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DERMATOLOGY
AS PRESENTED IN THE ROUNDS OF

Rounds
TM THE D IVISION OF D ERMATOLOGY,
®

M C G ILL U NIVERSITY H EALTH C ENTRE

Members of the
Division of Dermatology
Systemic Corticosteroid Use in Dermatology:
Defining, Detailing, and Demystifying Alfred Balbul, MD
Alain Brassard, MD
By L OUK IA MI TSOS, MD, PhD, and DE NIS SA SSEVILLE, MD, F RCPC Daniel Barolet, MD

Corticosteroids play a major role in the dermatologist’s armamentarium. First used for Wayne D. Carey, MD
inflammatory dermatoses in 1951, they remain the mainstay of dermatological therapy because Ari Demirjian, MD
of their anti-inflammatory and immunosuppressive properties.1 This issue of Dermatology Therese El-Helou, MD
Rounds reviews the pharmacology, dosing, and adverse effects (AEs) of these common agents.
William Gerstein, MD

Corticosteroids (CSs) have long been a mainstay of pharmacotherapy in a variety of disorders Fatemeh Jafarian, MD
and conditions for the suppression of inflammation and of the immune system. Research con- Manish Khanna, MD
ducted in 19292,3 led to the development of cortisone as a new compound in 1935.4 In dermatol- Audrey Lovett, MD
ogy, CSs are widely prescribed in either topical or systemic formulations in various potencies to
Raynald Molinari, MD
tailor therapy according to severity of the underlying condition, anatomic location of application,
area of involvement, and patient age.5 CSs, however, are associated with a number of serious Linda Moreau, MD, Director
adverse events, particularly with long-term use. Safe and effective use of this class of agents, there- Brenda Moroz, MD
fore, requires knowledge of their mechanism of action and potential complicating factors. Khue Huu Nguyen, MD
Overview of Systemic Corticosteroids Elizabeth A. O’Brien, MD
The basic structure of all CSs is the cyclopentanoperhydrophenanthrene ring, composed of Denis Sasseville, MD
3 hexane rings and 1 pentane ring. Modifications on this steroid structure result in synthetic Editor, Dermatology Rounds
agents with varying anti-inflammatory potencies, mineralocorticoid effects, and durations of Wendy R. Sissons, MD
action (Table 1). Active molecules, such as cortisol and prednisolone, have the essential hydroxyl Beatrice Wang, MD
group in position 11. Prednisone and cortisone must undergo conversion by the 11 hydroxylation
Kevin Watters, MD
enzyme in the liver to become activated. Prednisolone or cortisol should be administered in
patients with severe hepatic disease since they are unable to metabolize prednisone or cortisone.6 Shadi Zari, MD

Absorption and distribution

Over 50% of administered CSs are absorbed in the upper jejunum.6 Concomitant administra-
tion with food does not affect absorption, but may delay it. Peak plasma levels are achieved with- Centre universitaire
in 30-100 minutes. Metabolized primarily by the liver, metabolites are excreted by the kidney and de santé McGill
liver. Approximately 90%-95% of endogenous CSs are bound to cortisol-binding protein (also
known as transcortin) or to albumin in the circulation. The other 5% is unbound cortisol;7 this is McGill University
the active moiety. Many factors influence circulating quantities of cortisol-binding protein (CBP). Health Centre
It is increased in pregnancy, estrogen therapy, and hyperthyroidism. However, conditions such as McGill University Health Centre
hepatic failure, renal failure, and hypothyroidism decrease CBP levels and, therefore, increase Division of Dermatology
drug toxicity. Synthetic glucocorticoids have less avidity for CBP (estimated at 70%) and, thus, Royal Victoria Hospital
have a higher AE profile. 687 Pine Avenue West
Room A 4.17
Mechanism of action Montreal, Quebec H3A 1A1
Tel.: (514) 934-1934, local 34648
A schematic representation of the hypothalamic-pituitary-adrenal (HPA) axis is shown in Fax: (514) 843-1570
Figure 1. The HPA axis is a feedback loop that includes the hypothalamus and the pituitary and
adrenal glands. The hypothalamus produces corticotropin-releasing hormone (CRH) that is
released onto the anterior pituitary gland. The latter secretes adrenocorticotropin hormone The editorial content of
Dermatology Rounds is determined
(ACTH) into the systemic circulation that, in turn, stimulates the synthesis and systemic release solely by the Division of Dermatology,
of CS by the adrenal glands. The loop is completed by the negative feedback of cortisol on the McGill University Health Centre.
hippocampus, the hypothalamus, and the pituitary gland. The greatest amount of cortisol is
released during the early morning hours prior to waking. The basal rate of cortisol production is
20-30 mg daily;8 however, up to a 10-fold increase is possible in situations of stress.9
 Table 1: Systemic corticosteroid (CS) Figure 1: Hypothalamic-pituitary-adrenal axis
pharmacology function and regulation

Equiva- Mineralo- Plasma Duration

lent dose corticoid half-life of action
Hippocampus
(mg) potency (min) (hrs)
Short-acting
Cortisone 25 1 60 8-12 Hypothalamus Cytoplasm
CRF Nucleus
Hydro- 20 0.8 90 8-12 GRE X
cortisone Annexin 1
MAPK
TNF-α
GM-CSF
phosphatase IL-1, IL-2, IL-8
Intermediate-acting
Prednisone 5 0.25 60 24-36 Anterior Pituitary

Prednisolone 5 0.25 200 24-36 Glucocorticosteroid (Cortisol)

Adrenal Gland Glucocorticosteroid Receptor
Methylpred- 4 0 180 24-36
nisolone Activating Protein 1
NF-kB
Triamcinolone 4 0 300 24-36
Cortisol
Long-acting
Dexametha- 0.75 0 200 36-54 CRF = corticotropin releasing factor; ACTH = adrenocorticotropin
sone hormone; GRE = glucocorticosteroid response element;
MAPK = mitogen-activated protein kinase; TNF = tumour necrosis
Betametha- 0.6 0 200 36-54 factor; GM-CSF = granulocyte-macrophage colony-stimulating
sone factor; IL = interleukin; NF = nuclear factor

Cortisol enters the cellular cytoplasm and binds to the
CS receptor.10 This activated receptor complex then
translocates to the nucleus to either enhance or inhibit the
expression of target genes by 2 independent mechanisms.
In the first, direct binding of the activated glucocorticoid
receptor complex to a specific deoxyribonucleic acid
(DNA) sequence, known as the glucocorticoid response
element, in its promoter region induces transcription of
annexin I and mitogen-activated protein kinase (MAPK)
phosphatase 1. This limits the formation of prostaglandins
and leukotrienes. In the second mechanism, the receptor
complex binds to activator protein 1 (AP1) and nuclear
factor κB (NF-κB), thus inhibiting them. The end result is
inactivation of cytokines, interleukins (ILs), adhesion mol-
ecules, and proteases, which achieves a decreased inflam-
matory state.
Dermatological indications and contraindications
CSs are used to treat a vast array of acute and chronic
dermatological conditions; broad categories are listed in
Table 2. Absolute contraindications to systemic steroids
are systemic fungal infections, herpes simplex keratitis,
and hypersensitivity. Relative contraindications include
active tuberculosis (TB) or a positive tuberculin test (puri-
fied protein derivative [PPD]), active peptic ulcer disease
(PUD), or recent anastomotic surgery, hypertension,
depression or psychosis, diabetes mellitus (DM), osteo-
porosis, cataracts, and glaucoma.
Drug interactions
Most drug interactions are due to dexamethasone and
methylprednisolone, whereas prednisone and pred-
nisolone have fewer interactions. Medications that may
increase serum levels of CS are macrolide antibiotics and
azole antifungals via cytochrome P (CYP) 3A4 inhibition,
and hormonal contraceptives via decreased clearance.
Similarly, induction of CYP 3A4 by rifampin and anticon-
vulsants such as phenytoin and phenobarbital may
decrease serum levels of CS. Other effects are due to
potentiation of intrinsic AEs rather than true interactions.
Noteworthy are increased gastrointestinal (GI) toxicity
with nonsteroidal anti-inflammatory drugs (NSAIDs),
additive immunosuppression when coadministered with
other immunosuppressant drugs, decreased effectiveness
of antidiabetic agents due to induced hyperglycemia with
CS, and worsening hypokalemia with diuretics. Hypo-
kalemia is also responsible for the increased arrhythmias
after concomitant administration of digoxin and fluro-
quinolones.8
Dosing and Administration in Dermatology
Glucocorticoids differ in their relative anti-inflamma-
tory and mineralocorticoid effects and duration of ACTH
suppression. CSs with minimal mineralocorticoid effects
are usually selected to decrease sodium retention. More-
over, CSs with an intermediate half-life are preferred to
reduce AEs. Prednisone is usually the oral medication of
choice because it has a sufficiently prolonged action to
ensure the sustained effectiveness of a single daily dose
and minimal mineralocorticoid activity. The daily dose of
prednisone varies depending on severity of the dermato-
logical condition and ranges from 0.5-3 mg/kg/day.11,12
The most common initial dose is 40-60 mg/day for an
average-sized individual. Treatment regimens can be divid-
ed into low-dose (<10 mg of prednisone or equivalent per
day) and high-dose (>20 mg per day).13 Physiological
doses are equivalent to about 5-7 mg of prednisone.
CSs can be given as a single daily dose, a split dose, or
as an alternate-day dose. When initiating therapy, a single
daily dose is preferable, given in the morning when there is
maximal adrenocortical cortisol secretion. At this time,
the HPA-axis is least suppressed by medication since max-
 Table 2: Cutaneous indications for CS therapy as >4 weeks duration.14 In long-term therapy, CS-sparing
agents are usually added to the regimen, allowing the
Bullous dermatoses patient to be weaned off the steroids.
• Pemphigus vulgaris
• Bullous pemphigoid Tapering
• Cicatricial pemphigoid
• Linear immunoglobulin A bullous dermatosis CS tapering is required to avoid a flare of the dermato-
• Epidermolysis bullosa acquisita logical condition and prevent withdrawal symptoms due to
• Herpes gestationis persistent HPA axis suppression. There is a lack of clinical
• Erythema multiforme evidence to favour a particular regimen, and various taper-
• Toxic epidermal necrolysis ing durations have been studied. Two studies revealed that
(Stevens-Johnson syndrome)
there were no clinically significant differences in outcomes
Autoimmune connective tissue diseases between a 2- to 5-month tapering timeframe.15,16 Short-
• Dermatomyositis
term glucocorticoid therapy, even at high doses, can be
• Systemic lupus erythematosus
• Mixed connective-tissue disease stopped without tapering because HPA suppression will
• Eosinophilic fasciitis not persist and consequences are unlikely. In long-term
• Relapsing polychondritis therapy, however, tapering should be done in decrements
Neutrophilic dermatoses of 10% to 20% every 1 to 2 weeks, taking into account the
• Pyoderma gangrenosum underlying disease, patient frailty, and individual response.
• Acute febrile neutrophilic dermatosis For prednisone, this roughly translates into a decrease of:8
(Sweet syndrome) • 10 mg/day every 1-2 weeks for an initial dose
• Behçet disease >60 mg
Papulosquamous and eczematous dermatoses • 5 mg/day for 1-2 weeks for doses between
• Contact dermatitis 20-60 mg/day
• Atopic dermatitis • 2.5 mg/day for 1-2 weeks for doses between
• Photodermatitis
10-20 mg/day
• Exfoliative dermatitis
• Erythrodermas • 1 mg/day for 1-2 weeks for doses between
• Lichen planus 5-10 mg/day
Vasculitis
• 0.5 mg/day every 1-2 weeks for doses <5 mg/day
• Cutaneous and systemic
Intravenous (IV) therapy
Others
• Sarcoidosis IV CSs are given in 2 situations: for stress coverage in
• Urticaria/angioedema patients on long-term CS and HPA axis suppression, and
• Androgen excess (acne, hirsutism) in severe or life-threatening diseases to rapidly gain con-
• Type I reactive leprosy trol. Two methods of administration are available: methyl-
• Problematic hemangiomas of infancy prednisolone, devoid of mineralocorticoid activity, can be
• Kasabach-Merritt syndrome given at a dose of 2 mg/kg divided 4 times daily or as pulse
• Panniculitis
therapy of 500-1000 mg daily for 1-5 days. Pulse therapy
is usually given in a monitored setting due to potential
imal feedback suppression of ACTH secretion occurs from serious AEs (ie, sudden death, atrial fibrillation, anaphy-
endogenous production. To gain rapid control in severe laxis, and electrolyte imbalances). Slow administration of
disease, a split dose (subdividing the daily dose in up to 4 pulse steroids over 2 hours, along with concomitant infu-
doses) can maintain a steady plasma concentration. This sion of potassium and electrolytes controls before and
increases medication efficacy, but also increases HPA axis after therapy, help circumvent these effects.17,18
suppression. Therefore, conversion to a single daily dose
should be done as soon as possible. Intramuscular (IM) therapy
Alternate-day regimens – used once disease control is IM CS therapy is not widely used in dermatology. One
obtained – is double the usual daily dose given every sec- advantage is assured compliance since the physician
ond day. The rationale is that efficacy is determined more administers the dose. However, once the dose is adminis-
by anti-inflammatory intracellular transcription mecha- tered, there are disadvantages, including high interperson-
nisms than by actual drug presence in the circulation.8 In al variability with erratic absorption, lack of daily dose
this regimen, patients are not exposed to high daily gluco- control, and no diurnal variation. Therefore, this route of
corticoid concentrations and, therefore, have less HPA axis administration is considered to be less physiological.
suppression. Conversion from a daily to an alternate-day Tapering only occurs through biotransformation of the
regimen should be carried out gradually. One method is to drug. Other unique complications are lipoatrophy and
progressively diminish the dose on one day, while building sterile abscess formation at the injection site.19
it up the next.
Use of CS can be divided into short-term and long- Adverse Effects (AEs) Associated
term therapy. Short-term is defined as treatment for ≤3 with Corticosteroids
weeks and is usually reserved for acute conditions (ie, CS therapy is associated with numerous AEs. Short-
allergic contact dermatitis). Long-term therapy is defined term therapy is usually well-tolerated and has fewer AEs.20
 Table 3: Adverse events associated with CS therapy

Follow-up
Baseline At 1 month and
(pre-treatment ) then every 3 months Annual Treatment cessation
History Personal and family Polyuria
history: diabetes, Polydipsia
hypertension, Psychological effects
dyslipidemia, Sleep disturbance
glaucoma Bone pain
Abdominal pain
Physical BP BP
examination Height Height
Weight Weight

Laboratory Fasting glucose Fasting glucose AM cortisol

Lipid profile Lipid profile
Electrolytes Electrolytes

Imaging CXR
DEXA (at-risk patients) DEXA

Special tests Tuberculin skin test Slit lamp exam

(PPD)
Slit lamp exam

BP = blood pressure; CXR = chest x-ray; DEXA = dual-energy x-ray absorptiometry; PPD = purified protein derivative

AEs are typically dose-related and increase signifi-
cantly at higher doses. However, even low doses for
prolonged periods are associated with significant
morbidity and mortality.14,21,22 Clinicians need to
thoroughly evaluate and monitor (Table 3) their
patients at baseline and during follow-up visits when
prolonged CS therapy is anticipated. Given the
numerous AEs of CS, this article focuses on those
that are more common and preventable.
Skeletal
Osteoporosis is one of the most prevalent and
serious AEs of prolonged CS therapy. The prevalence
of CS-induced osteoporosis can be as high as 30%-
50% if no preventive measures are taken.23,24 Patients
at highest risk are the elderly, postmenopausal
women, smokers, alcoholics, and those with previous
osteoporosis or fractures, sedentary lifestyle, low
body-mass index, hyperthyroidism, higher CS dose,
and rheumatoid arthritis. Most of the bone loss
occurs in the first 6-12 months of corticotherapy;24
therefore, preventive treatment should be initiated
early if prolonged therapy is expected (>5 mg of
prednisone for >4 weeks). Patients should abstain
from smoking, minimize alcohol and caffeine con-
sumption, perform weight-bearing exercises, and take
calcium 1500 mg and vitamin D 800 IU daily (some
authors recommend even higher doses of vitamin
D).25 Patients should undergo annual bone density
testing; as dual-energy x-ray absorptiometry scans are
not all made equal, the patient should go to the same
location every year.26 First-line preventive therapy is
oral bisphosphonates; eg, alendronate (70 mg once a
week) or risedronate (35 mg once a week or 150 mg
once a month).24 Discussion of other second-line
treatments (eg, raloxifen, calcitonin) and newer mol-
ecules (eg, teriparatide and denosumab) is beyond
the scope of this article.
Osteonecrosis, also known as avascular or aseptic
necrosis of the femoral head, is one of the most feared
complications of CS therapy.6 It usually occurs after
6-12 months of CS therapy and is associated with risk
factors such as trauma, alcohol abuse, smoking, renal
transplantation, systemic lupus erythematosus (SLE),
and hypertriglyceridemia. Localized pain on exertion
progresses to pain at rest, and because findings on
plain x-rays may take 6 months to appear, magnetic-
resonance imaging is preferred for diagnosis given its
higher sensitivity and specificity.27 Conservative
treatment consists of stopping medications, rest, and
avoiding weight-bearing. More advanced cases
require referral to an orthopedic surgeon for core
decompression and fibular grafting. In most cases,
total hip arthroplasty is eventually required.28
Gastrointestinal
Many physicians concomitantly prescribe hista-
mine receptor antagonists or proton pump inhibitors
with CSs to avoid gastric and duodenal ulcers;
however, there is controversy in the literature on this
topic. CSs independently increase the risk of PUD,
but this increase is marginal (estimated relative risk
1.1-1.5),29,30 which is less than the risk associated
with NSAIDs. However, the combination of CSs and
NSAIDs results in a synergistic increase. Studies have
revealed a 2-fold increased risk of GI AEs in patients
taking CSs and NSAIDs compared to those taking
NSAIDs alone31 and a 4-fold increased risk of GI
complications when compared to nonusers of either
drug.30 Patients taking CSs in combination with

DERMATOLOGY
Rounds
TM
acetylsalicylic acid or other NSAIDs or with risk
factors for PUD require prophylaxis; however,
cytoprotection is debatable in patients taking gluco-
corticoids alone. Early symptoms of PUD are masked
by the anti-inflammatory effects of CSs, which
explains the higher degree of perforation.
Ocular
Glaucoma, mostly associated with topical oph-
thalmic steroid preparations, has been documented
with systemic CS at doses >10 mg/day.32 Cataracts
usually occur bilaterally after prolonged CS use and
can be distinguished from senile cataracts by their
posterior subcapsular location. Children are more
susceptible than adults. Cataract formation is usually
caused by doses >10 mg/day continuously for >1
year.33 Cataracts may stabilize if the CS dose is signif-
icantly lowered or the CS is discontinued.34 Ophthal-
mological evaluation should be performed annually
to detect and treat these complications.
Cardiometabolic
Metabolic and cardiovascular AEs associated with
CSs are numerous. Increases in blood pressure (BP)
may occur secondary to increased sodium and fluid
retention, particularly among CSs with strong miner-
alocorticoid effects (fludrocortisone and hydrocorti-
sone).35 Patients should be monitored every 2-3
months for BP elevations. Lipid abnormalities, particu-
larly hypertriglyceridemia, are common; the mecha-
nism may be related to insulin insufficiency and
ACTH suppression.36 All patients on prolonged CS
therapy should follow a calorie-restricted diet low in
saturated fats. Hyperglycemia is another potential
metabolic AE. Causal mechanisms include increased
hepatic gluconeogenesis, decreased peripheral glucose
uptake, and insulin resistance via alteration of receptor
functions.37,38 Development of de novo DM is uncom-
mon if the patient previously had normal glucose tol-
erance; most patients revert to their prior glycemic
status within a few months of CS cessation.39 Patients
with pre-existing DM or glucose intolerance common-
ly experience significant hyperglycemia and difficulty
with glycemic control during CS therapy. Frequent
blood glucose monitoring is required and patients
should be managed pharmacologically as routine type
II diabetics. Patients already on oral hypoglycemic
agents often require therapy with insulin.
Cutaneous
Multiple cutaneous effects can occur with sys-
temic CS therapy, including purpura, telangiectasias,
atrophy, striae, pseudoscars, acneiform or rosacea-like
eruptions, hirsutism, alopecia, hyper/hypopigmenta-
tion, acanthosis nigricans, facial plethora, and fat
redistribution causing the classic “buffalo hump” on
the upper back. Systemic CS-induced acne or folli-
culitis characteristically presents with uniform papu-
lopustules on the chest and back. Systemic CS
therapy may impair wound healing by inhibiting
DERMATOLOGY
Rounds
angiogenesis, fibroblast function, and collagen produc-
tion.20 Some of these AEs are permanent; therefore, a
high index of suspicion is required to prevent them.
Immunological
CSs are associated with multiple effects on the
immune system. There is an increased susceptibility
to bacterial, viral, fungal, and parasitic infections, in
particular cutaneous staphylococcal and superficial
fungal infections. A high index of suspicion is
required as fever and other signs of inflammation
may be masked. Alternate-day therapy and low-dose
therapy reduce the chance of opportunistic infec-
tion.40 Because TB reactivation remains a concern in
long-term therapy, a detailed exposure history should
be taken prior to therapy initiation.41 A PPD should
be performed and, if positive, a baseline chest x-ray. A
9-month course of isoniazid is recommended for
patients with latent TB.41 Patients with human
immunodeficiency virus, Wegener granulomatosis,
SLE, or on other immunosuppressive agents should
receive trimethoprim-sulfamethoxazole or dapsone
prophylaxis to prevent infection with Pneumocystis
jiroveci.42
Adrenal suppression
Exogenous CS can affect the entire HPA axis
and cause adrenal suppression within 4 weeks, even
at low doses. This can be mitigated by using single
morning doses or an intermediate-acting agent on
alternate days. The hypothalamus is suppressed
first; however, it is the first to recover, while the
adrenals are the slowest to recover. After prolonged
suppression, ACTH levels may not return to normal
for months and cortisol levels may take >1 year to
recover.8 HPA axis suppression can be verified by
measuring the morning serum cortisol level. Morn-
ing CS dose should be held on the day of the test.
Low cortisol levels (<10 g/dL) confirm impaired
HPA axis function. Adrenal function can be tested
with the ACTH stimulation test, where 250 g of
ACTH is administered and cortisol levels are mea-
sured at 30 minutes and 1 hour after administra-
tion; cortisol levels >16 g/dL indicate normal
adrenal function.8 With HPA axis suppression, the
body is unable to mount a stress response. Early
symptoms of adrenal crisis are weakness, fatigue,
anorexia, nausea, and fever. IV CSs are necessary
prior to major surgery or in severe illness to avoid
shock. The usual morning dose is taken with an
additional 100 mg hydrocortisone IV at induction
of anesthesia and 25 mg of hydrocortisone every 8
hours for 24 hours. 43 Minor surgical procedures
under local anesthesia do not require replacement
therapy.
A more common problem is the CS withdrawal
syndrome wherein the patient develops arthralgias,
headache, mood swings, lethargy, and nausea upon
rapid tapering of long-term CS therapy. A slower
taper prevents this problem.18,44
TM

Special considerations
CS use in children can cause growth retardation, even
at low doses of 5 mg/day. Alternate-day administration
minimizes growth retardation.45 Compensatory growth
occurs on discontinuation of therapy unless it was given in
adolescence and there was epiphyseal closure. Baseline
and routine monitoring of height and weight during visits
should be performed. Administration of high-dose CS dur-
ing the first trimester of pregnancy has been associated
with cleft palates in animal studies; however, this risk does
not appear to translate to humans.46 Prednisone is classi-
fied as category C in pregnancy.
Conclusion
CSs are extremely useful molecules in the treatment
of myriad dermatological conditions. They often provide
rapid response; however, it is essential to have an in-depth
knowledge of their mechanisms of action to be comfort-
able using these molecules and to avoid or mitigate
adverse effects. In an era of steroid phobia, physicians need
to convey the benefits of these medications, as well as the
importance of compliance and monitoring to prevent any
serious complications.
Dr. Mitsos is a Resident, Division of Dermatology, McGill
University, Montreal, Quebec
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This publication is made possible by an unrestricted educational grant from
LEO Pharma
© 2011 Division of Dermatology, McGill University Health Centre, Montreal, which is solely responsible for the contents. The opinions expressed in this publication do not necessarily
reflect those of the publisher or sponsor, but rather are those of the authoring institution based on the available scientific literature. Publisher: SNELL Medical Communication Inc.
in cooperation with the Division of Dermatology, McGill University Health Centre. ®Dermatology Rounds is a registered trade mark of SNELL Medical Communication Inc. All rights
reserved. The administration of any therapies discussed or referred to in Dermatology Rounds should always be consistent with the recognized prescribing information in Canada.
SNELL Medical Communication Inc. is committed to the development of superior Continuing Medical Education.
SNELL
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