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DERMATOLOGY
Systemic Corticosteroid Use in Dermatology: Defining, Detailing, and Demystifying
By LOUKIA MITSOS, MD, PhD, and DENIS SASSEVILLE, MD, FRCPC

AS
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PRESENTED IN THE ROUNDS OF

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THE

D IVISION

OF

D ERMATOLOGY,

M C G ILL U NIVERSITY H EALTH C ENTRE

Members of the Division of Dermatology
Alfred Balbul, MD Alain Brassard, MD Daniel Barolet, MD Wayne D. Carey, MD Ari Demirjian, MD Therese El-Helou, MD William Gerstein, MD Fatemeh Jafarian, MD Manish Khanna, MD Audrey Lovett, MD Raynald Molinari, MD Linda Moreau, MD, Director Brenda Moroz, MD Khue Huu Nguyen, MD Elizabeth A. OBrien, MD Denis Sasseville, MD Editor, Dermatology Rounds Wendy R. Sissons, MD Beatrice Wang, MD Kevin Watters, MD Shadi Zari, MD

Corticosteroids play a major role in the dermatologists armamentarium. First used for inflammatory dermatoses in 1951, they remain the mainstay of dermatological therapy because of their anti-inflammatory and immunosuppressive properties.1 This issue of Dermatology Rounds reviews the pharmacology, dosing, and adverse effects (AEs) of these common agents. Corticosteroids (CSs) have long been a mainstay of pharmacotherapy in a variety of disorders and conditions for the suppression of inflammation and of the immune system. Research conducted in 19292,3 led to the development of cortisone as a new compound in 1935.4 In dermatology, CSs are widely prescribed in either topical or systemic formulations in various potencies to 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 adverse events, particularly with long-term use. Safe and effective use of this class of agents, therefore, requires knowledge of their mechanism of action and potential complicating factors.

Overview of Systemic Corticosteroids

The basic structure of all CSs is the cyclopentanoperhydrophenanthrene ring, composed of 3 hexane rings and 1 pentane ring. Modifications on this steroid structure result in synthetic agents with varying anti-inflammatory potencies, mineralocorticoid effects, and durations of action (Table 1). Active molecules, such as cortisol and prednisolone, have the essential hydroxyl group in position 11. Prednisone and cortisone must undergo conversion by the 11 hydroxylation 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

Absorption and distribution

Over 50% of administered CSs are absorbed in the upper jejunum.6 Concomitant administration with food does not affect absorption, but may delay it. Peak plasma levels are achieved within 30-100 minutes. Metabolized primarily by the liver, metabolites are excreted by the kidney and 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 the active moiety. Many factors influence circulating quantities of cortisol-binding protein (CBP). It is increased in pregnancy, estrogen therapy, and hyperthyroidism. However, conditions such as hepatic failure, renal failure, and hypothyroidism decrease CBP levels and, therefore, increase drug toxicity. Synthetic glucocorticoids have less avidity for CBP (estimated at 70%) and, thus, have a higher AE profile.

Centre universitaire de sant McGill McGill University Health Centre

McGill University Health Centre Division of Dermatology Royal Victoria Hospital 687 Pine Avenue West Room A 4.17 Montreal, Quebec H3A 1A1 Tel.: (514) 934-1934, local 34648 Fax: (514) 843-1570

Mechanism of action
A schematic representation of the hypothalamic-pituitary-adrenal (HPA) axis is shown in 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 (ACTH) into the systemic circulation that, in turn, stimulates the synthesis and systemic release of CS by the adrenal glands. The loop is completed by the negative feedback of cortisol on the 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

The editorial content of Dermatology Rounds is determined solely by the Division of Dermatology, McGill University Health Centre.

Table 1: Systemic corticosteroid (CS) pharmacology Equiva- Mineralo- Plasma Duration lent dose corticoid half-life of action (mg) potency (min) (hrs) Short-acting Cortisone Hydrocortisone Prednisone Prednisolone Methylprednisolone Triamcinolone Long-acting Dexamethasone Betamethasone 0.75 0.6 0 0 200 200 36-54 36-54 25 20 1 0.8 60 90 8-12 8-12

Figure 1: Hypothalamic-pituitary-adrenal axis function and regulation

Hippocampus

Hypothalamus CRF

Cytoplasm GRE X

Nucleus
Annexin 1 MAPK phosphatase TNF- GM-CSF IL-1, IL-2, IL-8

Intermediate-acting 5 5 4 4 0.25 0.25 0 0 60 200 180 300 24-36 24-36 24-36 24-36
Cortisol Adrenal Gland Anterior Pituitary Glucocorticosteroid (Cortisol) Glucocorticosteroid Receptor Activating Protein 1 NF-kB

CRF = corticotropin releasing factor; ACTH = adrenocorticotropin hormone; GRE = glucocorticosteroid response element; MAPK = mitogen-activated protein kinase; TNF = tumour necrosis factor; GM-CSF = granulocyte-macrophage colony-stimulating 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 B (NF-B), thus inhibiting them. The end result is inactivation of cytokines, interleukins (ILs), adhesion molecules, and proteases, which achieves a decreased inflammatory state.

Similarly, induction of CYP 3A4 by rifampin and anticonvulsants 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. Hypokalemia is also responsible for the increased arrhythmias after concomitant administration of digoxin and fluroquinolones.8

Dosing and Administration in Dermatology

Glucocorticoids differ in their relative anti-inflammatory and mineralocorticoid effects and duration of ACTH suppression. CSs with minimal mineralocorticoid effects are usually selected to decrease sodium retention. Moreover, 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 dermatological 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 divided 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-

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 (purified protein derivative [PPD]), active peptic ulcer disease (PUD), or recent anastomotic surgery, hypertension, depression or psychosis, diabetes mellitus (DM), osteoporosis, cataracts, and glaucoma.

Drug interactions
Most drug interactions are due to dexamethasone and methylprednisolone, whereas prednisone and prednisolone 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.

Table 2: Cutaneous indications for CS therapy Bullous dermatoses Pemphigus vulgaris Bullous pemphigoid Cicatricial pemphigoid Linear immunoglobulin A bullous dermatosis Epidermolysis bullosa acquisita Herpes gestationis Erythema multiforme Toxic epidermal necrolysis (Stevens-Johnson syndrome) Autoimmune connective tissue diseases Dermatomyositis Systemic lupus erythematosus Mixed connective-tissue disease Eosinophilic fasciitis Relapsing polychondritis Neutrophilic dermatoses Pyoderma gangrenosum Acute febrile neutrophilic dermatosis (Sweet syndrome) Behet disease Papulosquamous and eczematous dermatoses Contact dermatitis Atopic dermatitis Photodermatitis Exfoliative dermatitis Erythrodermas Lichen planus Vasculitis Cutaneous and systemic Others Sarcoidosis Urticaria/angioedema Androgen excess (acne, hirsutism) Type I reactive leprosy Problematic hemangiomas of infancy Kasabach-Merritt syndrome Panniculitis

as >4 weeks duration.14 In long-term therapy, CS-sparing agents are usually added to the regimen, allowing the patient to be weaned off the steroids.

Tapering
CS tapering is required to avoid a flare of the dermatological condition and prevent withdrawal symptoms due to persistent HPA axis suppression. There is a lack of clinical evidence to favour a particular regimen, and various tapering durations have been studied. Two studies revealed that there were no clinically significant differences in outcomes between a 2- to 5-month tapering timeframe.15,16 Shortterm glucocorticoid therapy, even at high doses, can be stopped without tapering because HPA suppression will not persist and consequences are unlikely. In long-term therapy, however, tapering should be done in decrements of 10% to 20% every 1 to 2 weeks, taking into account the underlying disease, patient frailty, and individual response. For prednisone, this roughly translates into a decrease of:8 10 mg/day every 1-2 weeks for an initial dose >60 mg 5 mg/day for 1-2 weeks for doses between 20-60 mg/day 2.5 mg/day for 1-2 weeks for doses between 10-20 mg/day 1 mg/day for 1-2 weeks for doses between 5-10 mg/day 0.5 mg/day every 1-2 weeks for doses <5 mg/day

Intravenous (IV) therapy

IV CSs are given in 2 situations: for stress coverage in patients on long-term CS and HPA axis suppression, and in severe or life-threatening diseases to rapidly gain control. Two methods of administration are available: methylprednisolone, devoid of mineralocorticoid activity, can be given at a dose of 2 mg/kg divided 4 times daily or as pulse therapy of 500-1000 mg daily for 1-5 days. Pulse therapy is usually given in a monitored setting due to potential serious AEs (ie, sudden death, atrial fibrillation, anaphylaxis, and electrolyte imbalances). Slow administration of pulse steroids over 2 hours, along with concomitant infusion of potassium and electrolytes controls before and after therapy, help circumvent these effects.17,18

imal feedback suppression of ACTH secretion occurs from endogenous production. To gain rapid control in severe disease, a split dose (subdividing the daily dose in up to 4 doses) can maintain a steady plasma concentration. This increases medication efficacy, but also increases HPA axis suppression. Therefore, conversion to a single daily dose should be done as soon as possible. Alternate-day regimens used once disease control is obtained is double the usual daily dose given every second day. The rationale is that efficacy is determined more by anti-inflammatory intracellular transcription mechanisms than by actual drug presence in the circulation.8 In this regimen, patients are not exposed to high daily glucocorticoid concentrations and, therefore, have less HPA axis suppression. Conversion from a daily to an alternate-day regimen should be carried out gradually. One method is to progressively diminish the dose on one day, while building it up the next. Use of CS can be divided into short-term and longterm therapy. Short-term is defined as treatment for 3 weeks and is usually reserved for acute conditions (ie, allergic contact dermatitis). Long-term therapy is defined

Intramuscular (IM) therapy

IM CS therapy is not widely used in dermatology. One advantage is assured compliance since the physician administers the dose. However, once the dose is administered, there are disadvantages, including high interpersonal variability with erratic absorption, lack of daily dose control, and no diurnal variation. Therefore, this route of administration is considered to be less physiological. Tapering only occurs through biotransformation of the drug. Other unique complications are lipoatrophy and sterile abscess formation at the injection site.19

Adverse Effects (AEs) Associated with Corticosteroids

CS therapy is associated with numerous AEs. Shortterm therapy is usually well-tolerated and has fewer AEs.20

Table 3: Adverse events associated with CS therapy Follow-up Baseline (pre-treatment ) History Personal and family history: diabetes, hypertension, dyslipidemia, glaucoma BP Height Weight Fasting glucose Lipid prole Electrolytes CXR DEXA (at-risk patients) Tuberculin skin test (PPD) Slit lamp exam At 1 month and then every 3 months Polyuria Polydipsia Psychological effects Sleep disturbance Bone pain Abdominal pain BP Height Weight Fasting glucose Lipid prole Electrolytes DEXA Slit lamp exam AM cortisol Annual Treatment cessation

Physical examination Laboratory

Imaging Special tests

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

AEs are typically dose-related and increase significantly 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 consumption, 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 molecules (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, magneticresonance 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 histamine 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

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acetylsalicylic acid or other NSAIDs or with risk factors for PUD require prophylaxis; however, cytoprotection is debatable in patients taking glucocorticoids alone. Early symptoms of PUD are masked by the anti-inflammatory effects of CSs, which explains the higher degree of perforation.

angiogenesis, fibroblast function, and collagen production.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 infection.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

Ocular
Glaucoma, mostly associated with topical ophthalmic 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 significantly lowered or the CS is discontinued.34 Ophthalmological 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 mineralocorticoid effects (fludrocortisone and hydrocortisone).35 Patients should be monitored every 2-3 months for BP elevations. Lipid abnormalities, particularly hypertriglyceridemia, are common; the mechanism 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 uncommon if the patient previously had normal glucose tolerance; most patients revert to their prior glycemic status within a few months of CS cessation.39 Patients with pre-existing DM or glucose intolerance commonly 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.

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. Morning 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 measured at 30 minutes and 1 hour after administration; 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

Cutaneous
Multiple cutaneous effects can occur with systemic CS therapy, including purpura, telangiectasias, atrophy, striae, pseudoscars, acneiform or rosacea-like eruptions, hirsutism, alopecia, hyper/hypopigmentation, acanthosis nigricans, facial plethora, and fat redistribution causing the classic buffalo hump on the upper back. Systemic CS-induced acne or folliculitis characteristically presents with uniform papulopustules on the chest and back. Systemic CS therapy may impair wound healing by inhibiting

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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 during 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 classified 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 comfortable 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
References 1. Sulzberger MB, Witten VH, Yaffe SN. Cortisone acetate administered orally in dermatologic therapy. Arch Dermatol Syphilol. 1951;64:573-578. 2. Hartman IFA, Brownell KA. The hormone of the adrenal cortex. Science. 1930;72 (1855);76. 3. Swingle WW, Pffner JJ. The revival of comatose adrenalectomized cats with an extract of the suprarenal cortex. Science. 1930;72(1855):75-76. 4. Mason HL, Myers CS, Kendall EC. The chemistry of crystalline substances isolated from the suprarenal gland. J Biol Chem. 1936;114(3):613-631. 5. Tadicherla S, Ross K, Shenefelt PD, Fenske NA. Topical corticosteroids in dermatology. J Drugs Dermatol. 2009;8(12):1093-1105. 6. Lester RS, Knowles SR, Shear NH. The risks of systemic corticosteroid use. Dermatol Clin. 1998;16:277-88. 7. Schimmer BP, Parker KL. Adrenocortical steroids and their synthetic analogues. In: Goodmans and Gilmans The Pharmacological Basis of Therapeutics, 9th ed, McGraw-Hill 1996:1459-86. 8. Wolverton SE. Systemic corticosteroids. In: Wolverton SE, ed. Comprehensive Dermatologic Drug Therapy: Saunders, Elsevier;2007:127-161. 9. Michaud K, Matheson K, Kelly O, Anisman H. Impact of stressors in a natural context on release of cortisol in healthy adult humans: a meta-analysis. Stress. 2008;11(3):177-197. 10. Bloom E, Matulich DT, Lan NC, et al. Nuclear binding of glucocorticoid receptors: Relations between cytosol binding, activation, and the biological response. J Steroid Biochem. 1980;12:175. 11. Bennett ML, Fleischer AB, Chamlin SL, Frieden IJ. Oral corticosteroid use is effective for cutaneous hemangiomas: an evidence-based evaluation. Arch Dermatol. 2001;137 (9):1208-1213. 12. Parker SR, MacKelfresh J. Autoimmune blistering diseases in the elderly. Clin Dermatol. 2011;29(1):69-79. 13. Saag KG, Koehnke R, Caldwell JR, et al. Low dose long-term corticosteroid therapy in rheumatoid arthritis: an analysis of serious adverse events. Am J Med. 1994;96:115. 14. Nesbitt LT. Minimizing complications from systemic glucocorticoid use. Dermatol Clin. 1995;13:925-939. 15. Bignola C, De Simone G, Belloli C, et al. Steroid treatment in active Crohns disease: a comparison between two regimens of different duration. Aliment Pharmacol Ther. 1994;8:465. 16. Hings IM, Filipovich AH, Miller WJ, et al. Prednisone therapy for acute graft-versushost disease: short- versus long-term treatment. A prospective randomized trial. Transplantation. 1993;56:577.

17. Bonnotte B, Chauffert B, Martin F, et al. Side-effects of high-dose intravenous (pulse) methylprednisolone therapy cured by potassium infusion. Br J Rheumatol. 1998;37:109. 18. Salem M, Tainsh RE, Bromberg J, et al. Perioperative glucocorticoid coverage. A reassessment 42 years after emergence of a problem. Ann Surg. 1994;219:416-25. 19. Storrs FJ. Intramuscular corticosteroids: A second point of view. J Am Acad Dermatol. 1981;5:600-602. 20. Williams LC, Nesbitt LT. Update on systemic corticosteroids in dermatology. Dermatol Clin. 2001;19:63-77. 21. Wolfe F, Furst D, Lane N, et al. Substantial increases in important adverse events follow low dose prednisone therapy of rheumatoid arthritis (RA). Arthritis Rheum. 1995; 38:S312. 22. Wolfe F, Mitchell DM, Sibley JT, et al. The mortality of rheumatoid arthritis. Arthritis Rheum. 1994;37:481. 23. Iqbal MM. Osteoporosis: epidemiology, diagnosis and treatment. South Med J. 2000; 93:2-18. 24. Weinstein RS. Glucocorticoid-induced osteoporosis. Rev Endocr Metab Disord. 2001; 2(1):65-73. 25. American College of Rheumatology Ad Hoc Committee on Glucocorticoid Induced Osteoporosis : Recommendations for the prevention and treatment of glucocorticoidinduced osteoporosis. Arthritis Rheum. 2001;44:1496-1503. 26. Kolta S, Ravaud P, Fechtenbaum J, Dougados M, Roux C. Follow-up of individual patients on two DXA scanners of the same manufacturer. Osteoporos Int. 2000;11(8): 709-13. 27. Mankin HJ. Nontraumatic necrosis of bone (osteonecrosis). N Engl J Med. 1992;326: 1473-1479. 28. Scully SP, Aaron RK, Urbaniak JR. Survival analysis of hips treated with core decompression or vascularized bular grafting because of avascular necrosis. J Bone Joint Surg Am. 1998;80:1270-1275. 29. Messer J, Reitman D, Sacks HS, et al. Association of adrenocorticosteroid therapy and peptic-ulcer disease. N Engl J Med. 1983;309:21. 30. Piper JM, Ray WA, Daugherty JR, Grifn MR. Corticosteroid use and peptic ulcer disease: role of nonsteroidal anti-inammatory drugs. Ann Intern Med. 1991;114:735. 31. Gabriel SE, Jaakkimainen L, Bombardier C. Risk for serious gastrointestinal complications related to use of nonsteroidal anti-inammatory drugs. A meta-analysis. Ann Intern Med. 1991;115:787. 32. Franois J. Corticosteroid glaucoma. Ophthalmologica. 1984;188:76. 33. Black RL, Oglesby RB, Von Sallmann L, Bunim JJ. Posterior subcapsular cataracts induced by corticosteroids in patients with rheumatoid arthritis. JAMA. 1960;174:166. 34. Renfro L, Snow JS. Ocular effects of topical and systemic steroids. Dermatol Clin. 1992;10:505-512. 35. Clyburn EB, DiPette DJ. Hypertension induced by drugs and other substances. Semin Nephrol. 1995;15(2):72-86. 36. Berg AL, Nilsson-Ehle P. ACTH lowers serum lipids in steroid-treated hyperlipemic patients with kidney disease. Kidney Int. 1996;50:538. 37. Schcke H, Dcke WD, Asadullah K. Mechanisms involved in the side effects of glucocorticoids. Pharmacol Ther. 2002;96:23. 38. McMahon M, Gerich J, Rizza R. Effects of glucocorticoids on carbohydrate metabolism. Diabetes Metab Rev. 1988;4:17 39. Olefsky JM, Kimmerling G. Effects of glucocorticoids on carbohydrate metabolism. Am J Med Sci. 1976;271:202. 40. Stuck AE, Minder CE, Frey FJ. Risk of infectious complications in patients taking corticosteroids. Rev Infect Dis. 1989;11:954-963. 41. American Thoracic Society (ATS) and Centers for Disease Control and Prevention (CDC). Targeted tuberculin testing and treatment of latent tuberculosis infection. Am J Respir Crit Care Med. 2000;161:S221-S247. 42. Yale SH, Limper AH. Pneumocystis carinii pneumonia in patients without acquired immunodeciency syndrome: associated illnesses and prior corticosteroids therapy. Mayo Clin Proc. 1996;71:5-13. 43. Coursin DB, Wood KE. Corticosteroid supplementation for adrenal insufciency. JAMA. 2002;287(2):236. 44. Kahl L, Medsger TA. Severe arthralgias after wide uctuations in corticosteroid dosage. J Rheumatol. 1986;13:1063-65. 45. Allen DB. Growth suppression by glucocorticoid therapy. Endocrinol Metab Clin N Am. 1996;25:699-717. 46. Fraser FC, Sajoo A. Teratogenic potential of CS in humans. Tetralogy. 1995;51: 45-46.

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