyte antigen; HPA, Hypothalamic-pituitary-adrenal; IL, Interleukin; NF- κB, Nuclear factor-kappa
beta; OR, odds ratio; PASI, Psoriasis area and severity index; PGA, Physician global assessment; PsA, Psoriatic arthritis; PUVA,
Psoralen and ultraviolet A; QOL, Quality of life; SAE, Serious adverse event; TLR, Toll-like receptor; TNF, Tumor necrosis
factor; UVR, Ultraviolet radiation.
∗ Corresponding author at: North Shore University Health System, 9933 Woods Drive, Skokie, IL 60637, United States.
E-mail address: eric.schadler@uchospitals.edu (E.D. Schadler).
https://doi.org/10.1016/j.disamonth.2018.06.001 0011-5029/© 2018 Elsevier Inc. All rights reserved.
Please cite this article as: E.D. Schadler et al., Biologics for the primary care physician: Review and treatment of psoriasis,
Disease-a-Month (2018), https://doi.org/10.1016/j.disamonth.2018.06.001

ARTICLE IN PRESS JID: YMDA [mUS1Ga; July 12, 2018;14:21 ] 2 E.D. Schadler et al. / Disease-a-Month 0 0 0 (2018) 1–40
affect any area of the skin including the scalp, intertriginous areas, nails, palms, and soles. Location of lesions are important in
assessing the impact on quality of life for patients. These lesions also may cause itching, burning, and bleeding. Diagnosis of
psoriasis can typically be made clinically based on characteristic history and physical examination findings. In rare cases, biopsy
may be needed to rule out other papulosquamous disease. Histologic findings of psoriasis can be non-specific and include
marked epidermal hyperplasia, dilated vessels within the dermal papilla, and elongated rete ridges. Importantly, psoriasis is a
systemic disease and organ systems outside of the skin must be considered. Co- morbidities of psoriasis include psoriatic
arthritis, type 2 diabetes mellitus, cardiovascular disease, psychiatric disease, inflammatory bowel disease, neoplasms, and
ocular disease. Management of psoriasis depends on the severity of the disease. In mild to moderate cases, topical medications
are the cornerstone of treatment. Topical corticosteroids are the most commonly used and have limited systemic effects due to the
localized application of medication. In moderate to severe cases of psoriasis, topical medications are ineffec- tive and not
feasible. Phototherapy and non-biologic systemic medications have been useful treatments; however, phototherapy is time
consuming and non-biologic systemics have only modest response rates. In the last decade, biologic medications have become
an important component of care for treating moderate to severe psoriasis. These medications target various cytokines
responsible for psoriasis manifestations such as tumor necrosis factor (TNF- α), interleukin- 12, interleukin-23, and
interleukin-17. In the past 15 years, numerous biologic medications have been granted FDA approval, with the majority getting
approval in the past several years. Some of the commonly used biologics include etanercept, adalimumab, infliximab,
ixekizumab, secukinumab, brodalumab, guselkumab, ustekinumab, and tildrakizumab. Given the wealth of new biologics, current
treatment guidelines have rapidly become outdated. This review provides summarized information of landmark trials that led to
the approval of these medications.
© 2018 Elsevier Inc. All rights reserved.
Contents
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4 Epidemiology . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4 Genetics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . . . . 4 Triggering factors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5
Trauma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6 Obesity . . . . . . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6 Infections . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . 6 Medications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6 Sunlight. . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7 Stress. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . . . 7 Alcohol and smoking . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7

ARTICLE IN PRESS JID: YMDA [mUS1Ga; July 12, 2018;14:21 ] E.D. Schadler et al. / Disease-a-Month 0 0 0 (2018) 1–40 3
Endocrine factors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7 Definitions . . . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8 Clinical classification and features . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . 9 Psoriasis vulgaris . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9 Guttate
psoriasis. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9 Pustular psoriasis . . . . . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10 Erythrodermic psoriasis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
. . . . 10 Inverse psoriasis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10 Nail psoriasis . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11 Immunopathogenesis. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . . . . 12 Interleukin-17 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13
Interleukin-12 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14 Interleukin-23. . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14 Tumor necrosis factor- α . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . 14 Co-morbidities . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15 Psoriatic
arthritis (PsA) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15 Metabolic syndrome. . . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17 Cardiovascular disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
. . . . 17 Obesity & type 2 diabetes mellitus. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18 Psychological impact . . . . . . .
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18 Inflammatory bowel disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . 19 Substance abuse . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19 Neoplasms .
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19 Ocular disorders . . . . . . . . . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20 Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
. . . . . 20 Clinical aspects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20 Histological aspects . . . . .
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21 Medical management . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . . . . . 21 Biologics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22
TNF- α inhibitors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22 IL-12/IL-23 inhibitors. . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25 IL-17 inhibitors. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
26 Selective IL-23 inhibitors. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 26 Biologics in the pipeline . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 26 Management of patients on biologics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27
Topicals . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27 Phototherapy. . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 28 Oral systemics (non-biologic) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . 28 Landmark clinical trials . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 29 Etanercept. .
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 29 Adalimumab . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 30 Infliximab . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
. 31 Certolizumab pegol . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 31 Ustekinumab. . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 32 Secukinumab . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . 32 Ixekizumab . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 33 Brodalumab. .
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 33 Guselkumab . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 34 Tildrakizumab. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
34 Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 35 Financial disclosures . . . . . .
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 35 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . . . . . . . . 35

Introduction
Psoriasis is a chronic inflammatory disease historically considered a condition primarily of the skin. Although one striking
component of the condition are the characteristic scaly, erythematous papules and plaques, psoriasis is a multifaceted systemic
disease affecting patients internally, externally, and psychosocially in various manners. According to the National Psoriasis
Foundation, approximately 7.5 million Americans have a diagnosis of psoriasis. Consequently, psoriasis results in considerable
amounts of patient suffering, morbidity, and economic impact each year. This review will focus on the treatment of psoriasis
using biologic therapy. The aim is to familiarize physicians with the numerous biologic therapies that have been approved by the
FDA by highlighting the clinical trials that led to their approval. Before we get to this, however, it is important for clinicians to
have a thorough understanding of the disease. An initial review of the epidemiology, genetics, disease triggers, clinical features,
co-morbidities, and diagnosis will be presented.
Epidemiology
Psoriasis is a global disease that affects approximately 2%–3% of the world’s population. 1 Despite its worldwide reach, the
prevalence differs significantly among different ethnicities and geographic locations. In general, prevalence is largest at higher
latitudes; East Asia tends to have the lowest rates, whereas Northern Europe appears to be one the of highest. 2
From a gender standpoint, psoriasis is a disease that affects men and women without dis- cretion; however, in women the
condition tends have its onset at an earlier age. 3,4 Regardless, psoriasis may present at any age and can be subclassified based on
the age of onset. Type 1, or early-onset psoriasis, occurs before the age of 40 and encompasses approximately 70% of cases.
Within this group, a peak onset between 16 and 22 years of age exists. 5 Type 2, or late-onset psoriasis, occurs after the age of 40
and has a peak seen at 57–60 years of age. 5 Histologically, these two classifications have no distinguishable characteristics;
however, genetically there are differences that will be discussed in the section on genetics.
Reports have indicated the incidence of psoriasis may be increasing. Between the 1970s and 20 0 0, one study found that the
incidence nearly doubled. 6 It is unclear if the disease incidence has truly risen or if these reports instead demonstrate a dramatic
shift in diagnosing patterns and medical practice.
Genetics
Psoriasis is a complex disease with a multifactorial etiology. Ultimately, the interplay between genetics and exposure to a
trigging factor(s) result in manifestations of the disease. 5 Multiple studies have identified genetic loci, or psoriasis susceptibility
regions, that are implicated in the disease. Genetic linkage studies have identified 10 loci as potential psoriasis susceptibility
regions ( Table 1 ). 2 Although linkage studies are challenging to perform in complex diseases such as psoriasis, these results
provided a good starting place for future work.
Of the loci identified, PSORS1 is consistently replicated in studies and has been most thor- oughly investigated. This region
spans approximately 30 0,0 0 0 bases, contains 11 genes including human leukocyte antigen (HLA)-B and HLA-C, and is thought
to account for 35%–50% of the hereditary nature of psoriasis. 2 Nair et al. further explored this region using DNA sequencing.
They identified the HLA-C w 6 allele as the ultimate susceptibility risk allele located in the PSORS1 region. 7 As mentioned
previously, the age of onset of psoriasis differs from a genetic standpoint. Within early-onset psoriasis (type 1), over 90% of the
time HLA-C w 6 was expressed; in contrast, 50% of patients with late-onset psoriasis (type 2) and only 7% of the healthy control
population expressed the risk allele. 4 With this in mind, type 1 psoriasis can be more

Table 1 This table lists the 10 psoriasis susceptibility regions identified using linkage studies. Of these, PSORS1 has the most
supporting results.
Loci Name Location
PSORS1 6p21.3 PSORS2 17q25 PSORS3 4q PSORS4 1q21 PSORS5 3q21 PSORS6 19p13 PSORS7 1p PSORS8 16q PSORS9
4q31-34 PSORS10 18p11.23
Table 2 List of factors identified as triggers for the development of psoriasis.
Triggering Factors
Trauma Sunlight (UV light) Obesity Stress Infections Alcohol and smoking Medications Endocrine factors
accurately associated with patients who have early-onset psoriasis, a positive family history, and expression of the HLA-C w 6
allele whereas type 2 psoriasis includes patients with late-onset psoriasis, a negative family history, and lack HLA-C w 6
expression. 2
As laboratory techniques become more sophisticated, the ability to study the genetic basis of psoriasis continue to improve.
Genome-wide association studies (GWAS) are one example that have allowed for in depth analysis of the disease. Multiple
studies have taken this challenge head on and identified an additional 41 genetic loci associated with psoriasis. 2 Not only did
these studies identify genetic locations of interest, they also confirmed Nair et al. groups findings regarding the HLA-C locus.
Lastly, these studies revealed an association between psoriasis and other genes involved in inflammatory signaling. Some of
these genes include nuclear factor (NF)-kB, tumor necrosis factor (TNF) and interleukin (IL) −23/TH17 pathways. 2 Not
surprisingly, many of the loci found as a result of GWAS have been reported in other autoimmune conditions. Microarray
analysis of skin biopsy specimens is another technique that has improved our knowledge of psoriasis. Using this technique, over
1300 genes were found to be differently expressed when comparing psoriatic skin to healthy skin. 4 These analyses confirmed the
role of multiple key pathways in psoriasis pathogenesis that will be discussed in greater detail later.
From a hereditary standpoint, a positive family history is present in 35% to 90% of patients diagnosed with the disease. 4 One
study found a 41% risk of a child developing psoriasis if both parents were affected. 8 This risk decreased to 14% if only one
parent was affected, and 6% if a sibling carried the diagnosis. Using a large Danish twin registry, Lønnberg et al. found the
concordance for psoriasis was greater in both monozygotic and dizygotic twins compared to the general population. 9 In the
authors population, a monozygotic twin had an eightfold increase and dizygotic twin a fourfold increase risk compared to the
general population when their co-twin had psoriasis.
Triggering factors
The genetic component of psoriasis serves as a “primer” in disease development. Triggering factors serve as the ignition of
this primer resulting in the clinical manifestations. Table 2 shows a list of some of the known triggering factors of psoriasis.

Trauma
Heinrich Koebner recognized in 1872 that patients with psoriasis developed skin lesions in unaffected areas following trauma.
This principle is today known as the Koebner phenomenon, and helps explain the characteristic distribution of lesions on
extensor surfaces of the elbows, knees, and sacral regions. Within these areas the skin experiences continuous friction and
microtrauma resulting in epidermal damage. This disruption of the epidermis induces an inflammatory response, which in turn
leads to the development of psoriatic lesions. 10
Obesity
The psoriatic population tends to be obese. Currently, there are two viewpoints regarding the link between obesity and
psoriasis. On one hand, obesity has been shown to be a direct consequence of the disease course. Alternatively, other studies
have shown patients with obesity are at additional risk of developing psoriasis and obesity serves as a trigger. Each of these
stances have their own supporting data. More likely, these two thoughts are not mutually exclusive and both true. The Nurses’
Health Study (NHS) has evaluated obesity as a potential triggering factor. They followed a cohort of 67,300 women and over a
12-year period and found a significant association between increasing body mass index (BMI) and risk of psoriasis. 11 Compared
to women with a BMI less than 25, the relative risk of developing psoriasis was greater in women with BMI ranges of 25.0–29.9
[RR: 1.21 (95% CI, 1.03–1.43)], 30.0 to 34.9 [RR: 1.63 (95% CI, 1.33–2.00)], and 35.0 or greater [RR: 2.03 (95% CI,
1.58–2.61)]. 11 In addition to overall weight influencing psoriasis onset, changes in weight also have been shown to predispose
patients to psoriasis. Setty et al. identified a graded association between weight changes and risk of psoriasis. 12 After controlling
for other variables, patients who gained 35 pounds or more between age 18 and weight updated every 2 years experienced a
relative risk incidence of 1.88 (95% CI, 1.44–2.46) compared to patients who maintained their weight within 5 lbs.
Infections
Infections have been implicated in the pathogenesis of numerous diseases by triggering a cascade of internal changes. In
psoriasis, various infections have been shown to have an inducing and/or an exacerbating effect on the disease. Streptococcal
infections in particular have demonstrated a strong relationship to the sudden development of generalized guttate psoriasis. 13
One theory regarding the mechanism of this association involves bacterial T-cell activating toxins that induce expression of
cutaneous lymphocyte antigen (CLA), a skin homing receptor. 14 This antigen draws the inflammation to the skin resulting in
psoriatic lesions in genetically predisposed individuals. Other infections that may result in triggering psoriasis include
Staphylococcus aureus, Malassezia species, Candida, and viruses, such as human papillomavirus and human immunodeficiency
virus. 15
Medications
An array of medications can induce psoriasis in patients with susceptibility to the disease. Medications can also aggravate
existing disease. Table 3 shows a list of drug that have been implicated either as a class or from individual case reports. 10,15 For
brevity, not all drugs have been included; however, key medications to be aware of include β-blockers, lithium, non-steroidal
anti-inflammatory drugs (NSAIDs), and antimalarial agents. For further interest regarding the proposed mechanisms of action
and studies support please refer to the literature.

Table 3 Short list of drugs or classes that have been implicated in psoriasis.
Beta-blockers ∗ Lithium NSAIDs Hydroxychloroquine Cytokines ( α- and β-interferon) Antibiotics (penicillin, amoxicillin,
ampicillin, doxycycline) Psychiatric drugs (fluoxetine, olanzapine) Carbamazepine
∗ Most commonly encountered drug resulting in exacerbation
Sunlight
Ultraviolet radiation (UVR) can be used as a therapeutic agent for psoriasis; however, in some individuals, UVR can
paradoxically exacerbate the disease. 10,16 Two patterns have been established. About half of patients with sensitivity to UVR
experience a polymorphous light eruption (a hypersensitivity reaction to UVR that does not have any similarity to psoriasis
clinically), which later develops into psoriatic lesions. The other half develop psoriatic lesions without the preceding
non-psoriatic eruption. Generally, UVR is beneficial for most patients with psoriasis and likely contributes to the decreased
disease prevalence near the equator.
Stress
If you speak to a patient who suffers from psoriasis, chances are high they will attribute flares of their disease to periods of
additional stress. One study by Verhoeven et al. determined that cognitive and behavior patterns of worrying and scratching were
independently related to more severe psoriasis conditions 4 weeks later (as measured by the psoriasis area and severity index and
pruritus scales). 17 The mechanism of this is currently debated, but strong evidence has supported alterations in the
hypothalamic-pituitary-adrenal (HPA) axis responsible for regulation of stress hormones, and sympathoadrenal system
responsible for producing catecholamines. 18,19 Stress has also been established as a common trigger associated with initial
presentations of psoriasis patients. 20
Alcohol and smoking
Several studies have identified smoking habits and alcohol consumption as two environ- mental factors that play a role in the
development and worsening of psoriasis. One study performed in Italy found that the odds ratios (OR) of having psoriasis was
higher in patients who were previous or current smokers. 21 As the number of cigarettes smoked per day increased so too did the
OR’s of developing psoriasis. Additionally, examination of ex-smokers revealed a decrease in risk with increasing time since
quitting. Excessive alcohol consumption has also been associated with onset of psoriasis and severity of disease. Patients who
drink more heavily are more likely to have more severe and extensive disease, as well as higher degrees of systemic
inflammation. 22
Endocrine factors
The importance of the endocrine system on psoriasis has been briefly illustrated in the role of the HPA axis as a mediator of
the stress trigger. Additionally, some hormones have been found to affect psoriasis directly. These include androgens, prolactin,
and thyroid hormone. As

mentioned in the epidemiology section of this review, the age of onset for psoriasis has peaks near puberty and menopause –
times when hormones are in flux. Considering the skin’s ability to respond to hormonal signals, and its role as a neuroendocrine
organ, it should come as no surprise that psoriasis can be closely tied to endocrine factors.
Pregnancy is one example of a period, in which the endocrine system changes. During pregnancy there are dramatic shifts in
levels of estrogen, progesterone, and cortisol. Also, a variety of immunologic changes occur during this process. Although a
majority of pregnancy patients do well during pregnancy, they may experience new-onset, improvement, or worsening of
psoriasis. 23 In the immediate post-partum period psoriasis tends to exacerbate.
Definitions
In clinical practice, standardized definitions for psoriasis are challenging due to the spectrum of presentation and the
subjective impact of the disease on the individual. For example. is a treatment considered successful if all skin manifestations on
a patient resolve, yet they continue to have debilitating joint involvement? Despite this ambiguity, it is important from a clinical
trials standpoint to have reproducible definitions that can serve unifying and comparative purposes. Below are some common
definitions used in the psoriasis literature that may have clinical or research importance.
A. Active disease – A patient who is afflicted with one or more features of psoriasis has active
disease. B. Severity of disease – Severity is often signified based on body surface area (BSA) involvement and intensity of
plaque characteristics including erythema, induration, and scale. Practically speaking, these markers are meaningless in defining
mild, moderate, and severe disease without also considering the individual impacts on quality of life (QOL). Often these areas
are intrinsically linked, but not always. Below are proposed definitions using QOL-based definitions for mild, moderate, and
severe disase. 24
1. Mild disease – Disease that does not alter quality of life, has impacts that can be min- imized by the patient, and may not
require treatment. If treatment is required, the appropriate therapeutic classes have no serious risks. Generally, mild disease
covers less than 5% BSA. 2. Moderate disease – Disease that affects quality of life and can be improved with treatment.
Therapeutic options have minimal side effect risks. Generally, moderate disease involves between 2 and 20% BSA. 3. Severe
disease – Disease that affects quality of life and requires therapeutics that present higher risks to patients. These patients are
willing to accept more severe medication side effects and risk to improve their condition. Generally, severe disease covers
more than 10% BSA. Severe disease may be deemed a result of disease location (face, feet, hands, etc.), symptoms (sleep loss,
pruritus, bleeding, etc.), or presence of an arthritic component. C. Response – In clinical practice, response is subjective and is
defined as a decrease in the extent, severity, or an improved quality of life. An adequate clinical response is determined by
physician assessment of disease and discussions with the patient to assess their satisfaction with their disease state. D. Remission
– Complete clearing of psoriasis. 25 For majority of patients and treatments, this
is an unrealistic goal. E. Treatment success – the Medical Advisory Board defines this as a 50% improvement from
the baseline psoriasis area and severity index score (defined below). F. Relapse – In patients who previously achieved
treatment success, but then falls below the
50% improvement mark. 25

G. Rebound – This is a sudden or drastic change in severity and or character of psoriasis that is worse than prior to treatment. 25
A disease rebound may occur following withdrawal of a treatment. H. Duration of therapeutic effect – The time between stopping
a therapy and experiencing a
50% reduction in prior response. 25 I. Psoriasis area and severity index (PASI) – Used in clinical trials to quantitively evaluate
the severity of psoriasis. The score accounts for the degree of erythema, induration, and scale by rating each from 0 to 4 with 0
being “absent” and 4 being “very severe”. Investigators determine this score separately for 4 different body areas: head
(including face, scalp, and neck), upper extremities, trunk, and lower extremities (includes genital region and buttocks). In
addition to evaluating these plaque characteristics, the extent of involvement is determined for each body region and assigned a
score from 0 to 6. After each value is assigned a simple equation is used to calculate a PASI score. Raw scores range from 0 to 72
with 72 representing the most severe disease possible and 0 being completely clear.
1. PASI 75, 90, and 100 – These represent 75%, 90%, and 100% reductions – usually by
treatment – in PASI score when compared to the patient’s baseline. J. Physician global assessment (PGA) – another
assessment used in clinical trials to assign a gestalt score representing severity of disease. The assessment accounts for the same
plaque components as the PASI (erythema, induration, and scale), but does not include the extent of disease. There are 5-point
and 6-point scales that can be used. Because the PGA does not account for extent, a patient could theoretically have a miniscule
plaque with extraordinary erythema, induration, and scale resulting in a maximum PGA score, but a PASI calculation that would
be near 0. K. Serious adverse event (SAE) – used in clinical trials and defined as any medical event that results in death, requires
or prolongs a hospitalization, results in significant disability, or is a congenital abnormality.
Clinical classification and features
Psoriasis exists in a variety of clinical and anatomic phenotypes including plaque, guttate, pustular, erythrodermic,
palmoplantar, inverse, and nail psoriasis. Plaque psoriasis, or psoriasis vulgaris, accounts for an overwhelming majority of cases (
∼90%). 26 A large proportion of research aimed at psoriasis has focused on the plaque form of the disease.
Psoriasis vulgaris
Psoriasis vulgaris, more commonly referred to as plaque psoriasis, is characterized by erythematous papules that coalesce
into well-defined plaques ( Figs. 1 and 2 ). Plaques may have steep, “drop-off” edges or be relatively smooth. Silvery white scale
is characteristic of the disease. The removal of scale may result in pinpoint bleeding known as Auspitz sign. This is a
consequence of increased vascularity within the papillary dermis. Lesions tend to be located on extensor surfaces with elbows
and knees symmetrically involved in many cases.
Guttate psoriasis
Guttate psoriasis is an acute, often generalized onset of numerous, smaller sized lesions that favor the trunk and extremities.
The papules are monomorphic, and appear as droplets (“gutta” is Latin for drop). 26 Guttate psoriasis has been strongly
associated with upper respiratory, specifically streptococcal infections making this phenotype common in children and
adolescents, in whom these infections are more prevalent. Fortunately, guttate psoriasis tends to be self-limited;

ARTICLE IN PRESS JID: YMDA [mUS1Ga; July 12, 2018;14:21 ]
10 E.D. Schadler et al. / Disease-a-Month 0 0 0 (2018) 1–40
Fig. 1. Discrete plaques with thick silvery scale characteristic of plaque psoriasis.
however, some patients will go on to develop chronic plaque psoriasis. In one small study, 38.9% (n = 14) of patients with an
episode of guttate psoriasis progressed to chronic plaque psoriasis. 27
Pustular psoriasis
As the name implies, pustular psoriasis is characterized by numerous pustules overlying an erythematous base. 26
Interestingly, pustules are sterile and not a result of an infectious source. 28 Pustular psoriasis may appear in a localized
distribution or be generalized. Palmoplantar pustular psoriasis is one form of localized disease. Unfortunately, the condition is
notoriously difficult to treat and causes significant impacts on the QOL of patients due to the location. Physicians unfamiliar with
this clinical variety may be concerned about superinfection in such patients, however, due to cutaneous overexpression in
defensins, superinfection almost never happens in psoriatic skin. 29 Pustular psoriasis is sometimes induced by sudden
withdrawal of treatment, specifically, if a patient has been erroneously managed with systemic corticosteroids.
Erythrodermic psoriasis
Erythrodermic psoriasis can be a result of an escalation of preexisting psoriasis, discontinuation of therapy, a drug-reaction,
or a systemic infection. 26 It is characterized by a generalized, confluent erythema with fine scale over 90% of the patient’s body.
Erythrodermic psoriasis is an emergency and typically requires impatient management for close monitoring.
Inverse psoriasis
Inverse psoriasis differs from psoriasis vulgaris in that locations affected are often in folds such as the inframammary,
axillary, perineal, intergluteal, and inguinocrural regions. Plaques

E.D. Schadler et al. / Disease-a-Month 0 0 0 (2018) 1–40 11
Fig. 2. Psoriasis plaques may be associated with significant erythema.
tend to be erythematous and indurated, but have much less scale due to moisture in these locations. 26
Nail psoriasis
Nail psoriasis may occur in isolation; however, more commonly it is a feature in patients with psoriasis present elsewhere.
Studies have revealed that approximately 50% of psoriasis patients have nail involvement. This finding can be an important tool
in suspecting psoriatic arthritis. 30 In one study, patients with nail dystrophy were three times more likely to develop psoriatic
arthritis than those without. 31 In a different study of 69 patients with psoriatic arthritis, 83% of patients had characteristic nail
disease. 32 The results of nail psoriasis can be apparent

Fig. 3. Nail changes that may occur in patients with psoriasis including nail crumbling, oil spots, and subtle pitting.
within the nail matrix or nail bed. Involvement of the matrix is established by clinical features of nail pitting, leukonychia, red
spots in the lunula, and superficial crumbling. Nail bed involvement is characterized by onycholysis, oil-drop or salmon spots,
hyperkeratosis, and splinter hemorrhages. 30 Fig. 3 illustrates some of these changes that may be seen in patients with nail
psoriasis.
Immunopathogenesis
The pathogenesis of psoriasis has switched from being considered a disease related to a dysfunctional skin barrier toward one
with much greater complexity. Put simply, studies have supported an altered immune system as primary cause for psoriasis. At its
core, psoriasis is a T-cell mediated disease with an elaborate interplay between immune cells from the innate immune system,
adaptive system, and cytokines. Therapies targeting these keys players have proven to be effective therapeutics, further
supporting their role in psoriasis pathogenesis.
Initial pathogenesis may start with activation of the innate immune system, specifically dendritic cell activation. Dendritic
cells are antigen presenting cells (APC) that serve as a bridge between innate and adaptive immunity. 33 Within psoriatic
plaques, myeloid dermal dendritic cells appear in increased quantity implicating them in the disease process. 34 Multiple studies
by Gilliet, Lande, et al. have exhibited this process of dendritic cell activation. 35,36 Their studies suggest keratinocytes respond
to a triggering factor by producing LL37, an antimicrobial peptide, which can complex with self-DNA and RNA. Normally,
dendritic cells refrain from inappropri- ately recognizing self-DNA by two mechanisms: fast degradation of DNA by nucleases,
and the location of toll-like receptors (TLR) within endosomes. Self-DNA does not enter cells sponta- neously and therefore does
not get recognized by APC’s. However, LL37-DNA and LL37-RNA complexes can enter dendritic cells, and stimulate TLR-9
and TLR-7 respectively. This results in activation of dendritic cells to self-antigens.

After activation of the innate immune system, the adaptive immunity becomes involved. Activated dendritic cells result in the
production of numerous cytokines including IL-12 and IL-23. 37 These interleukins will be described in more detail later.
Briefly, IL-23 binds to the IL-23 receptor (IL-23R) and promotes T-cells of the Th17 class to expand. On the other hand, IL-12
acts on T-cells to induce the Th1 class of T-cells to expand.
The Th17 class is at the center of psoriasis immunopathogenesis. These cells produce a number of inflammatory cytokines
including IL-17A, IL-17F, IL-22, IL-26, IL-6, IL-21, TNF- α, and interferon- γ . 37 The IL-17 cytokine is currently a leading
target for research and therapeutics along with IL-23. Receptors to IL-17 can be found primarily on keratinocytes. 38 Stimulation
of these receptors create a host of responses, one of which is a proliferative response. More details on this important cytokine will
be described in the section below.
This loop of dendritic cell activation, increased T-cell expression, cytokine release, and keratinocyte proliferation results in
the well-demarcated plaques seen in psoriasis. Products produced by keratinocytes at the end of this process act back on dendritic
cells to cause a self-amplifying loop and perpetual inflammation. 38
In the following paragraphs we will describe the pathogenetic roles of specific molecules.
Interleukin-17
IL-17 is a proinflammatory, homodimeric glycoprotein discovered in 1993. 39 Six homogenous cytokines have since been
discovered; together they exist as a family and are labeled IL-17A through IL-17F. Genes for IL-17A and IL-17F are closely
situated on chromosome 6 and expressed simultaneously; the two cytokines share approximately 50% of their protein structure.
40 The related structure and expression of these two cytokines implies they are most likely also related in their function. IL-17A
has been found to be the most potent of the family inducing a psoriasis phenotype; however, IL-17F may also be involved.
The Th17 helper T-cell is the primary source of IL-17. Traditionally, helper T-cells were categorized as either a Th1 or Th2
class. Discovery of IL-17A led to the discovery that a unique type of helper T-cell class was responsible for its production. Using
murine models, the Th17 cell class was determined to develop from naïve T-cells when in the presence of TGF- β and IL-6. 41
Importantly, activated dendritic cells can produce all the necessary signals to initiate this maturation process to mature Th17
cells. 39
IL-17 has been implicated in numerous processes including allergy, autoimmune disease, host defense and malignancy. From
binding to the IL-17 receptor to eliciting the downstream effects, the signaling pathway of IL-17 continues to be uncovered.
Current research has supported two different pathways exist after IL-17 binding: one dependent on a ACT1 adaptor protein, and
the other independent of the adaptor. 39 ACT1 is able to interact with tumor necrosis factor receptor-associated factor 6 (TRAF6)
which subsequently activates nuclear factor (NF)- κB. This pathway plays a key role in inflammation through its ability to
induce the transcription of inflammatory genes. 41 In addition to interacting with TRAF6, ACT1 also activates p38
mitogen-activated protein kinases which are critical for stabilization of cytokine and chemokine mRNA. 39 The independent
pathway acts through Janus kinase (JAK) to alter gene transcription.
Functionally, IL-17 results in transcription of genes responsible for chemotaxis, inflammation, antimicrobial peptide
formation, and production of tissue remodeling substances. 39 Key chemokine genes that are upregulated include CXCL-1,
CXCL-2, CXCL-5, CXCL-8 (IL-8), and CXCL-10, all resulting in attraction of neutrophils. 39,42 Proinflammatory cytokines
produced include IL-6, TNF- α, and IL-1 β. The expression of IL-6 – the same cytokine with a role in Th17 cell maturation –
sets up a positive feedback loop. 39 Neutrophilic expansion results from increased expression of granulocyte colony stimulating
factor (G-CSF). With the production of tissue remodeling substances, IL-17 has a key role in psoriatic arthritis by promoting
osteolysis and production of cytokines that result in bone erosion. 39

Interleukin-12
In 1989 the heterodimeric glycoprotein IL-12 was discovered. The cytokine is one of four members in the IL-12 family. 43
IL-12 is composed of a p35 subunit and a p40 subunit. Notably, IL-12 and IL-23 share the p40 subunit allowing for a common
therapeutic target.
The key cells expressing IL-12 are activated myeloid dendritic cells. Once the cytokine is released, it acts on a heteromeric
receptor composed of IL-12R β1 and IL-12R β2. These receptors are expressed on T-cells, natural killer cells, and dendritic
cells. 43 Binding of IL-12 to the receptor results in TYK2/JAK2/STAT signal transduction, and activation of the STAT4
transcription factor. 43 The downstream effect of IL-12 binding is the differentiation of naïve T-cells to class 1 helper T-cells.
These Th1 cells are responsible for the release of numerous inflammatory cytokines including interferon- γ (IFN- γ ), IL-2, and
TNF. 44 Additionally, Th1 cells are responsible for synthesis of chemokines that perpetuate the inflammatory response by
recruiting additional cells. 45
Interleukin-23
IL-23 is a pro-inflammatory heterodimeric glycoprotein discovered in 20 0 0. 46 The cytokine consists of a p19 subunit
combined with a p40 subunit. It was initially thought to be IL-12 because of a similar p40 subunit, but with its unique p19 unit
it is now considered part of the IL-12 family. 43 Studies have found elevated mRNA levels coding for these subunits in lesional
skin from psoriasis patients when compared to healthy controls. 47 Interestingly, mRNA expression in non-lesional skin from
patients with psoriasis was also elevated when compared to controls.
Multiple cells within the body express IL-23. These include activated myeloid dendritic cells, macrophages, monocytes,
epithelial cells, and endothelial cells. 37,46 Once expressed, IL-23 binds to a heteromeric receptor complex to continue the signal
pathway. These IL-23 receptor complexes are formed from an IL-23R subunit and an IL-12R β1 subunit. 37 The first of these
subunits is unique to the IL-23 receptor complex, whereas the second, IL-12R β1 subunit, is also found in the IL-12 receptor
complex as previously mentioned. After IL-23 binds to the receptor complex, these subunits require intracellular proteins for
continued signaling. In this case, the Janus Kinase family become involved in signal transduction. Unlike IL-12R β1, which is
associated with TYK2, the IL-23R subunit is associated with JAK2. After a series of phosphorylation events, signal transducer
and activator of transcription (STAT) becomes active and translocates into the nucleus. STAT3 is the primary transcription factor
involved in the IL-23 pathway,. 37
Expression of IL-23 results in numerous downstream effects related to the development of psoriasis. First and arguably most
important, IL-23 is critically involved with Th17 cells. Al- though IL-23 does not induce the transition from naïve to mature
Th17 cells, the cytokine plays a key role in the expansion and survival of these cells. 41 (Also see above section on IL-17). Next,
IL-23 alters the expression of TNF- α by stimulating macrophages. One study in mice found that injecting mice with IL-23
resulted in epidermal thickening and features of psoriasis. 47 Concomitant injection of an anti-TNF antibody eliminated this
finding; notably, administering an anti-IL-17 antibody along with IL-23 did not negate the epidermal thickening. 47 This
indicates the epidermal thickening is a result of a TNF-dependent process. Lastly, IL-23 has been found to directly affect
keratinocytes by increasing keratin 16 (K16) gene expression. which is associated with epidermal hyperplasia. 47,48
Tumor necrosis factor- α
TNF- α is a pro-inflammatory cytokine secreted primarily by macrophages and activated T-cells. 49 In its active form, TNF-
α exists as a trimer before binding to receptors.
Two high-affinity receptors bind TNF- α: TNF receptor 1 (TNFR1) and TNF receptor 2 (TNFR2). 50 One difference
between these two transmembrane receptors is the location of

expression. TNFR1 is expressed throughout most tissues, whereas TNFR2 is expressed primarily in immune cells. 50 TNF- α is
notorious for its role in inflammation. Activation of TNFR1 is the primary driver of this. Formation of the TNF- α/TNFR1
complex results in downstream signaling and ultimately the release of NF- κB through a complex interaction of proteins and
degradation pathways. 50 Free NF- κB translocates into the nucleus and regulates gene expression of inflammatory cytokines.
TNF- α has been referred to as the “master regulator” in regard to its role in the cytokine production cascade. In the presence
of interferon- γ , TNF- α results in activation of macrophages. Not only does TNF- α initiate inflammation, but it also
perpetuates it by stimulating the release of interferon- β; this produces a synergistic effect by expressing additional genes that
code for inflammation. 50
TNF- α has an array of other roles, affecting atherosclerosis and osteolysis. These are particularly important for the psoriasis
population who experience increased cardiovascular mortality and suffer from bone diseases such as psoriatic arthritis. Its role in
atherosclerosis is thought to occur by modulating and inhibiting scavenger-receptor mediated accumulation of lipoproteins by
macrophages. 51 In regards to osteolysis, TNF- α induces osteoclast differentiation, promotes bone resorption via inducing
RANKL secretion, and increases the number of circulating osteoclast precursors. 50,52 , 53
Co-morbidities
Several significant co-morbidities exist in the psoriasis population. Physicians must remain vigilant when managing these
patients to treat the entire disease, and not focus solely on skin manifestations. Table 4 lists some of the known co-morbidities
associated with psoriasis.
Psoriatic arthritis (PsA)
Psoriatic arthritis is a seronegative spondyloarthropathy occurring in patients with psoriasis, and very rarely in patients
without. Compared to the general United States population, rates of PsA in psoriasis populations are enormous – 6% to 42% in
the psoriasis population versus 0.1%–0.24% in the general population. 55,56 PsA can occur in both young and old patients. There
is a peak onset occurring around 40–50 years of age. 57 Those who develop PsA have signs of active cutaneous psoriasis around
70% time. Despite this visible marker to raise suspicion, a large portion of patients with psoriasis have active PsA which remains
undiagnosed. One observational study in Germany included 1,511 patients. Of this population, 20.6% were determined to have
PsA and a staggering 85% of them were newly diagnosed. 58
Clinically patients may present with axial disorders, peripheral joint inflammation, enthesitis, tenosynovitis, or dactylitis also
known as a “sausage digit”. Within this cohort, PsA causes a significant impact on quality of life. In one study, 77% of patients
responded that PsA is a “problem” or “large problem” in everyday life. 56
The pathogenesis of PsA is thought to be autoimmune and places CD8 + T-cells at the center of disease. 59 Like psoriasis,
PsA involves the presence of susceptibility genes placing an individual at risk. Not surprisingly, these genes include HLA-C w
6 – the same allele that places individuals at risk for psoriasis. In patients with this risk allele, features of musculoskeletal
diseases tend to occur much later after the initial skin manifestations of psoriasis. 59 Other alleles include HLA- B27 and
HLA-B39. In these risk alleles onset of PsA is more likely to occur concomitantly with skin manifestations. 59 Studies have
shown the prevalence of PsA increases significantly with increasing body surface area involvement of psoriatic lesions. 56
Following a trigger the body reacts with an immune response resulting in an inflammatory infiltrate of the synovium and
entheses. High cytokine levels of TNF- α, IL-1, IL-6, IL-8, IL-10, and matrix metalloproteinases can be found in the synovium.
55 Long-term joint destruction occurs as a result of ongoing inflammation.

Table 4 Co-morbidities frequently occurring in psoriasis population.
Co-morbidity Screening recommendations? 54 , ∗
Psoriatic arthritis (PsA) Screen patients for early signs of PsA using the CASPAR criteria. Utilize
rheumatologist for diagnosis and treatment if needed. Metabolic syndrome Screening
overlaps with other co-morbidity screening. Cardiovascular disease The American Heart Association guidelines indicates the
following in
patients without risk factors:
• Blood pressure evaluated at least every 2 years with
target < 120/80 mmHg
• BMI measured at least every 2 years; target < 25 Kg/m 2
• Waist circumference measured at least every 2 years; target for
men < 40 inches, women < 35 inches
• Pulse evaluated at least every 2 years
• Fasting lipid panel measured at least every 5 years (or 2 if risk
factors)
• Fasting blood sugar measured at least every 5 years (or 2 if risk
factors) With knowledge that psoriasis increases risk we recommend blood
pressure, vitals, and weight at each clinic visit. Additionally, laboratory data tends to be available more frequently due to
monitoring of prescribed medications. Obesity Routine clinical practices should detect obesity, we recommend
recording weights at each visit. Type 2 Diabetes mellitus Screening overlaps with other
co-morbidity screening. Psychological impact (depression,
anxiety, suicide)
Screen using one of numerous screening tests or asking about
symptoms. At minimum we recommend exploring questions of mood and behavior at each visit. Inflammatory bowel disease No
established screening guidelines; physicians should be aware of the
association to recognize signs and symptoms. Substance abuse Ask appropriate history
questions at each visit. Neoplasms Practice with an increase vigilance for signs and symptoms. Patients on
immunosuppressive or PUVA therapy should undergo an annual full skin exam. Continue age appropriate screenings per the
American Cancer Society recommendations. Ocular disorders No established screening guidelines; be aware of the association to
recognize signs and symptoms.
∗ Recommendations taken from the National Psoriasis Foundation Clinical Consensus
Table 5 CASPAR criteria for classifying patients with PsA. 60
CASPAR criteria are met in patients with inflammatory articular disease and at least 3 points from the
following categories:
1. Evidence of current psoriasis, history of psoriasis, or family history (1st or 2nd degree relative) of psoriasis. Patients with a
current history gain 2 points; other categories are 1 point each. 2. Evidence of psoriatic nail changes 3. Negative rheumatoid
factor test 4. Current or history of dactylitis 5. Radiographic features of bone formation near joint margins on x-ray. Excludes
osteophyte formation.
Early diagnosis of PsA is critical to prevent permanent joint damage and improve patient quality of life. Diagnosis requires
dermatologist and primary care physicians to be active in their search for early signs of disease. Unfortunately, no serologic tests
exist for diagnosis. CASPAR ( C l AS sification criteria for P soriatic AR thritis) is a highly specific (98.7%) tool used to define
patients with PsA ( Table 5 ). 60 It is important to keep in mind these criteria were garnered from patients with well-established
disease and may be of limited use in the early course of disease. Other screening questionnaires available are the psoriatic
arthritis screen and evaluation (PASE), Toronto psoriatic arthritis screen (ToPAS), and the psoriatic and arthritic questionnaire
(PAQ). 61–63 During appointments, detailed joint examinations should be performed. Additionally,

radiographic imaging can be a helpful aid. Findings of joint erosion, joint space narrowing, bony proliferation, osteolysis
(“pencil-in-cup” deformity), ankylosis, spur formation, and spondylitis are classic findings. Erosive changes at the DIP joints are
sensitive and specific for PsA. 55 Lastly, appropriate utilization of experts in rheumatology should be utilized by dermatologists
and primary care physicians who need additional assistance in screening, diagnosing, or managing this complex population.
Metabolic syndrome
Metabolic syndrome is a cluster of abnormalities that are associated with the development of cardiovascular disease and type
2 diabetes mellitus. The clinical diagnosis of metabolic syndrome requires patients to meet criteria laid out by the National
Cholesterol Education Program Adult Treatment Panel III. These include: 1. Elevated waist circumference defined as ≥ 102 cm in
men or ≥ 88 cm in women; 2. Elevated triglycerides ≥150 mg/dL or on treatment for hyper- triglyceridemia; 3. Reduced HDL-C
defined as < 40 mg/dL in men or < 50 mg/dL in women; 4. Elevated blood pressure (bp) defined as systolic bp ≥ 130 mmHg or
diastolic bp ≥ 85 mmHg or on an antihypertensive medication for history of hypertension; and 5. Elevated fasting glucose ≥ 100
mg/dL or on treatment for hyperglycemia. 64 If patients meet three of these criteria, a diagnosis of metabolic syndrome is made.
Shockingly, approximately 35% of all US adults and 50% of adults over 60 years of age meet the criteria for this syndrome. 65
In a large meta-analysis including nearly 1.5 million patients from 20 different countries, patients with psoriasis were over
twice as likely to meet metabolic syndrome criteria compared to the general population 66 The underlying pathogenesis of this
association relies on the Th1 and Th17 response that drives psoriasis. The inflammatory “stew” of cytokines released from these
cells affect numerous components of the body. TNF has been shown to induce insulin-signaling defects, reduce production of
adiponectin (important for regulating glucose and fatty acids), stimulate the expression of adhesion molecules on endothelial
cells, and have a role in hypertension. 67 IL-6 has been linked to insulin resistance and may alter the function of hepatocytes to
result in increased acute phase proteins such as C-reactive protein. 67 Lastly, there is a shared genetic component that may
associate psoriasis and metabolic syndrome. PSOR2, PSOR3, and PSOR4 are known susceptibility loci for the development of
psoriasis as mentioned in the genetics section of this review. These are also associated with susceptibility to developing
metabolic syndrome, type 2 diabetes, and cardiovascular disease. 68
Treatment of metabolic syndrome should focus on the patient specific areas of concern. For each of the criteria, weight loss
and lifestyle modification is typically first implemented change for patients to make. Weight loss goals should be a 7% to 10%
decrease from baseline over a period of 6 to 12 months. 64 Lifestyle modifications such as physical activity and dieting are
important components of management. Physical activity for more than 30 minutes a day has been shown to improve metabolic
and atherosclerotic cardiovascular disease risk. Diets can improve cholesterol, triglycerides, and promotes weight loss.
Ultimately, medications may be necessary for improving individual criteria that do not respond adequately to these measures.
Cardiovascular disease
It should be no surprise after learning the prevalence of metabolic syndrome in the psoriasis population that these patients are
also at increased risk for cardiovascular disease (CVD). One large meta-analysis concluded patients with psoriasis experience a
24% increased relative risk of CVD; this risk was found to exist independent of smoking status, obesity, and hyperlipi- demia.
69,70 Not only are these patients at increased risk to experience CVD, they also experience a poorer CVD-related prognosis
compared to the general population. 71 Clearly, careful attention must be afforded to these patients to minimize these risks.

The link between psoriasis and CVD has a foundation in metabolic syndrome. Ultimately, this overlap has been thought to be
due the body’s state of chronic inflammation secondary to T-cell activation. Chronic inflammation has been known to be a factor
in CVD pathogenesis and cytokines that mediate psoriasis overlap significantly with CVD mediators. Armstrong et al. have
described the role of Th1 and Th17 cells in this overlap. 72 IL-12-activated Th1 cells release TNF- α, leading to endothelial
dysfunction and T-cell homing to sites of atherosclerosis. Simultane- ously, IL-17 released from Th17 cells can interact with
receptors on vascular smooth muscle and endothelial cells creating a pro-inflammatory feedback loop secondary to a variety of
cytokines, chemokines, and adhesion molecules. This cascade results in atherosclerotic plaque instability. Together, these two
pathways result in an increased amount of instable atherosclerosis.
Appropriate therapies aimed at managing any risk factors should be provided accordingly. Patient education is crucial for
adherence to management and modification of their risk. As always, lifestyle modification should be the primary step in
reducing the morbidity and mortality from CVD. Importantly, primary care physicians are paramount in the assistance in
screening and managing this at-risk population.
Obesity & type 2 diabetes mellitus
Many of these comorbidities overlap; obesity, type 2 diabetes, and cardiovascular disease are each closely related and each
serve as a component to the overarching metabolic syndrome. Hence, it is logical a patient with one of these co-morbidities is
likely to have others.
Obesity in psoriasis is complex and as mentioned may be an initiator and a byproduct of the disease. Since the link was first
identified, large clinical trials have helped to substantiate the connection. One Italian study including over 10,0 0 0 psoriasis
patients found the average BMI to be 30.6 Kg/m 2 . 73 Cohen et al. concluded that obesity and type 2 diabetes mellitus were
nearly twice as common in the psoriasis population they studied. 73
The pathogenesis of these two conditions is discussed in the section on metabolic syndrome. In short, inflammation results
in mediators that alter insulin secretion, resistance, and adiponectin production which alter the body’s ability to control blood
sugar and fat.
Management of these co-morbidities is important from a general health standpoint, but may also result in better overall
control of psoriasis. 74 Additionally, the co-morbidities have important implications on treatment. Studies have found the
effectiveness of different therapeutics are negatively affected by an increased BMI. This is particularly true for the medications
that are not weight based. 75
Psychological impact
In the beginning of this review, psoriasis was introduced as a disease affecting patients internally, externally, and
psychosocially. Thus far, the internal and external somatic consequences of psoriasis have been made apparent. Equally
important are the psychological and social consequences of the disease. Patients with psoriasis are more likely to experience
social or professional stigmatization, have lower self-esteem, and impaired sense of self-worth. 76
Rates of depression, anxiety, and suicidality are increased in the psoriasis population. 77–79 A study including nearly 5,0 0 0
participants with various dermatologic conditions found that clinical depression was present in 10.1% (4.3% in the controls),
clinical anxiety in 17.2% (11.1% in controls), and suicidal ideation in 12.7% (8.3% in controls). 77 Unfortunately, patients with
psoriasis (n = 626) exceeded each of these averages. Individual analysis revealed 13.8% (n = 84) experienced depression, 22.7%
(n = 139) anxiety, and 17.3% (n = 106) suicidality. 77 One study set out to determine the main determinants of these
psychological conditions in patients with psoriasis. 76 Their results were revealing. Depression was found to be significantly
related to a patient’s subjective assessment of disease severity and having a negative emotional attitude

toward their body. Controlling for the negative body-image reduced the correlation between depression and disease severity
indicating the three components are closely intertwined. Regarding anxiety, particularly social anxiety, experiences of
stigmatization and belief that self-worth is tied to appearance were strongly predictive.
Fortunately, it appears that treating psoriasis can improve the psychosocial symptoms that are associated with the disease.
80–82 Continued studies to observe the effects of new therapeutics on depression and psychological factors are important, as
some have been reported to increase the risk of suicide. Physicians should constantly aim to understand the psychological impact
of psoriasis on a patient to patient basis and attempt to mitigate these risks accordingly.
Inflammatory bowel disease
Crohn’s disease and ulcerative colitis cause significant morbidity and mortality. Depending on the severity of psoriasis, the
10-year incidence of Crohn’s disease in patients with psoriasis was 2–5 per 10 0 0 patients. 83 This same study found the
incidence of ulcerative colitis in these patients was 7–10 per 10 0 0 patients. In comparison, the annual incidence of these two
conditions in the general population according to the Crohn’s & Colitis Foundation are 0.11 and 0.12 per 10 0 0 patients,
respectively.
Similar to psoriasis, a dysfunctional immune system is the foundation on which Crohn’s disease and ulcerative colitis occurs.
These diseases also have a strong genetic component. In fact, studies have shown Crohn’s disease and psoriasis share different 7
susceptibility loci. 84 In addition to this genetic overlap, the cytokines that drive the diseases are also quite similar. In particular
IL-23, IL-12, IL-17 and TNF- α are the main mediators that are shared.
There are no guidelines or recommendations to actively screen patients with psoriasis for inflammatory bowel disease. Such
process could be costly and inefficient. Instead, physicians should be vigilant for signs and symptoms of these conditions and
refer to gastroenterologist accordingly.
Substance abuse
Patients with psoriasis have high rates of excessive alcohol consumption and tobacco use. 22,85 , 86 One study in the UK
identified approximately 1 in 5 psoriasis patients had problems with alcohol using the CAGE questionnaire. 22 Of these patients,
13% thought they had a current drinking problem and 18% admitted to having a past drinking problem. In Norway, daily
cigarette usage was found to be greater in psoriasis patients (48%) compared to those without the disease (36%). 86 Psoriasis
patients were also less likely to have never smoked compared to the general population. The use of these substances creates many
health issues for an already unhealthy population. Additionally, physicians must be careful with therapeutics in psoriasis patients
with substance abuse issues. This is particularly true with medications known to have hepatotoxicity such as methotrexate.
Questions about self-medicating behaviors with alcohol and tobacco use should discussed with patients. Physicians with stronger
patient relationships are more likely to be successful in navigating this topic. Education and patient counseling are a cornerstone
of treatment with escalation of certain therapies. Currently, studies to determine the use of other recreational or illicit drugs are
not readily available in the literature.
Neoplasms
Given that psoriasis is a disease associated with a dysregulated immune system, there has been concern regarding the risk of
malignancy in these patients. Specifically, cancers such as lymphoma have been identified as worrisome. The largest available
study included over 90 0,0 0 0 patients (153,197 diagnosed with psoriasis) and demonstrated patients with psoriasis were at

increased risk of lymphoma. 87 The strongest association was found in Hodgkin’s lymphoma and cutaneous T-cell lymphoma.
Another cancer found at increased frequency in psoriasis patients is squamous cell carcinoma (SCC) of the skin. 88 Psoriasis
sub-populations treated with psoralen and ultraviolet A (PUVA), coal-tar, or cyclosporine are at even higher risk of SCC. 54
Studying the rates of solid malignancies is difficult, and numerous factors must be controlled to get an accu- rate picture. For
example, the increased smoking rates, alcohol consumption, and treatment with potentially carcinogenic therapies like
phototherapy make this a hard association to ascertain.
There are no established guidelines in screening patients with psoriasis for malignancy. Table 4 describes the general
recommendations provided by the National Psoriasis Foundation Clinical Consensus.
Ocular disorders
Ophthalmic complications of psoriasis may occur at numerous anatomic locations including the eyelids, conjunctiva, cornea,
uvea, and lens. Few studies have assessed the prevalence of these complications in psoriatic patients; however, reports have
stated approximately 10% of psoriasis cases experience an ophthalmic complication. 89 Uveitis specifically appears to have one
of the strongest associations. When occurring, the inflammation tends to be anterior, bilateral, and chronic. 89
The etiology of this association is currently unknown. Results of a study by Okamoto et al. suggested patients with psoriasis
exhibit a damaged blood-aqueous barrier even in the absence of a history of ocular disease. 90 This may account for the added
susceptibility.
Authors have suggested annual or biannual examination in patients with severe psoriasis to screen for ocular disorders. 91 At
follow-up visits dermatologist or primary care physicians should ask a thorough ocular review of systems and screen for common
ophthalmic disorders including dry eyes, blepharitis, conjunctivitis, and uveitis.
Diagnosis
Clinical aspects
The diagnosis of psoriasis is made clinically using history and physical examination findings. Patients will often present with
new onset lesion(s) that won’t go away. Lesions are character- istically well-demarcated, erythematous papules and plaques with
palpable edges and overlying scale. Symptomatically, these patients may complain of pruritus, irritation, burning, sensitivity,
pain, bleeding, or any combination of above. 92 Itching is by far the most common with one study reporting the symptom in
63.8% of cases; other symptoms reported were irritation (59.7%), burning (46.1%), sensitivity (39%), pain (26%), and bleeding
(25.4%). 92 Additionally, about 1 in 4 patients may complain of water bothering their skin. The physical examination of the
entire integument (including the scalp, intertriginous, and anogenital regions), and the nails, should include a joint exam in search
of any additional evidence of disease.
When the stereotypical lesions are absent, psoriasis can be more challenging to diagnose. The broad differential diagnosis of
other papulosquamous disorders should routinely be applied and can aid in the diagnosis of these more difficult cases. These
include dermatologic conditions such as atopic dermatitis, seborrheic dermatitis, nummular dermatitis, tinea corporis, lichen
planus, mycosis fungoides, pityriasis rubra pilaris, and pityriasis rosea. Scrapings for potassium hydroxide preparation assist in
ruling out fungal infections. Time course along with the presence of a herald patch will support pityriasis rosea over psoriasis. In
atypical cases of psoriasis, a biopsy may be necessary to confirm the diagnosis.
Equally important to obtaining the diagnosis, are the steps that follow. Significant patient education regarding the disease
course, co-morbidities, treatment options, and implications of the diagnosis should occur. One study found patients with psoriasis
often lack important

information of their disease resulting in poorer adherence to treatments. 93 A survey by Brown et al. aimed to identify areas
where psoriasis patients wanted more knowledge about. Most common answers were the triggers of disease (75%), treatment
options with mechanisms of actions (55%), and side effects of treatment options (53%). 94
Histological aspects
The histology of psoriatic lesions differs depending on the age of the lesion. Murphy and Grant-Kels describe the histologic
components of psoriasis. 95 In the earliest stages, findings may be minimal and consist primarily of dermal change with a sparse
perivascular lymphocytic infiltrate of T-cells. With time, subepidermal blood vessels become more prevalent, tortuous, and
dilated. Their location within the dermal papilla may result clinically in the pinpoint bleeding after removal of scale (Ausptiz
sign). Dermal edema, spongiosis, and exocytosis of neutrophils and lymphocytes may be seen.
It isn’t until the early plaque stage develops that epidermal hyperplasia begins to become obvious. Mounds of parakeratosis –
abnormally retained nuclei in the stratum corneum indicating abnormal keratinocyte maturation – are seen, with underlying loss
of the granular layer. 96 Additionally, the dermal infiltrate becomes more substantial and composed of lymphocytes, histiocytes,
neutrophils, and red blood cells.
A mature psoriasis lesion will have the following characteristics: marked epidermal hyperplasia, elongated rete ridges with
bulbous enlargement, significant dilation and tortuosity of blood vessels in the dermal papilla, and epidermal thinning above the
dermal papillae. Often, marked hyperkeratosis is present, accounting for the scale that is visible clinically. In approximately 75%
of cases, Munro’s micro-abscesses – collections of neutrophils in the epidermis – can be identified.
Differences between psoriatic and normal epidermal cells have been found, leading to some of the histologic findings
described above. Compared to the 311-hour cell cycle of normal epidermal keratinocytes, those in psoriatic epidermis exhibit a
dramatically shortened cell cycle of only 36 hours. 97 The cited study also found the proliferative cell population was doubled in
skin affected by psoriasis. Taken together, a 28-fold greater production of cells compared to normal skin explains the increased
epidermal mass in the psoriatic plaque. 97
Medical management
Physicians have a multitude of treatment options to choose from in treating patients with psoriasis. These treatments include
numerous topicals, non-biologic systemic medications, biologics, and phototherapy. A variety of factors should be considered
when choosing which medication is best for a patient. This includes consideration of disease severity, co-morbidities, insurance
coverage, and safety. Often a physician’s perception of “best choice” may differ from the patient’s depending on which of these
factors are most heavily weighed. A study performed by Alcusky et al. examined patients with moderate or severe psoriasis to
determine which variables dermatologists and their patients considered when choosing a biologic medication option. 98
Physicians rated safety, low likelihood of adverse advents, and overall perception of efficacy as most important. They were
concerned with objective measures such as reduction in affected body surface area and maintenance of response over time.
Physicians considered drug mechanism of action and ability to tailor the dosing least important. Conversely, patients had greater
concern regarding the subjective symptoms associated with lesions and improvement in quality of life. They also were concerned
with the degree of erythema, scaling, and induration, out-of-pocket costs, and safety of the medication. Clearly, physicians must
avoid the pitfall of choosing medications based solely on a medical expertise perspective, but also need to consider patient
preferences. This will help ensure a common goal with improved patient satisfaction and adherence to treatment.

Severity of disease is the critical determination when choosing an appropriate therapeutic. Using a topical medication as the
core treatment modality in a patient with extensive body surface area involvement would be inappropriate. Alternatively, the risk
and cost involved in systemic medications outweigh their use in patients with small, localized lesions that could be easily
managed with a topical drug. Choosing an appropriate modality is paramount to effective and efficient care of patients with
psoriasis. In general, for mild to moderate disease topical treatments should be used. Patients with moderate to severe psoriasis
may require control with systemic medications or phototherapy.
The primary goal of this section is to introduce the numerous biologic treatments available to patients with moderate or severe
plaque psoriasis. Very briefly, we will mention topical, phototherapy, and non-biologic systemic therapeutics.
Biologics
Biologics are complex glycoproteins produced with or from a living organism. 99 Their ability to target and influence highly
specific targets of the immune system have resulted in their rapid development as a standard component of medical care.
Biologics encompass a variety of classes including monoclonal antibodies, cytokines, fusion proteins, RNA, antisense
oligonucleotides, and kinase inhibitors. 100 Each class uses unique mechanisms to achieve their theraputic goal. Classes most
commonly used in psoriasis include monoclonal antibodies and fusion proteins.
Monoclonal antibodies are created using a single B-lymphocyte clone that binds a specific antigenic epitope. 100 Thus, the
antibody produced is very specific to the targeted antigen. Using a different lymphocyte clone in this process will result in the
formation of a unique antibody with different specificity. Targets of these monoclonal antibodies are numerous and may include
cell surface receptors or ligands. By binding surface receptors, antibodies prohibit the binding of native ligands to their receptor
thus blocking the downstream signaling that would normally occur. Blockage of an entire receptor prevents all ligands from
binding that receptor. Alterna- tively, targeting the ligands directly accomplishes the same goal but in a different, more direct
manner. For therapeutic purposes antibodies must be stable and have strong binding properties to be efficient. The
immunogenicity of non-human antibodies will elicit a host response – which was an expected limitation to the use of early
monoclonal antibodies. Techniques to humanize antibodies (which reduces their immunogenicity) have improved these issues
and resulted in efficacious, although costly, therapeutics.
Fusion proteins are created using genetic engineering to combine two unique proteins together. These often consists of a
peptide chain fused with a Fc region of human IgG. Usually, this class of biologic acts as a competitive inhibitor and thus prevent
ligand binding to its receptor (e.g. etanercept) or as direct ligand of a receptor and thus blocking proinflammatory cell
interactions (e.g. alefacept). 100
The biologics used in psoriasis vary in class and target. As a result, each molecule behaves differently, and produces a
different downstream result. Although clinicians often group different biologic classes together according to their target (e.g.
TNF-inhibitors), each theraputic may function uniquely.
Table 6 shows an overview some of newer biologic drugs, their mechanism of action, and different reported psoriasis area and
severity index (PASI) scores that will be discussed in more detail in the “Landmark clinical trials” section.
TNF- α inhibitors Etanercept (Enbrel®, Amgen). Etanercept is a TNF-receptor fusion protein, and thus acts by com- petitively
inhibiting the binding of TNF- α to TNF receptors 1 and 2. Etanercept was approved for the treatment of psoriatic arthritis in
2002. It wasn’t until May of 2004 the drug was also FDA approved for the treatment of plaque psoriasis in adults. More recently,
approval was granted for use in children age 4–17 with chronic plaque psoriasis making it the first biologic treatment approved
for this population. Important considerations for the physician prior to prescribing

Table 6 Current list of FDA approved biologics used in adult plaque psoriasis.
Drug Name Dose Place of Action Specific Action PASI 75 PASI 90 PASI 100
Etanercept 50 mg injections twice a week for three
months; maintenance injections of 50 mg weekly.
Ligand Receptor fusion protein
Leonardi et al. Leonardi et al. Not reported that binds TNF- α
Week 12: 49% Week 12: 22% Papp et al. Papp et al. Week 12: 49% Week 12: 21% Adalimumab 80 mg loading dose; 40 mg
injections
every other week.
Ligand Binds TNF- α REVEAL REVEAL REVEAL
Week 16: 71% Week 16: 37% Week 16:
14% Infliximab 5 mg/kg IV induction at weeks 0, 2,
and 6 then every 8 weeks
Ligand Binds TNF- α EXPRESS 1 EXPRESS 1 Not reported
Week 10: 80% Week 10: 57% Week 50: 61% Week 50: 45% EXPRESS 2 EXPRESS 2
Week 10: 75.5% Week 50: 34.3% Week 50: 54.5% Certolizumab
Pegol
400 mg every other week Ligand Binds TNF- α CIMPASI-1 CIMPASI-1 CIMPASI-1
Week 16: 76% Week 16: 44% Week 16: 13% Week 48: 87% Week 48: 60% Week 48: 24% CIMPASI-2 CIMPASI-2
CIMPASI-2
Week 16: 83% Week 16: 55% Week 16: 19% Week 48: 81% Week 48: 62% Week 48: 38% Ustekinumab Patients ≤ 100 kg: 45
mg doses at
weeks 0, 4, and 12, followed by injections every 12 weeks Patients > 100 kg: same as above but
with 90 mg dose
Ligand Binds the p40 subunit
of IL-12 and IL-23
PHOENIX-1 PHOENIX-1 PHOENIX-1
Week 12: 45 mg: 67.1% Week 12: 45 mg: 41.6% Week 12: 45 mg: 12.5%
90 mg: 66.4% 90 mg: 36.7% 90 mg: 10.9% PHOENIX-2 PHOENIX-2 PHOENIX-2
Week 12: 45 mg: 66.7% Week 12: 45 mg: 42.3% Week 12: 45 mg: 18.1%
90 mg: 75.7% 90 mg: 50.9% 90 mg: 18.2%
( continued on next page )

Table 6 ( continued )
Drug Name Dose Place of Action Specific Action PASI 75 PASI 90 PASI 100
Secukinumab 300 mg weekly for 4 weeks, then
300 mg monthly beginning at week 8
Ligand Binds IL-17A ERASURE ERASURE ERASURE
Week 12: 81.6% Week 12: 59.2% Week 12: 28.6% FIXTURE Week 52: 60.0% Week 52: 39.2%
Week 12: 77.1% FIXTURE FIXTURE
Week 12: 54.2%
Week 12: 24.1% Ixekizumab 160 mg initial loading dose; 80 mg
every 2 weeks for 3 months; 80 mg monthly
Ligand Binds IL-17A UNCOVER-1 UNCOVER-1 UNCOVER-1
Week 12: 82.6% Week 12: 64.6% Week 12: 33.6% UNCOVER-2 UNCOVER-2 UNCOVER-2
Week 12: 77.5% Week 12: 59.7% Week 12: 30.8% UNCOVER-3 UNCOVER-3 UNCOVER-3
Week 60: 83% Week 60: 73% Week 60:
55% Brodalumab 210 mg weekly for 3 weeks, then
210 mg every 2 weeks
Receptor Binds IL-17 Receptor A
(IL-17RA)
AMAGINE-1 AMAGINE-1 AMAGINE-1
Week 12: 83.3% Week 12: 70.3% Week 12: 41.9%% AMAGINE-2 AMAGINE-2 AMAGINE-2
Week 12: 86.3% Week 12: 70% Week 12: 44.4% Week 52: 80% Week 52: 75% Week 52: 56% AMAGINE-3 AMAGINE-3
AMAGINE-3
Week 12: 85.1% Week 12: 69% Week 12: 36.7% Week 52: 80% Week 52: 73% Week 52: 53% Guselkumab 100 mg at weeks 0
and 4 followed by
every 8-week injections
of IL-23
VOYAGE-1 VOYAGE-1 VOYAGE-1
Week 16: 91.2% Week 16: 73.3% Week 16: 37.4% Week 48: 87.8% Week 48: 76.3% Week 48: 47.4% VOYAGE-2
VOYAGE-2 VOYAGE-2
Week 16: 86.5% Week 16: 70.0% Week
16: 34.1% Tildrakizumab 100 mg at weeks 0 and 4, followed by
injections every 12 weeks
of IL-23
reSURFACE1 reSURFACE1 reSURFACE1
Week 12: 100 mg: 64% Week 12: 100 mg: 35% Week 12: 100 mg: 42%
200 mg: 62% 200 mg: 35% 200 mg: 14% ReSURFACE 2 ReSURFACE 2 ReSURFACE 2
Week 12: 100 mg: 61% Week 12: 100 mg: 39% Week 12: 100 mg: 12%
200 mg: 66% 200 mg: 37% 200 mg: 12%

etanercept include a patient assessment for history of malignancy and risk of infection. A black box warning for etanercept
regarding the risks of serious infections and malignancy was added to the label based on data from trials. Additionally some
reports have implicated TNF-inhibitors in new-onset or worsening of heart failure. 101 As a result physicians should be caution
of using this medication in the heart failure population. The recommended dosing for etanercept consists of 50 mg injections
twice a week for three months followed by maintenance injections of 50 mg weekly. Studies also found that starting doses of 25
mg or 50 mg weekly for the first three months were efficacious.
Adalimumab (Humira®, AbbVie). Adalimumab is a monoclonal antibody against TNF- α. It functions by binding the host
TNF ligand thereby preventing interaction with TNF receptors. In Jan- uary of 2008, adalimumab was approved for the treatment
of adults with moderate to severe plaque psoriasis based on results of the REVEAL study. 102 Previously the medication was ap-
proved for use in psoriatic arthritis. As of 2017, adalimumab gained approval for use in finger- nail psoriasis. This makes it the
first biologic with data on this difficult to treat indication. As with other TNF inhibitors physicians should be aware of the risk of
malignancy, infection, and new-onset or worsening of heart failure. A black box warning has also been added to this medication
regarding the increased risk of serious infection and malignancy. Recommend dosing for the drug is an initial loading dose of 80
mg followed by 40 mg injections every other week.
Infliximab (Remicade®, Janssen Pharmaceutica). Infliximab is a monoclonal anti-TNF- α antibody that works in the same
manner as adalimumab. It was approved for the treatment of psoriatic arthritis in 2005 and later in 2006 gained approval for
chronic plaque psoriasis. This approval came as a result of two phase-3 trials, EXPRESS 1 and EXPRESS 2. 103,104 As with
other TNF- inhibitors, the same black box warning regarding risk of infection and malignancy is added to the label. Infliximab is
administered as an infusion rather than injection. Recommended dosing of infliximab begins with a 5 mg/kg IV induction at
weeks 0, 2, and 6 followed by 5 mg/kg maintenance infusions every 8 weeks.
Certolizumab Pegol (Cimzia®, UCB). Certolizumab pegol is a PEGylated TNF- α antibody fragment approved for use in
Crohn’s disease, rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis. The PEG moiety extends lifetime of the
molecule in circulation. In May of 2018, the drug received FDA approval for the treatment of moderate to severe plaque psoriasis
in adults. Unlike other biologics, certolizumab pegol has been found not to be transferred through breastmilk and has minimal to
no placental transfer. 105,106 As a result, this medication may become a targeted therapy in the treatment of pregnant and
nursing women with psoriasis requiring systemic medication. Current dosing approved for plaque psoriasis is 400 mg (2
injections of 200 mg each) every other week. In patients less than 90 kg, physicians can consider lower the dosage to involve an
induction period of 400 mg initially and at week 2 and 4, followed by 200 mg maintenance injections every other week.
IL -12/IL -23 inhibitors Ustekinumab (Stelara ®; Janssen Pharmacetuica). Ustekinumab is a dual inhibitor that targets IL-23 and
IL-12. It is an antibody that binds the p40 subunit which is shared between IL-23 and IL- 12. Binding of this subunit prevents
each interleukin from interacting with the receptor. Ustek- inumab was FDA approved for treatment of adults with psoriasis in
September of 2009. The drug was also granted approval for the treatment of psoriatic arthritis based off the results of the
PSUMMIT trials, and more recently, was approved for use in adolescents aged 12 and older with plaque psoriasis. 107–109
Dosing of ustekinumab is weight based. Patients less than or equal to 100 kg should receive 45 mg at weeks 0, 4, and every 12
weeks subsequently; patients greater than 100 kg should be up-titrated to receive 90 mg injections during the same time period.
Three phase-3 trials were performed to demonstrate the efficacy of ustekinumab in psoriasis (PHOENIX-1, PHOENIX-2, and
ACCEPT). 110–112

IL-17 inhibitors Secukinumab (Cosentyz®, Novartis). Secukinumab is a humanized, IgG monoclonal antibody that targets
IL-17A. The FDA approved this drug in January of 2015 making it the first anti-IL-17 antibody on the market for the treatment
of psoriasis in adults. In addition, the drug is approved for use in psoriatic arthritis and severe scalp psoriasis. 113–115 ,
Secukinumab should be avoided in patients with inflammatory bowel disease as should the other IL-17 inhibitors. Recommended
dosing of the medication involves an induction phase of 300 mg dose once weekly for 4 weeks, followed by a maintenance phase
of 300 mg monthly beginning at week 8.
Ixekizumab (Taltz®, Eli Lilly and Company). Ixekizumab is a humanized monoclonal antibody specifically targeting IL-17A
ligand. Binding to IL-17A prevents the interaction of this cytokine with its receptor. Ixekizumab was approved for the treatment
of adults with plaque psoriasis in March of 2016. Efficacy was demonstrated by three phase-3 trials (UNCOVER-1,2, and 3).
116,117 Later in 2017 the drug was also approved for psoriatic arthritis based on results of the SPIRIT trials. 118,119 IL-17 is
involved in regulation of the gastrointestinal tract. As a result, caution must be used in patients with concomitant inflammatory
bowel disease. Recommended dosing for this medication include a 160mg-loading dose, an induction phase of 80 mg every 2
weeks for 3 months, and a maintenance phase of 80 mg monthly.
Brodalumab (Siliq ®; Valeant Pharmaceuticals). Brodalumab is a monoclonal antibody directed against IL-17 receptor A. The
IL-17 receptor exists as dimer complex of which receptor A is a common subunit. Binding of this subunit interferes with the
ability for IL-17 to complex with the receptor. It was granted FDA approval in February of 2017 for use in adults with chronic
plaque psoriasis based on three phase-3 trials. 120,121 Physicians prescribing this medication should take care to identify any
prior or current suicidal behaviors. A black box warning for brodalumab for increased risk of suicidal ideation or behavior has
been added to labels. Current dosing recom- mendation is 210 mg once weekly for 3 weeks followed by 210 mg every 2 weeks.
Selective IL-23 inhibitors Guselkumab (Tremfya ®; Janssen Pharmaceutica). Guselkumab is a monoclonal antibody that func-
tions by binding the p19 subunit of IL-23. This allows for selective targeting of IL-23. It is the first selective IL-23 inhibitor on
the market and was granted FDA approval in July 2017 for use in adults. Recommended dosing of the medication is 100 mg at
weeks 0, 4, followed by dosing every 8 weeks.
Tildrakizumab (Ilumya®, Sun Pharmaceutical Industries Ltd.). Tildrakizumab is an IgG humanized antibody targeting the p19
subunit of IL-23. As a result, tildrakizumab is selective for IL-23 inhibition alone. The drug received approval by the FDA for
treatment of adults with moderate to severe plaque psoriasis in March of 2018. Dosing for tildrakizumab is every 12 weeks
following induction injections at week 0 and 4. This 12-week dosing schedule makes tildrakizumab and ustekinumab particularly
beneficial for patients with adherence issues. Two phase-3 randomized controlled trials were used to demonstrate efficacy of
tildrakizumab in psoriasis (reSURFACE 1 and reSURFACE 2). 122
Biologics in the pipeline
Several new biologics are currently under study and shown promising preliminary data. Many of these drugs share similar
mechanisms of actions as described above. Others have novel mechanisms of action and it will be intriguing to see their final
results. A couple of these many drugs currently in phase three trials include bimekizumab and risankizumab.
Bimekizumab is currently starting phase 3 trials and had promising phase 2b results. The drug is an IL-17 inhibitor, but is
unique to any other IL-17 antibody on the market. Unlike current IL-17 inhibitors that only bind IL-17A, bimekizumab inhibits
both IL-17A and IL-17F. Al- though IL-17F is a much less potent inflammatory agent than IL-17A, studies on bimekizumab
have demonstrated increased efficacy and rapid onset of action with this dual inhibition. The 12

week phase 2 study, BE ABLE evaluated multiple doses of bimekizumab (64 mg, 160 mg, 160 mg with a 320 mg loading dose,
320 mg, and 480 mg every 4 weeks) versus placebo. 123 The efficacy increased in a dose-dependent manner from placebo to 320
mg of drug. In the 320 mg group PASI 75/90/100 scores were achieved by 93/79/56% at week 12. Rates were also high in the
160 mg group who received a 320 mg loading dose (85/75/60). Onset of action was rapid – after just one injection all groups
displayed meaningful improvement compared to placebo.
Risankizumab, is another inhibitor of the p19 subunit of IL-23. It has demonstrated safety and efficacy in multiple phase 3
trials that are yet to be published. In a phase 2 head-to-head comparison with ustekinumab, risankizumab demonstrated
superiority in treating moderate to severe plaque psoriasis. 124 166 subjects were randomized to receive 180 mg of risankizumab
as a one-time injection, 90 mg or 180 mg of risankizumab at weeks 0, 4, and 16, or ustekinumab using the standard weight based
dosing. With 90 mg of risankizumab injections, PASI 75/90/100 was achieved by 98/73/41% at week 12. In the 180 mg group,
the percent of subjects achieving a PASI 75/90/100 were 88/81/48%. Only 72/40/18% of the ustekinumab patients achieved
PASI 75/90/100 respectively. Onset of action was rapid with decreased PASI scores by week 2. Risankizumab thus also
improved quality of life for patients. Analysis of patients with psoriatic arthritis revealed 69% of subjects randomized to the 90
mg dosage, and 83% on the 180 mg dosage had a greater than 50% reduction in pain by week 24.
Unlike the biologics mentioned thus far that interact with one of the cytokines implicated in disease, new drugs with differing
mechanisms of action are under also investigation. Nei- hulizumab is an antibody with a unique mechanism of action. It acts to
induce apoptosis of late- stage activated T-cells. By preferentially eliminating the population of T-cells that are pathogenic for
psoriasis but maintaining the host immature T-cells a theoretical reduced risk of malignancy and infections has been proposed
and supported by early proof-of-concept studies. Tregaliumab, as suggested in the name, acts to activate regulatory T-cells. It
accomplishes this as an anti-CD4 antibody that binds and subsequently activates T-cells. Until studies in psoriasis are performed
it is unclear if this drug will become one of many therapeutics for the disease.
Management of patients on biologics
Management of this patient population will depend on a physician’s frequency of prescribing these powerful medications.
We recommend basic blood work including complete metabolic panel and complete blood counts be obtained initially every 3
months to examine for any abnormalities. Once patients have been on a stable dose, blood work can be spaced out to every 6
months or more depending on physician comfort. Yearly tuberculosis screening should be performed. This is for both patient
safety and a requirement for majority of insurances. During our clinic visits blood pressure, pulse, and weight measurements are
recorded at each follow-up visit for monitoring. Questions regarding mood and signs of anhedonia are routine to screen for any
red flags of depression or potential suicidality. A complete review of systems with focus on questions pertaining to prolonged
infections, palpable lymph nodes, fatigue, unexpected weight loss, joint pain, and abdominal pain should be discussed. Complete
skin examination should be performed to detect skin cancers and track improvement or worsening of their psoriasis. Care should
be taken to check all folds, as psoriasis is commonly found in unchecked clefts. Given the reported risks of lymphoma, lymph
node examination should be performed at each visit in these patients. Signs of edema should be checked in patients on
TNF-inhibitors to evaluate for signs of new or worsening heart failure.
Topicals
Topical medications are the mainstay of treatment for patients with mild to moderate psoriasis. These medications are also
often used concomitantly with systemic drugs in patients with more extensive disease. Practically speaking, patients with
psoriasis will at some point use a topical medication. Benefits include reduced side effect profiles, lower costs, and delivery of
medication in an effective and non-invasive manner. This last part is unique to dermatology.

Despite, their widespread use, there are disadvantages of topicals to consider. Their strength is less than that of systemic
medication, they absorb slowly lending them vulnerable to removal, and adherence to the use of topicals is challenging for
patients. One review found that in short- term studies only 50% to 60% of applications are performed by patients. 93 Topical
medications can be time consuming to apply or associated with unpleasant sensations such as a greasy residue or foul odor
leading to poor adherence. Unfortunately, asking patients about their use is not a great for evaluating their adherence as patients
tended to overestimate their usage of topical medications. 125 Improving adherence can be done with improving patient
education, stronger doctor-patient relationships, and discussions of treatment goals/expectations.
Topicals indicated for use in patients with psoriasis include topical corticosteroids, vitamin D analogues, retinoids, calcineurin
inhibitors, and – mostly historical – anthralin and tar. Corticosteroids are far and above the most common and are available in
multiple different potency formulations, allowing choices tailored for each patient based on location and severity of lesions.
Combination formulations are also available for use including corticosteroid/vitamin D analogues, corticosteroid/retinoid, and
corticosteroid/salicylic acid combinations.
The vehicle of the topical is a critical component to consider. Topicals may be formulated as ointment, cream, lotion, gel,
foam, or a variety of other forms. As the vehicle becomes more occlusive, penetration of the active drug increases. Physicians
should be sure to discuss the vehicle options with patients – remember, adherence is key for successful treatment with topical
medications. If someone avoids applying their ointment because of the greasy characteristic the therapy will ultimately fail.
Phototherapy
Phototherapy involves the use of ultraviolet radiation (UVR) as a treatment modality. UVR wavelengths range from 100 to
400 nm with the therapeutically relevant range from 290 nm and up. Its use in psoriasis tends to be most beneficial in patients
with extensive disease making treatment with topicals infeasible. Phototherapy can be delivered as ultraviolet B (UVB),
ultraviolet A plus psoralen (PUVA), ultraviolet A1 (UVA1), and excimer laser, a monochromatic UVB source at 308 nm. 126
Today, PUVA is rarely used due to an increased skin cancer risk associated with excessive use. Instead, UVB is the primary
phototherapy modality used in psoriasis patients. Narrowband UVB (NB-UVB, mostly delivering 311 nm radiation) is currently
the most prevalent phototherapeutic modality, as its spectrum is most effective among UVB sources in treating psoriasis.
Phototherapy works most likely based on altered cytokine expression, apoptosis of lymphocytes, and by promoting
cutaneous immunosuppression. 127 Approximately 40%–80% of patients treated with UVB therapy achieve a 75% reduction in
their PASI. 126 Unfortunately, phototherapy is a time intensive treatment requiring 2–3 times weekly clinic visits during the
clearance phase of several weeks. This time commitment and the distance from a phototherapy center may be barriers for patients
to access phototherapy. Those planning for treatment with phototherapy should be directed to a dermatologist with expertise in
the area to ensure treatment safety.
Oral systemics (non-biologic)
Systemic medications outside the realm of biologics can be used in the treatment of moderate to severe psoriasis. Because
their side effects are potentially much greater than topical medications, systemic drugs are reserved for patients not achieving
adequate control with topicals. Common oral systemics include apremilast, methotrexate, cyclosporine, and acitretin.
Apremilast is an orally administered phosphodiesterase 4 (PDE4) inhibitor taken twice daily. By inhibiting the breakdown of
cyclic adenosine monophosphate (cAMP) via PDE4 inhibition, apremilast results in decreased production of inflammatory
cytokines. Clinical trials of this

medication showed improvement in plaque, nail, scalp, and palmoplantar psoriasis. In general, it is considered to have a modest
effect size and indirect comparisons to biologics have shown reduced treatment effects. 128 In a phase three study of this
medication, 33.1% of subjects achieved a PASI 75 at week 16. 129
Methotrexate is a cheap, relatively effective therapy for psoriasis that has been used for decades. It works in the treatment of
psoriasis due to its anti-inflammatory, anti-proliferative, and immunosuppressive actions. 130 Methotrexate is a dihydrofolate
reductase inhibitor resulting in reduced synthesis of purines and pyrimidines necessary for DNA synthesis. Downstream, this
decreases hyperplasia of the epithelium and induces apoptosis of T-cells. 131 Data from a comparator study found that 41.9% (n
= 90) of subjects randomized to methotrexate achieved a PASI 75 score at week 16. 132 The main limitation of this drug is the
liver toxicity that occurs with long-term use.
Cyclosporine is an immunosuppressive that works by inhibition of calcineurin. A result of this inhibition is a decreased
production of IL-2. Like methotrexate, cyclosporine has also been used for decades in patients with psoriasis. Cyclosporine has a
rapid onset of action; however, care must be taken with the drug concerning hypertension and nephrotoxicity, and therefore
cyclosporine is not a good choice for long-term management of psoriasis.
Lastly, acitretin is an oral systemic used in psoriasis patients. This is a vitamin-A-derived retinoid that has only modest effects
on psoriasis. Because of this, the therapeutic is often used as a combination therapy rather than monotherapy. Acitretin functions
as a treatment in psoriasis by interfering with epidermal cell growth and differentiation. 133
Landmark clinical trials
The approval of biologic medications is challenging and expensive. Trials working with medications for psoriasis aim to
demonstrate a theraputic effect by a decrease in PASI score with treatment. The components of the PASI and PGA assessments
can be found in the “definitions” section of this paper. Fig. 4 below shows an example of a PASI worksheet. As a reminder, a
higher PASI score correlates with more severe disease. Rather than focus on the individual score alone, the improvement in PASI
score is the most important variable to evaluate the success of a medication. This clinical scoring has remained relatively
consistent and reports of 75, 90, and 100% improvements in PASI scores are now the standard for reporting. The subsequent
presentation of trials is not to encourage the use of one drug over another. Instead, it is intended to be a common source of
previously reported information, remembering every patient can respond differently to each of these medications. For ease of
reading, PASI scores have been rounded to the nearest whole number.
Etanercept
Leonardi et al. reported findings from a large (n = 672), 24-week, randomized control trial. 134 Four treatment groups were
defined – a low dose (25 mg weekly), medium dose (25 mg twice weekly), high dose (50 mg twice weekly), and placebo group.
At week 12, the percent of subjects achieving a PASI 75/90 in the placebo cohort was 4/1%. In the low dose group these
percentages increased to 14/3%, respectively. Within the medium dose group 34/12% achieved these PASI scores. Lastly, the
high dose group experienced the greatest success with 49/22% achieving a PASI 75/90. At the week 24 endpoint, PASI 75/90 in
the low dose: 25/6%, medium does: 44/20%, and high dose: 59/30% were increased compared to week 12.
A second study reported by Papp et al. randomized 583 subjects to receive placebo, etanercept 25 mg twice a week, or
etanercept 50 mg twice a week for 12 weeks. 135 After this time point all subjects received 25 mg of etanercept twice a week for
an additional 12 weeks. As expected, treatment groups significantly outperformed placebo. The PASI 75/90 scores for the 25 mg
twice weekly versus 50 mg twice weekly were as follows: 34/11% vs 49/21%, respectively. Following week 12, researchers
wanted to identify if subjects initially on 50 mg twice weekly

Fig. 4. The PASI score is calculated by summing the severity scores for each region and multiplying them by their corresponding
area and involvement scores. Each region score is then summed to give an overall PASI score. Of note, the buttock is included
within the lower extremities.
would experience a sustained response following a dose reduction to 25 mg twice weekly. A total of 179 subjects underwent this
dosage change. Of the 51% who had achieved a PASI 75 at week 12, 23% of them lost it by week 24 while on the reduced
dosage. Of the 49% who did not achieve a PASI 75 at week 12, only 32% went on to achieve this endpoint at week 24.
These trials demonstrated etanercept as a well-tolerated biologic with similar rates of adverse events (AE) and infection
occurring in each dosing scheme. Majority of adverse events were mild to moderate in severity. As mentioned, a risk of
malignancy was conferred to patients on this medication. One meta-analysis of 15,418 individuals on anti-TNF therapy
demonstrated only 0.84% of these patients received a cancer diagnosis (excluding non-melanoma skin cancer). 136
Adalimumab
The 52-week REVEAL study consisted of three periods. 102 In the initial period, subjects (n = 1212) were randomized to
receive placebo or active drug (80 mg loading dose followed by 40 mg injections biweekly). At week 16, PASI 75/90/100 for the
treatment group was 71/37/14%, respectively. Next, subjects who achieved a PASI 75 (n = 606) at week 16 continued into an
open-label period. During this period injections of 40 mg were administered biweekly through week 31. Placebo assigned
subjects from the first period were administered the loading dose on week 16, and continued onto 40 mg biweekly dosage. At
week 33, 84% achieved a PASI 75 and continued to the final period consisting of a re-randomized to either placebo or continued
adalimumab injections. Following re-randomization, the percentage of patients losing adequate response was significantly greater
in placebo (28%) compared to active treatment (5%), p < 0.001. Not surprising, the time it took for loss of response was much
shorter for subjects on placebo.

In the long-term extension, 840 patients from REVEAL and three other trials were continued on adalimumab. 137 Of the
patients who continued into the extension and had been on adalimumab for the duration of the REVEAL study, PASI 75/90/100
scores at week 160 were 76/50/31%, respectively.
Safety of the drug was demonstrated in both trials. Only 2% of subjects in the REVEAL study discontinued treatment due to
an AE. The only infections occurring at rates greater than 2% in the treatment groups included upper respiratory infection,
nasopharyngitis, and sinusitis. Rates of malignancy, serious infections, and serious adverse events (SAE) were comparable
between treatment and placebo groups. Adalimumab was associated with increased risks of non-melanoma skin cancer as had
been described in other clinical trials. Similar data was demonstrated in the long-term extension.
Infliximab
In EXPRESS 1, 378 subjects were randomized in a 4:1 ratio to receive infliximab at 5 mg/kg or placebo for 50 weeks. 103 At
week 24, subjects in the placebo arm blindly enter into active treatment receiving infliximab 5 mg/kg infusions for the
remainder of the study. The active treatment arm significantly outperformed placebo in PASI 75/90 and physician global
assessment scores (all p < 0.0 0 01). Within the treatment arm at week 10, PASI 75/90 scores were 80/57%, respectively.
Response was well maintained to week 24 with PASI 75/90 scores of 82/58%. By week 50, analysis of only patients on
infliximab for the entirety of the study revealed decreasing PASI 75/90 scores of 61/45%.
The EXPRESS 2 trial aimed to examine the effect of intermittent versus continuous maintenance dosing. 104 To accomplish
this the trial was split into an initial treatment period where subjects were randomized to receive infliximab at 3 mg/kg, 5 mg/kg,
or placebo at weeks 0, 2, and 6. At week 10 PASI 75 for the 3 mg/kg and 5 mg/kg cohort was 70% and 76% respectively. In the
second period subjects initiated on infliximab and achieved a PASI 75 were randomized to receive dosing every 8 weeks, or
intermittent dosing. Subjects in the intermittent dosing group received treatment during visits if they lost their PASI 75. Subjects
dosed every 8 weeks maintained their response more successfully than the intermittent dosing group for both 3 and 5 mg/kg
concentrations. At week 50, PASI 75/90 scores for the 5 mg/kg cohort dosed every 8 weeks was 55/34% respectively. In
comparison, the 5 mg/kg cohort dosed intermittently had PASI scores of 38/10%. PASI scores were lower for 3 mg/kg groups,
but exhibited a similar trend when comparing continuous and intermittent dosing schemes.
Infliximab was well tolerated in these subjects. Comparison of AE rates at week 24 revealed a slightly higher percentage in
the active treatment (82%) versus placebo groups (71%). Most common AE included upper respiratory infections, headache and
fatigue. In the infliximab groups from EXPRESS 1 three serious infections occurred. In EXPRESS 2, AE rates were comparable
between the continuous and intermittent infusion cohorts. Through week 50, only 2 malignancies occurred after excluding
squamous cell or basal cell cancers of the skin (n = 10). Of note, all 10 of these subjects with skin cancers had prior phototherapy.
Certolizumab pegol
CIMPASI-1 and CIMPASI-2 are the phase 3 trials that demonstrated the efficacy and safety of certolizumab pegol (CZP). 138
These replicate trials randomized 461 subjects to receive 400 mg CZP every 2 weeks, 200 mg CZP every 2 weeks (following 400
mg injections at week 0, 2, and 4), or placebo every 2 weeks in a 2:2:1 ratio. At week 16 the PASI 75/90/100 scores in subjects
receiving the 400 mg of CZP every 2 weeks from CIMPASI-1 were 76/44/13%. In the 200 mg cohort these scores were
66/36/14%. In comparison, the PASI scores in the 400 mg and 200 mg cohorts from CIMPASI-2 were 83/55/19% and
81/53/15%. By week 48, subjects in CIMPASI-1

receiving 400 mg vs 200 mg of CZP experienced higher PASI 75/90/100 scores (87/60/24% vs 67/43/22%). In CIMPASI-2,
respective scores were achieved in 81/62/38% vs 79/60/31%.
A third phase 3 trial, CIMPACT, included an etanercept active comparator group. 139 By week 12, 400 mg of CZP was found
to be superior and 200 mg of CZP non-inferior to etanercept. PASI 75/90/100 for these three cohorts at week 12 were
67/34/NA% (400 mg CZP) vs 61/31/NA% (200 mg CZP) vs 53/27/NA% (etanercept).
As previously mentioned, the CRIB and CRADLE studies demonstrated minimal to no placental and breastmilk transfer of
certolizumab pegol. The structure of CZP is what prevents this transfer. Because certolizumab is an Fc-free biologic it cannot
bind to the neonatal Fc receptor for IgG responsible for transfer across the placenta. 138
Safety of certolizumab pegol was well demonstrated and similar to other biologics. As with all TNF-inhibitors, the same
warnings and precautions should be followed. In CIMPASI-1 rates of SAE through week 16 were similar between placebo and
200 mg CZP cohorts, but slightly higher in the 400 mg CZP cohort (2.0% vs 2.1% vs 5.7%). A similar trend was found in
CIMPASI-2 with SAEs occurring in 0%, 2.2%, and 4.6%. The most common AEs reported in this medication included
nasopharyngitis and upper respiratory infection. Rate of malignancy through week 48 for the 400 mg cohort was low in both
trials (0.7% and 0.8%). Both cases represented a basal cell carcinoma.
Ustekinumab
In PHOENIX-1 766 subjects were randomized to receive 45 mg of ustekinumab, 90 mg of ustekinumab, or placebo. 112 At
week 12 subjects receiving 45 mg or 90 mg of drug experienced the following PASI 75/90/100 scores: 67/42/13% vs 66/37/11%.
Subjects on placebo then crossed into active treatment until week 40 with similar response as those initially randomized to
treatment. Maximum efficacy in patients on ustekinumab from the beginning of the trial was experienced around week 24.
Lastly, patients meeting a PASI 75 response at week 40 entered a randomized withdrawal phase. The median time to loss of the
PASI 75 response was approximately 15 weeks.
PHOENIX-2 randomized 1230 subjects into the same groups as PHOENIX-1. 111 At week 12, the percent of subjects
achieving a PASI 75/90/100 in the 45 mg group was 67/42/18%. In the 90 mg group these numbers increased to 76/51/18%. At
week 28, these PASI 75/90/100 scores for the 45 mg and 90 mg groups increased to 71/49/21% vs 79/56/29%.
The ACCEPT trial exchanged the placebo group for an active comparator, etanercept. 110 They randomized 903 subjects. The
45 mg and 90 mg ustekinumab groups both showed superiority compared to subjects on etanercept.
A 5-year follow-up of subjects in the PHOENIX-2 trial showed at week 244 that 77% and 79% of subjects achieved a PASI
75 in the 45 mg and 90 mg groups respectively.
Again, nasopharyngitis, URI, headache, and arthralgia were most commonly experienced AEs. Rates of discontinuation due to
AE were similar across treatment and placebo groups. Rates of AE, SAE, and discontinuation did not exhibit any dose response.
Following maintenance injections to week 76, no increase in MACE, SAEs, AEs, serious infection, or malignancy was found.
Secukinumab
The ERASURE trial was a 52-week study and randomized 738 subjects to receive placebo, 300 mg of drug, or 150 mg of
drug. 140 Subjects receiving 300 mg of secukinumab were more likely to achieve PASI endpoints compared to the 150 mg
group. At week 12 examination of the 30 0 mg group, PASI 75/90/10 0 was 82/59/29%. In the 150 mg group PASI 75/90/100
scores were achieved by 72/39/13%. At week 52, PASI 90/100 for the 300 mg group was well maintained at 60/39%.

The FIXTURE trial was identical in design with the exception of an etanercept comparison group. 140 In total, 1,306 subjects
were randomized. Comparison of the 300 mg secukinumab group vs etanercept group revealed the following respective PASI
75/90/100 scores: 77/54/24% vs 27/21/4%.
The SCULPTURE trial was a 52-week study that extended for an additional 2 years to examine long-term outcomes. 141 Of
the 168 subjects who received 300 mg of secukinumab every 4 weeks for 3 years, 64% had a PASI 90 score and 43% a PASI
100.
The most frequently experienced AEs were nasopharyngitis, headache, and diarrhea during induction. Overall the percentage
of patients experiencing an AE was similar between the 300 mg group, 150 mg group, and etanercept group (56%, 58%, and 58%
respectively). Likewise, the rates of SAEs were similar between the groups (6.8, 6.0, and 7.0 respectively per 100-patient years).
Exposure-related malignancy rates showed no clinically significant difference between drug and placebo groups.
Ixekizumab
The UNCOVER-1 trial lasted 12 weeks and randomized a total of 1,296 subjects to receive 80 mg every 2 weeks, 80 mg
every 4 weeks, or placebo. 117 Subjects dosed every 2 weeks experienced better outcomes than every 4 weeks. 82% from the
2-week cohort and 76% from the 4-week cohort achieved a physician global assessment score of 0 (clear) or 1 (almost clear) at
week 12. Additionally, comparing 2-week vs 4-week dosing after 12 weeks of treatment, revealed PASI 75/90/100 of 89/71/35%
vs 83/65/34%
UNCOVER-2 randomized 1224 subjects into similar groups as UNCOVER-1 but with an additional group assigned to 50 mg
of etanercept twice weekly. 116 Subjects dosed every 2 weeks experienced similar PASI and PGA scores at week 12 as
previously reported (PASI 75/90/100: 90/71/41%, and PGA of 0 or 1: 83%). Similarly, the every 4-week dosing group was
comparable to UNCOVER 1 data (PASI 75/90/100: 78/60/31%, and PGA of 0 or 1: 73%). The etanercept group in this study
achieved a PGA score of 0 or 1 in 36% and a PASI 75/90/100 of 42/19/5%.
Following week 12, subjects with a PGA score of 0 or 1 from UNCOVER 1 and 2 were randomized to receive placebo,
ixekizumab every 12 weeks, or ixekizumab every 4 weeks until week 60. Of subjects receiving every 4-week injections, 74%
maintained their PGA score at week 60, whereas only 39% and 7% of the every 12-week and placebo groups maintained their
score.
UNCOVER-3 randomized 1,346 subjects and was a long-term study. 116 At week 60 PASI 75/90/100 for patients on
ixekizumab were obtained in 83/73/55%.
Safety analysis of these three trials revealed the most common adverse events included nasopharyngitis, URI, injection site
reactions, and headache. Rates of serious adverse events were similar between ixekizumab and placebo groups. During the
induction phase, there were no differences in exposure-adjusted incidence rates of cancer, major adverse cardiac events (MACE)
or cerebrovascular events between the ixekizumab and placebo groups. In UNCOVER-2 and UNCOVER-3, similar rates of
infection (26% vs 22%) and non-fatal SAEs (2% vs 2%) were found between the ixekizumab group and etanercept group
respectively.
Brodalumab
In AMAGINE-1 661 subjects were randomized to receive 140 mg of drug, 210 mg of drug, or placebo every 2 weeks. 120
Subjects receiving 210 mg of active drug outperformed other groups and at week 12. Within the group administered 210 mg,
83/70/42% obtained PASI 75/90/100 scores.
Examination of AMAGINE-2 and AMAGINE-3 together included 3,712 total randomized patients. 121 These studies utilized
the same groups as AMAGINE-1 with addition of an ustekinumab group. In AMAGINE-2, Week 12 and 52 PASI 75/90/100
scores for patients receiving

210 mg of drug were 86/70/44% and 80/75/56%. In AMAGINE-3, these scores were 85/69/37% and 80/73/53%. In comparison,
the ustekinumab group in these two studies experienced a lower percentage of subjects obtaining a PASI 75/90/100
(AMAGINE-2: 7-/61/22%; AMAGINE-3: 69/57/19%). Like the other anti-IL-17A antibodies, the most frequent AEs reported for
brodalumab included nasopharyngitis, URI, headache, and arthralgia. SAEs through the entirety of the study occurred at a rate of
8.3 in subjects treated with brodalumab and 13.0 with ustekinumab within AMAGINE-2; rates of 7.9 and 4.0 respectively were
found in AMAGINE-3.
Guselkumab
In VOYAGE 1 a total of 837 patients were randomized to placebo, guselkumab 100 mg every 8 weeks, or adalimumab 40 mg
every 2 weeks. 142 At week 16, PASI 75/90/100 scores for the guselkumab group were 91/73/37%. By week 48, these scores
were changed to 88/76/47%. PASI 75/90/100 for the adalimumab group at week 16 (73/50/17%) and at week 48 (63/48/23%)
were lower than the guselkumab group.
VOYAGE 2 was designed similarly to VOYAGE 1, but contained a randomized withdrawal and re-treatment group starting at
week 28. 143 Only subjects who achieved a PASI 90 were included in the withdrawal and re-treatment period. Of the patients
randomized into the withdrawal group after week 24, the median time to loss of PASI 90 was approximately 15.2 weeks.
The most common AEs were infection including nasopharyngitis and URI. Rates of infection for placebo, guselkumab, and
adalimumab groups were 19%, 22%, and 23% respectively. At the end of study, the percentage of patients experiencing a SAE
was similar for the guselkumab and adalimumab groups (4.9% vs 4.5%). Rates of serious infections, MACE, and malignancy
were low across all groups.
Tildrakizumab
The first study, reSURFACE 1, was a three-part study running a total of 3 years. 122 In the first part, trial sites randomized
772 patients in a 2:2:1 fashion to receive 200 mg of tildrakizumab, 100 mg of tildrakizumab, or placebo for 12 weeks. At week
12, subjects on tildrakizumab achieved much greater rates of PASI 75 and PGA scores of 0 or 1 compared to placebo (p < 0.0 0
01). In the 20 0 mg dosing group, the percentage who achieved a PASI 75/90,100 at week 12 was 62/35/14%; rates in the 100 mg
tildrakizumab group were similar at 64/35/42%. In part two, the placebo group was re-randomized to either 100 mg or 200 mg of
tildrakizumab at week 12. These subjects exhibited similar response as subjects initially exposed to tildrakizumab. Finally, part
three consisted of a randomization to one of two arms beginning at week 28. The first consisted of tildrakizumab 200 mg or
treatment withdrawal. The second arm was treated with tildrakizumab 100 mg or withdrawn from treatment. If subjects
withdrawn from treatment relapsed, they resumed treatment with the dose of tildrakizumab used in their perspective arm. Of the
patients re-randomized to placebo, 57% from the 200 mg group and 49% from the 100 mg group maintained their PASI 75
response until week 64 (36 weeks following discontinuation of drug from part two of study).
The second study, reSURFACE 2, was a similar three-part design to reSURFACE 1, but included an active comparator group
randomized to etanercept. 122 As expected, tildrakizumab groups significantly outperformed placebo groups. Importantly, the
200 mg tildrakizumab group achieved significantly higher rates of PASI 75compared to the etanercept group. A significant
difference in PASI 75 only was found when comparing the 100 mg tildrakizumab to etanercept groups.
Adverse events related to the study medication were comparable to the other biologics. Nasopharyngitis was the most
commonly reported in both trials. Severe infections, malignancy, and drug-related hypersensitivity were all extremely rare
occurring in < 1%.

Conclusion
Psoriasis is a complex disease that negatively impacts patients physically and emotionally in a myriad of ways. Public
awareness of the condition has improved over time; however, continued education is necessary to reduce the social impacts and
stigma of psoriasis. Fortunately, research has produced therapeutics that have achieved unparalleled results in the treatment of
psoriasis. Nearly a decade ago, complete or nearly complete reduction in skin lesions were unheard of. Today, biologics continue
to push the envelope of possibility; achieving 90% or 100% reductions have become an achievable goal rather than a hope or
dream. Biologics have rapidly become the premier class of treatment in patients with moderate to severe psoriasis. As trials
continue to demonstrate the safety and efficacy of these medications, hopefully physicians will become more familiar and
comfortable in their use.
Financial disclosures
Eric Schadler has served as a sub-investigator for clinical studies sponsored by companies that manufacture drugs used for the
treatment of psoriasis including AbbVie, Boehringer- Ingelheim, Bristol Myers Squibb, Eli Lilly, Janssen, Novartis, and UCB.
Dr. Stephanie Mehlis has served as a consultant and/or paid speaker for and/or served as principal investigator in clinical
studies sponsored by companies that manufacture drugs used for the treatment of psoriasis including AbbVie, Amgen,
Boehringer-Ingelheim, Bristol Myers Squibb, Celgene, Eli Lilly, GlaxoSmithKline, Janssen, Maruho, Novartis, Pfizer, and UCB.
Dr. Bernhard Ortel has no financial disclosures.
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