Pharmacology and therapeutics
Systemic glucocorticoids: important issues and practical guidelines for the dermatologist Roni P. Dodiuk-Gad1,2, MD, Sophia Ish-Shalom3,4, MD and Neil H. Shear1,5, MD, FRCPC
1 Department of Dermatology, Department of Medicine, Sunnybrook Health Sciences Centre, University of Toronto, Toronto, ON, Canada, 2Department of Dermatology, Ha’emek Medical Center, Afula, Israel, 3 Metabolic Bone Diseases Unit, Rambam Health Care Campus, Haifa, Israel, 4 Department of Endocrinology, Bruce Rappaport Faculty of Medicine, Technion, Israel Institute of Technology, Haifa, Israel, and 5Clinical Pharmacology and Toxicology, Department of Medicine, Sunnybrook Health Sciences Centre, University of Toronto, Toronto, ON, Canada
Correspondence Neil H. Shear, MD, FRCPC Sunnybrook Health Sciences Center Dermatology Division, Faculty of Medicine 2075 Bayview Avenue, Room M1-737 Toronto, ON M4N 3M5, Canada E-mail: [email protected] Conflicts of interest: None.
Abstract Background The potent anti-inflammatory and immunosuppressive effects of systemic glucocorticoids have led to their wide use in the treatment of dermatologic diseases. However, glucocorticoids have been designated the “archetypal double-edged sword of medicine” as a result of their various potential adverse side effects. Dermatologists face major challenges in their usage and require knowledge of both the risks related to their usage and strategies with which to manage them. Objectives This brief review includes an evidence-based, strategic approach to the general risk management of systemic glucocorticoids with a focus on preventing glucocorticoid-induced osteoporosis (GIOP). Methods We assess which classes of corticosteroid are most likely to provoke allergic cross-reactions and outline the mechanism for glucocorticoid resistance. We examine how glucocorticoids both help and impair normal physiology. Results Five reactivity groups are defined, based on the structural and clinical characteristics of glucocorticoids. Tests for allergy reactions and mechanisms for glucocorticoid resistance are described. Guidelines for the prevention and treatment of GIOP are introduced. Conclusion Glucocorticoids play an important teleologic role in maintaining blood glucose levels adequate for brain function by inducing a catabolic state through the production of carbohydrates at the expense of proteins and fat stores. It is hoped that the various recommendations for the protection of patients treated with systemic
doi: 10.1111/ijd.12642
glucocorticoids will provide physicians with practical guidelines for prescribing.
Introduction Edward Kendall and his colleagues described compound E (cortisone) in 1935,1 and 14 years later its therapeutic properties were demonstrated in patients with rheumatoid arthritis.2 In 1950, Tadeusz Reichstein, Edward Kendall, and Philip Showalter Hench were awarded the Nobel Prize for Physiology and Medicine for their discoveries relating to the structure and biologic effects of the hormones of the adrenal cortex. In his acceptance speech, Dr. Kendall declared that: . . .today the chemical structure of cortisone is known in every detail, but one more chapter remains to be written – what physiologic processes are modified by cortisone and how this influence is exerted.3 Herein, we discuss some of the important clinical issues associated with the use of systemic glucocorticoids. ª 2015 The International Society of Dermatology
What is the Cyclopentanoperhydrophenanthrene Nucleus? All corticosteroids, including both glucocorticoids, such as cortisol, and mineralocorticoids, such as aldosterone, are synthesized from cholesterol molecules in the adrenal cortex.4 Their structure is based on a cyclopentanoperhydrophenanthrene nucleus, which comprises three rings of six carbon atoms and one ring of five carbon atoms and represents the basic four-ring structure of cholesterol, plus three hexane rings and one pentane ring (Fig. 1).5 Modifications in the basic four-ring structure result in systemic agents with different potencies, mineralocorticoid effects, durations, of action, and metabolisms. International Journal of Dermatology 2015
1
2
Pharmacology and therapeutics
Guidelines for prescribing systemic glucocorticoids
Dodiuk-Gad et al.
Do Glucocorticoids Cause Type I Allergy?
Figure 1 The molecular structure of hydrocortisone (cortisol) with the conventional numbering of carbon atoms. The letters A, B, C and D denote the four basic rings; each carbon is assigned a number from 1 to 21
Which Classes of Corticosteroid are Most Likely to Provoke Allergic Cross-Reactions? Five reactivity groups have been defined, based on structural and clinical characteristics.6,7 These are labeled A, B, C, D1, and D2 (Table 1). Two types of cross-reaction occur: (i) intra-group cross-reactions caused by structural similarities or a shared metabolic pathway, and (ii) intergroup cross-reactions caused by a predisposition to the induction of allergic reactions (Table 1). Table 1 Classes of corticosteroid and possible cross-reactions
Class
Corticosteroid
A
Hydrocortisonea, prednisolone and methylprednisolonea, cortisone, prednisone, tixocortol pivalateb Triamcinolone acetonide, fluocinolone acetonide, halcinonide, desonide, fluocinonide, halcinonide, budesonideb, amcinonide, flunisolide Betamethasone, dexamethasone, paramethasone, desoxymethasone, fluocortolone Clobetasone-17-butyrate, clobetasol-17-propionate, beclomethasone dipropionate, betamethasone valerate, betamethasone dipropionate Hydrocortisone-17-propionate, hydrocortisone -17-butyrateb, methylprednisolone aceponate, prednicarbate
B
C
D1
D2
a
Most common inducer of type I allergy.32 Most common inducer of type IV allergy.32
b
International Journal of Dermatology 2015
Possible cross-reactions Class D2
Class A and budesonide-S isomer (Class B)
Type I allergy, which occurs at a prevalence of 0.1%, is induced mainly by hydrocortisone and methylprednisolone (Class A). Type IV allergy, which has a prevalence of 0.2–5.0%, is induced mainly by tixocortol pivalate (Class A), budesonide (Class B), and hydrocortisone 17 butyrate (Class D2).5 The prick test, intradermal test, and patch test are common diagnostic tools.8 Because of the anti-inflammatory action of glucocorticoids, a patch test may produce a false negative reading or the edge effect, whereby a ring of erythematous induration develops around the patch test site but no reaction occurs in the center as a result of the higher concentration of allergen in the center of the patch. Glucocorticoids may induce a false negative as a result of their vasoconstricting action (whitening of the skin) or a false positive attributable to a vasodilating action (erythema of the skin). Patch tests are usually read on day 6 or 7 or later.5,9 Treatment decisions must take into account inter-group cross-reactions (Table 1).
Is Glucocorticoid Resistance Real? What is the Mechanism? Few case reports on glucocorticoid resistance in the context of dermatology have been published,10,11 but the mechanisms described in studies on inflammatory bowel diseases12 may apply to dermatology.13 1 Impaired glucocorticoid signaling caused by the dysfunction of the glucocorticoid receptor (GR), the activity of which is regulated by the balance between two isoforms, GRa and GRb. GRa positively mediates GR activit, and GRb inhibits GRa. Increased expression of GRb may impair signaling. 2 Overexpression of the multidrug resistance gene (MDR1)/P-glycoprotein 1 (Pgp), which encodes for a drug efflux pump P-glycoprotein-170 that actively transports glucocorticoids out of target cells. 3 Functional interference with the glucocorticoid response by constitutive epithelial activation of proinflammatory mediators, which directly inhibits the anti-inflammatory action of a limited number of GRa molecules by preventing GR transcriptional activity. Intravenous immunoglobulin may improve GR binding in glucocorticoid-resistant patients.14
How do Glucocorticoids Help and Impair Normal Physiology? Glucocorticoids play an important teleologic role in maintaining blood glucose levels adequate for brain function ª 2015 The International Society of Dermatology
Dodiuk-Gad et al.
Guidelines for prescribing systemic glucocorticoids
by inducing a catabolic state through the production of carbohydrates at the expense of proteins and fat stores. The lipolysis process results in increased amounts of triglycerides and fat redistribution (lipodystrophy), which causes the habitus characteristic of Cushing’s syndrome. In addition, glucocorticoids cause peripheral insulin resistance, which impedes glucose absorption by various body tissues.15 This process may explain some of the adverse effects of glucocorticoids (Table 2).
Table 2 Adverse effects of glucocorticoid therapy Musculoskeletal18
Ophthalmologic33
Gastrointestinal4
Metabolic4
Cardiovascular34
Psychiatric and neurologic35
Endocrine34
Hematologic and cellular4
Cutaneous36
Osteoporosis Osteonecrosis Myopathy Muscle atrophy Growth retardation Cataracts Glaucoma Infection Hemorrhage Exophthalmus Refraction changes Peptic ulcer disease Nausea and vomiting Pancreatitis Esophagitis Intestinal perforation Fatty liver changes Hyperglycemia Hyperlipidemia Hypocalcemia Hypokalemia Increased appetite and weight Hypertension Atherosclerosis Edema Mood changes Psychiatric disorders Sleep disturbances Pseudotumor cerebri Peripheral neuropathy Seizures Hypothalamic–pituitary–adrenal axis suppression Adrenal crisis Withdrawal syndrome Menstrual irregularity Leukocytosis Lymphopenia Eosinopenia Immunosuppression Infections Atrophy Vascular effects Hirsutism Hyperpigmentation Acneiform eruption Infection
ª 2015 The International Society of Dermatology
Pharmacology and therapeutics
Are there Guidelines for the Prevention and Treatment of Glucocorticoid-Induced Osteoporosis? Glucocorticoid-induced osteoporosis (GIOP) is the most common cause of secondary osteoporosis and is associated with substantial morbidity.16–18 It is estimated that 30% of all patients treated with glucocorticoids for six months or more will develop osteoporosis.16 Fractures are often the presenting manifestation of GIOP in patients receiving long-term glucocorticoid therapy,16 a fact that highlights the underdiagnosis and undertreatment of GIOP despite greater awareness among physicians. The latest recommendations of the American College of Rheumatology for preventing and treating GIOP, issued in 2010,19 outline a more targeted approach but are complicated to use. New drugs and the World Health Organizations Fracture Risk Assessment Tool (FRAX) are some of the developments described. FRAX is a computerbased algorithm that provides models for the assessment of fracture probability in postmenopausal women and men aged >40 years.20,21 The model uses easily obtained clinical risk factors to estimate 10-year fracture probability (Table 3). The estimate can be used alone or with Table 3 Patient information required for FRAX
calcula-
tion20,21 Clinical
Metabolic bone status
Habits
Age Gender Weight and height Rheumatoid arthritis: clinical or laboratory evidence to support the diagnosis Oral glucocorticoids: current or previous exposure to oral glucocorticoids for >3 months at a dose equivalent to prednisolone ≥ 5 mg/day BMD: the site and reference technology is DXA at the femoral neck. T-scores are based on NHANES reference values for women aged 20–29 years. The same absolute values are used in men Previous fracture in adult life occurring spontaneously or arising from trauma which, in a healthy individual, would not have resulted in a fracture Parent’s hip fracture: history of hip fracture in the patient’s mother or father Secondary osteoporosis: having a disorder strongly associated with osteoporosis: type 1 (insulin-dependent) diabetes; osteogenesis imperfecta in adults; untreated longstanding hyperthyroidism; hypogonadism or premature menopause (50 years
FRAXd Riske for major osteoporotic fracture per 10 years (i) 4 weeks at a dose equivalent to 20 mg/day of prednisone are often given PCP prophylaxis.30 In HIV-positive patients, PCP prophylaxis is recommended if long-term systemic glucocorticoid treatment is planned.31
Table 6 US trade names and chemical formulae of drugs Generic name
US trade name
Chemical formula
Prednisone Denosumab Alendronate Risedronate Zoledronic acid Teriparatide
Deltasone Prolia, Xgeva Fosamax Actonel Aclasta Forteo
C21H26O5 C6404H9912N1724O2004S50 C4H13NO7P2 C7H11NO7P2 C5H10N2O7P2 C181H291N55O51S2
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Guidelines for prescribing systemic glucocorticoids
Table 6 lists the US trade name and chemical formula of each of the drugs in this review. Conclusion We hope that this short summary will provide physicians with practical medical guidelines to follow in prescribing glucocorticoids. References 1 Kendall E, Mason HL, McKenzie BF, et al. Recent developments in the investigation of the hormone of the suprarenal cortex. Proc Staff Meet Mayo Clin 1935; 10: 245–246. 2 Hench PS, Kendall EC, Slocumb C, et al. The effect of a hormone of the adrenal cortex (17-hydroxy-11-dehydrocorticosterone; compound E) and of pituitary adrenocorticotropic hormone on rheumatoid arthritis. Proc Staff Meet Mayo Clin 1949; 24: 181–197. 3 Kendall EC, Reichstein T, Hench PS. Nobel Prize Lecture. The Nobel Prize in Physiology or Medicine 1950. http:// www.nobelprize.org/nobel_prizes/medicine/laureates/ 1950/kendall-lecture.html. [Accessed September 25, 2013.] 4 Jackson S, Gilchrist H, Nesbitt LT. Update on the dermatologic use of systemic glucocorticosteroids. Dermatol Ther 2007; 20: 187–205. 5 Baeck M, Marot L, Nicolas JF, et al. Allergic hypersensitivity to topical and systemic corticosteroids: a review. Allergy 2009; 64: 978–994. 6 Coopman S, Degreef H, Dooms-Goossens A. Identification of cross-reaction patterns in allergic contact dermatitis from topical corticosteroids. Br J Dermatol 1989; 121: 27–34. 7 Goossens A, Matura M, Degreef H. Reactions to corticosteroids: some new aspects regarding crosssensitivity. Cutis 2000; 65: 43–45. 8 Ventura MT, Calogiuri GF, Muratore L, et al. Crossreactivity in cell-mediated and IgE-mediated hypersensitivity to glucocorticoids. Curr Pharm Des 2006; 12: 383–391. 9 Davis MD, el-Azhary RA, Farmer SA. Results of patch testing to a corticosteroid series: a retrospective review of 1188 patients during 6 years at Mayo Clinic. J Am Acad Dermatol 2007; 56: 921–927. 10 Rupprecht M, Rupprecht R, Kornhuber J, et al. Elevated glucocorticoid receptor concentrations before and after glucocorticoid therapy in peripheral mononuclear leukocytes of patients with atopic dermatitis. Dermatologica 1991; 183: 100–105. 11 Inui S, Sumikawa Y, Asada H, et al. Glucocorticoid resistance in atopic dermatitis associated with decreased expression of glucocorticoid receptor-a in peripheral blood mononuclear cells. J Dermatol 2010; 37: 496–499.
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12 Faubion WA Jr, Loftus EV Jr, Harmsen WS, et al. The natural history of corticosteroid therapy for inflammatory bowel disease: a population-based study. Gastroenterology 2001; 121: 255–260. 13 Farrell RJ, Kelleher D. Glucocorticoid resistance in inflammatory bowel disease. J Endocrinol 2003; 178: 339–346. 14 Gelfand EW. Intravenous immune globulin in autoimmune and inflammatory diseases. N Engl J Med 2012; 367: 2015–2025. 15 Schimmer BP, Parker KL. Adrenocortical steroids and their synthetic analogs. In: Hardman JG, Limbird LE, eds. Goodman and Gilman’s Pharmacological Basis of Therapeutics, 9th edn. New York, NY: McGraw Hill, 1996: 1459–1486. 16 Bultink IE, Baden M, Lems WF. Glucocorticoid-induced osteoporosis: an update on current pharmacotherapy and future directions. Expert Opin Pharmacother 2013; 14: 185–197. 17 Weinstein RS. Clinical practice. Glucocorticoid-induced bone disease. N Engl J Med 2011; 365: 62–70. 18 Clarke BL. Corticosteroid-induced osteoporosis: an update for dermatologists. Am J Clin Dermatol 2012; 13: 167–190. 19 Grossman JM, Gordon R, Ranganath VK, et al. American College of Rheumatology 2010 recommendations for the prevention and treatment of glucocorticoid-induced osteoporosis. Arthritis Care Res (Hoboken) 2010; 62: 1515–1526. 20 Kanis JA, Oden A, Johansson H, et al. FRAX and its applications to clinical practice. Bone 2009; 44: 734– 743. 21 World Health Organization Collaborating Centre for Metabolic Diseases, University of Sheffield. FRAX WHO Fracture Risk Assessment Tool. http://www.shef. ac.uk/FRAX [Accessed September 25, 2013] 22 Kanis JA, Hans D, Cooper C. Task Force of the FRAX Initiative. Interpretation and use of FRAX in clinical practice. Osteoporos Int 2011; 22: 2395–2411. 23 Hansen KE, Wilson HA, Zapalowski C, et al. Uncertainties in the prevention and treatment of glucocorticoid-induced osteoporosis. J Bone Miner Res 2011; 26: 1989–1996. 24 Dore RK, Cohen SB, Lane NE, et al. Study Group. Effects of denosumab on bone mineral density and bone turnover in patients with rheumatoid arthritis receiving concurrent glucocorticoids or bisphosphonates. Ann Rheum Dis 2010; 69: 872–875. 25 McClung M, Harris ST, Miller PD, et al. Bisphosphonate therapy for osteoporosis: benefits, risks, and drug holiday. Am J Med 2013; 126: 13–20. 26 Brixen KT, Christensen PM, Ejersted C, et al. Teriparatide (biosynthetic human parathyroid hormone 1–34): a new paradigm in the treatment of osteoporosis. Basic Clin Pharmacol Toxicol 2004; 94: 260–270. 27 Black DM, Bauer DC, Schwartz AV, et al. Continuing bisphosphonate treatment for osteoporosis – for
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29
30
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Guidelines for prescribing systemic glucocorticoids
whom and for how long? N Engl J Med 2012; 366: 2051–2053. Whitaker M, Guo J, Kehoe T, et al. Bisphosphonates for osteoporosis – where do we go from here? N Engl J Med 2012; 366: 2048–2051. Sowden E, Carmichael AJ. Autoimmune inflammatory disorders, systemic corticosteroids and pneumocystis pneumonia: a strategy for prevention. BMC Infect Dis 2004; 4: 42. Sepkowitz KA, Brown AE, Armstrong D. Pneumocystis carinii pneumonia without acquired immunodeficiency syndrome. More patients, same risk. Arch Intern Med 1995; 155: 1125–1128. Aberg J, Powderly W. HIV: primary and secondary prophylaxis for opportunistic infections. Clin Evid (Online) 2010; 2010: 0908.
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Pharmacology and therapeutics
32 LaBerge L, Pratt M. Immediate and delayed hypersensitivity to systemic corticosteroids: 2 case reports. Dermatitis 2012; 23: 288–290. 33 Carnahan MC, Goldstein DA. Ocular complications of topical, peri-ocular, and systemic corticosteroids. Curr Opin Ophthalmol 2000; 11: 478–483. 34 Fardet L, Kassar A, Cabane J, et al. Corticosteroidinduced adverse events in adults: frequency, screening and prevention. Drug Saf 2007; 30: 861–881. 35 Warrington TP, Bostwick JM. Psychiatric adverse effects of corticosteroids. Mayo Clin Proc 2006; 81: 1361–1367. 36 Hengge UR, Ruzicka T, Schwartz RA, et al. Adverse effects of topical glucocorticosteroids. J Am Acad Dermatol 2006; 54: 1–15. 37 Shaw M. When is perioperative steroid coverage necessary? Cleve Clin J Med 2002; 69: 9–11.
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Systemic glucocorticoids: important issues and practical guidelines for the dermatologist Roni P. Dodiuk-Gad1,2, MD, Sophia Ish-Shalom3,4, MD and Neil H. Shear1,5, MD, FRCPC
1 Department of Dermatology, Department of Medicine, Sunnybrook Health Sciences Centre, University of Toronto, Toronto, ON, Canada, 2Department of Dermatology, Ha’emek Medical Center, Afula, Israel, 3 Metabolic Bone Diseases Unit, Rambam Health Care Campus, Haifa, Israel, 4 Department of Endocrinology, Bruce Rappaport Faculty of Medicine, Technion, Israel Institute of Technology, Haifa, Israel, and 5Clinical Pharmacology and Toxicology, Department of Medicine, Sunnybrook Health Sciences Centre, University of Toronto, Toronto, ON, Canada
Correspondence Neil H. Shear, MD, FRCPC Sunnybrook Health Sciences Center Dermatology Division, Faculty of Medicine 2075 Bayview Avenue, Room M1-737 Toronto, ON M4N 3M5, Canada E-mail: [email protected] Conflicts of interest: None.
Abstract Background The potent anti-inflammatory and immunosuppressive effects of systemic glucocorticoids have led to their wide use in the treatment of dermatologic diseases. However, glucocorticoids have been designated the “archetypal double-edged sword of medicine” as a result of their various potential adverse side effects. Dermatologists face major challenges in their usage and require knowledge of both the risks related to their usage and strategies with which to manage them. Objectives This brief review includes an evidence-based, strategic approach to the general risk management of systemic glucocorticoids with a focus on preventing glucocorticoid-induced osteoporosis (GIOP). Methods We assess which classes of corticosteroid are most likely to provoke allergic cross-reactions and outline the mechanism for glucocorticoid resistance. We examine how glucocorticoids both help and impair normal physiology. Results Five reactivity groups are defined, based on the structural and clinical characteristics of glucocorticoids. Tests for allergy reactions and mechanisms for glucocorticoid resistance are described. Guidelines for the prevention and treatment of GIOP are introduced. Conclusion Glucocorticoids play an important teleologic role in maintaining blood glucose levels adequate for brain function by inducing a catabolic state through the production of carbohydrates at the expense of proteins and fat stores. It is hoped that the various recommendations for the protection of patients treated with systemic
doi: 10.1111/ijd.12642
glucocorticoids will provide physicians with practical guidelines for prescribing.
Introduction Edward Kendall and his colleagues described compound E (cortisone) in 1935,1 and 14 years later its therapeutic properties were demonstrated in patients with rheumatoid arthritis.2 In 1950, Tadeusz Reichstein, Edward Kendall, and Philip Showalter Hench were awarded the Nobel Prize for Physiology and Medicine for their discoveries relating to the structure and biologic effects of the hormones of the adrenal cortex. In his acceptance speech, Dr. Kendall declared that: . . .today the chemical structure of cortisone is known in every detail, but one more chapter remains to be written – what physiologic processes are modified by cortisone and how this influence is exerted.3 Herein, we discuss some of the important clinical issues associated with the use of systemic glucocorticoids. ª 2015 The International Society of Dermatology
What is the Cyclopentanoperhydrophenanthrene Nucleus? All corticosteroids, including both glucocorticoids, such as cortisol, and mineralocorticoids, such as aldosterone, are synthesized from cholesterol molecules in the adrenal cortex.4 Their structure is based on a cyclopentanoperhydrophenanthrene nucleus, which comprises three rings of six carbon atoms and one ring of five carbon atoms and represents the basic four-ring structure of cholesterol, plus three hexane rings and one pentane ring (Fig. 1).5 Modifications in the basic four-ring structure result in systemic agents with different potencies, mineralocorticoid effects, durations, of action, and metabolisms. International Journal of Dermatology 2015
1
2
Pharmacology and therapeutics
Guidelines for prescribing systemic glucocorticoids
Dodiuk-Gad et al.
Do Glucocorticoids Cause Type I Allergy?
Figure 1 The molecular structure of hydrocortisone (cortisol) with the conventional numbering of carbon atoms. The letters A, B, C and D denote the four basic rings; each carbon is assigned a number from 1 to 21
Which Classes of Corticosteroid are Most Likely to Provoke Allergic Cross-Reactions? Five reactivity groups have been defined, based on structural and clinical characteristics.6,7 These are labeled A, B, C, D1, and D2 (Table 1). Two types of cross-reaction occur: (i) intra-group cross-reactions caused by structural similarities or a shared metabolic pathway, and (ii) intergroup cross-reactions caused by a predisposition to the induction of allergic reactions (Table 1). Table 1 Classes of corticosteroid and possible cross-reactions
Class
Corticosteroid
A
Hydrocortisonea, prednisolone and methylprednisolonea, cortisone, prednisone, tixocortol pivalateb Triamcinolone acetonide, fluocinolone acetonide, halcinonide, desonide, fluocinonide, halcinonide, budesonideb, amcinonide, flunisolide Betamethasone, dexamethasone, paramethasone, desoxymethasone, fluocortolone Clobetasone-17-butyrate, clobetasol-17-propionate, beclomethasone dipropionate, betamethasone valerate, betamethasone dipropionate Hydrocortisone-17-propionate, hydrocortisone -17-butyrateb, methylprednisolone aceponate, prednicarbate
B
C
D1
D2
a
Most common inducer of type I allergy.32 Most common inducer of type IV allergy.32
b
International Journal of Dermatology 2015
Possible cross-reactions Class D2
Class A and budesonide-S isomer (Class B)
Type I allergy, which occurs at a prevalence of 0.1%, is induced mainly by hydrocortisone and methylprednisolone (Class A). Type IV allergy, which has a prevalence of 0.2–5.0%, is induced mainly by tixocortol pivalate (Class A), budesonide (Class B), and hydrocortisone 17 butyrate (Class D2).5 The prick test, intradermal test, and patch test are common diagnostic tools.8 Because of the anti-inflammatory action of glucocorticoids, a patch test may produce a false negative reading or the edge effect, whereby a ring of erythematous induration develops around the patch test site but no reaction occurs in the center as a result of the higher concentration of allergen in the center of the patch. Glucocorticoids may induce a false negative as a result of their vasoconstricting action (whitening of the skin) or a false positive attributable to a vasodilating action (erythema of the skin). Patch tests are usually read on day 6 or 7 or later.5,9 Treatment decisions must take into account inter-group cross-reactions (Table 1).
Is Glucocorticoid Resistance Real? What is the Mechanism? Few case reports on glucocorticoid resistance in the context of dermatology have been published,10,11 but the mechanisms described in studies on inflammatory bowel diseases12 may apply to dermatology.13 1 Impaired glucocorticoid signaling caused by the dysfunction of the glucocorticoid receptor (GR), the activity of which is regulated by the balance between two isoforms, GRa and GRb. GRa positively mediates GR activit, and GRb inhibits GRa. Increased expression of GRb may impair signaling. 2 Overexpression of the multidrug resistance gene (MDR1)/P-glycoprotein 1 (Pgp), which encodes for a drug efflux pump P-glycoprotein-170 that actively transports glucocorticoids out of target cells. 3 Functional interference with the glucocorticoid response by constitutive epithelial activation of proinflammatory mediators, which directly inhibits the anti-inflammatory action of a limited number of GRa molecules by preventing GR transcriptional activity. Intravenous immunoglobulin may improve GR binding in glucocorticoid-resistant patients.14
How do Glucocorticoids Help and Impair Normal Physiology? Glucocorticoids play an important teleologic role in maintaining blood glucose levels adequate for brain function ª 2015 The International Society of Dermatology
Dodiuk-Gad et al.
Guidelines for prescribing systemic glucocorticoids
by inducing a catabolic state through the production of carbohydrates at the expense of proteins and fat stores. The lipolysis process results in increased amounts of triglycerides and fat redistribution (lipodystrophy), which causes the habitus characteristic of Cushing’s syndrome. In addition, glucocorticoids cause peripheral insulin resistance, which impedes glucose absorption by various body tissues.15 This process may explain some of the adverse effects of glucocorticoids (Table 2).
Table 2 Adverse effects of glucocorticoid therapy Musculoskeletal18
Ophthalmologic33
Gastrointestinal4
Metabolic4
Cardiovascular34
Psychiatric and neurologic35
Endocrine34
Hematologic and cellular4
Cutaneous36
Osteoporosis Osteonecrosis Myopathy Muscle atrophy Growth retardation Cataracts Glaucoma Infection Hemorrhage Exophthalmus Refraction changes Peptic ulcer disease Nausea and vomiting Pancreatitis Esophagitis Intestinal perforation Fatty liver changes Hyperglycemia Hyperlipidemia Hypocalcemia Hypokalemia Increased appetite and weight Hypertension Atherosclerosis Edema Mood changes Psychiatric disorders Sleep disturbances Pseudotumor cerebri Peripheral neuropathy Seizures Hypothalamic–pituitary–adrenal axis suppression Adrenal crisis Withdrawal syndrome Menstrual irregularity Leukocytosis Lymphopenia Eosinopenia Immunosuppression Infections Atrophy Vascular effects Hirsutism Hyperpigmentation Acneiform eruption Infection
ª 2015 The International Society of Dermatology
Pharmacology and therapeutics
Are there Guidelines for the Prevention and Treatment of Glucocorticoid-Induced Osteoporosis? Glucocorticoid-induced osteoporosis (GIOP) is the most common cause of secondary osteoporosis and is associated with substantial morbidity.16–18 It is estimated that 30% of all patients treated with glucocorticoids for six months or more will develop osteoporosis.16 Fractures are often the presenting manifestation of GIOP in patients receiving long-term glucocorticoid therapy,16 a fact that highlights the underdiagnosis and undertreatment of GIOP despite greater awareness among physicians. The latest recommendations of the American College of Rheumatology for preventing and treating GIOP, issued in 2010,19 outline a more targeted approach but are complicated to use. New drugs and the World Health Organizations Fracture Risk Assessment Tool (FRAX) are some of the developments described. FRAX is a computerbased algorithm that provides models for the assessment of fracture probability in postmenopausal women and men aged >40 years.20,21 The model uses easily obtained clinical risk factors to estimate 10-year fracture probability (Table 3). The estimate can be used alone or with Table 3 Patient information required for FRAX
calcula-
tion20,21 Clinical
Metabolic bone status
Habits
Age Gender Weight and height Rheumatoid arthritis: clinical or laboratory evidence to support the diagnosis Oral glucocorticoids: current or previous exposure to oral glucocorticoids for >3 months at a dose equivalent to prednisolone ≥ 5 mg/day BMD: the site and reference technology is DXA at the femoral neck. T-scores are based on NHANES reference values for women aged 20–29 years. The same absolute values are used in men Previous fracture in adult life occurring spontaneously or arising from trauma which, in a healthy individual, would not have resulted in a fracture Parent’s hip fracture: history of hip fracture in the patient’s mother or father Secondary osteoporosis: having a disorder strongly associated with osteoporosis: type 1 (insulin-dependent) diabetes; osteogenesis imperfecta in adults; untreated longstanding hyperthyroidism; hypogonadism or premature menopause (50 years
FRAXd Riske for major osteoporotic fracture per 10 years (i) 4 weeks at a dose equivalent to 20 mg/day of prednisone are often given PCP prophylaxis.30 In HIV-positive patients, PCP prophylaxis is recommended if long-term systemic glucocorticoid treatment is planned.31
Table 6 US trade names and chemical formulae of drugs Generic name
US trade name
Chemical formula
Prednisone Denosumab Alendronate Risedronate Zoledronic acid Teriparatide
Deltasone Prolia, Xgeva Fosamax Actonel Aclasta Forteo
C21H26O5 C6404H9912N1724O2004S50 C4H13NO7P2 C7H11NO7P2 C5H10N2O7P2 C181H291N55O51S2
International Journal of Dermatology 2015
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6
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Guidelines for prescribing systemic glucocorticoids
Table 6 lists the US trade name and chemical formula of each of the drugs in this review. Conclusion We hope that this short summary will provide physicians with practical medical guidelines to follow in prescribing glucocorticoids. References 1 Kendall E, Mason HL, McKenzie BF, et al. Recent developments in the investigation of the hormone of the suprarenal cortex. Proc Staff Meet Mayo Clin 1935; 10: 245–246. 2 Hench PS, Kendall EC, Slocumb C, et al. The effect of a hormone of the adrenal cortex (17-hydroxy-11-dehydrocorticosterone; compound E) and of pituitary adrenocorticotropic hormone on rheumatoid arthritis. Proc Staff Meet Mayo Clin 1949; 24: 181–197. 3 Kendall EC, Reichstein T, Hench PS. Nobel Prize Lecture. The Nobel Prize in Physiology or Medicine 1950. http:// www.nobelprize.org/nobel_prizes/medicine/laureates/ 1950/kendall-lecture.html. [Accessed September 25, 2013.] 4 Jackson S, Gilchrist H, Nesbitt LT. Update on the dermatologic use of systemic glucocorticosteroids. Dermatol Ther 2007; 20: 187–205. 5 Baeck M, Marot L, Nicolas JF, et al. Allergic hypersensitivity to topical and systemic corticosteroids: a review. Allergy 2009; 64: 978–994. 6 Coopman S, Degreef H, Dooms-Goossens A. Identification of cross-reaction patterns in allergic contact dermatitis from topical corticosteroids. Br J Dermatol 1989; 121: 27–34. 7 Goossens A, Matura M, Degreef H. Reactions to corticosteroids: some new aspects regarding crosssensitivity. Cutis 2000; 65: 43–45. 8 Ventura MT, Calogiuri GF, Muratore L, et al. Crossreactivity in cell-mediated and IgE-mediated hypersensitivity to glucocorticoids. Curr Pharm Des 2006; 12: 383–391. 9 Davis MD, el-Azhary RA, Farmer SA. Results of patch testing to a corticosteroid series: a retrospective review of 1188 patients during 6 years at Mayo Clinic. J Am Acad Dermatol 2007; 56: 921–927. 10 Rupprecht M, Rupprecht R, Kornhuber J, et al. Elevated glucocorticoid receptor concentrations before and after glucocorticoid therapy in peripheral mononuclear leukocytes of patients with atopic dermatitis. Dermatologica 1991; 183: 100–105. 11 Inui S, Sumikawa Y, Asada H, et al. Glucocorticoid resistance in atopic dermatitis associated with decreased expression of glucocorticoid receptor-a in peripheral blood mononuclear cells. J Dermatol 2010; 37: 496–499.
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12 Faubion WA Jr, Loftus EV Jr, Harmsen WS, et al. The natural history of corticosteroid therapy for inflammatory bowel disease: a population-based study. Gastroenterology 2001; 121: 255–260. 13 Farrell RJ, Kelleher D. Glucocorticoid resistance in inflammatory bowel disease. J Endocrinol 2003; 178: 339–346. 14 Gelfand EW. Intravenous immune globulin in autoimmune and inflammatory diseases. N Engl J Med 2012; 367: 2015–2025. 15 Schimmer BP, Parker KL. Adrenocortical steroids and their synthetic analogs. In: Hardman JG, Limbird LE, eds. Goodman and Gilman’s Pharmacological Basis of Therapeutics, 9th edn. New York, NY: McGraw Hill, 1996: 1459–1486. 16 Bultink IE, Baden M, Lems WF. Glucocorticoid-induced osteoporosis: an update on current pharmacotherapy and future directions. Expert Opin Pharmacother 2013; 14: 185–197. 17 Weinstein RS. Clinical practice. Glucocorticoid-induced bone disease. N Engl J Med 2011; 365: 62–70. 18 Clarke BL. Corticosteroid-induced osteoporosis: an update for dermatologists. Am J Clin Dermatol 2012; 13: 167–190. 19 Grossman JM, Gordon R, Ranganath VK, et al. American College of Rheumatology 2010 recommendations for the prevention and treatment of glucocorticoid-induced osteoporosis. Arthritis Care Res (Hoboken) 2010; 62: 1515–1526. 20 Kanis JA, Oden A, Johansson H, et al. FRAX and its applications to clinical practice. Bone 2009; 44: 734– 743. 21 World Health Organization Collaborating Centre for Metabolic Diseases, University of Sheffield. FRAX WHO Fracture Risk Assessment Tool. http://www.shef. ac.uk/FRAX [Accessed September 25, 2013] 22 Kanis JA, Hans D, Cooper C. Task Force of the FRAX Initiative. Interpretation and use of FRAX in clinical practice. Osteoporos Int 2011; 22: 2395–2411. 23 Hansen KE, Wilson HA, Zapalowski C, et al. Uncertainties in the prevention and treatment of glucocorticoid-induced osteoporosis. J Bone Miner Res 2011; 26: 1989–1996. 24 Dore RK, Cohen SB, Lane NE, et al. Study Group. Effects of denosumab on bone mineral density and bone turnover in patients with rheumatoid arthritis receiving concurrent glucocorticoids or bisphosphonates. Ann Rheum Dis 2010; 69: 872–875. 25 McClung M, Harris ST, Miller PD, et al. Bisphosphonate therapy for osteoporosis: benefits, risks, and drug holiday. Am J Med 2013; 126: 13–20. 26 Brixen KT, Christensen PM, Ejersted C, et al. Teriparatide (biosynthetic human parathyroid hormone 1–34): a new paradigm in the treatment of osteoporosis. Basic Clin Pharmacol Toxicol 2004; 94: 260–270. 27 Black DM, Bauer DC, Schwartz AV, et al. Continuing bisphosphonate treatment for osteoporosis – for
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whom and for how long? N Engl J Med 2012; 366: 2051–2053. Whitaker M, Guo J, Kehoe T, et al. Bisphosphonates for osteoporosis – where do we go from here? N Engl J Med 2012; 366: 2048–2051. Sowden E, Carmichael AJ. Autoimmune inflammatory disorders, systemic corticosteroids and pneumocystis pneumonia: a strategy for prevention. BMC Infect Dis 2004; 4: 42. Sepkowitz KA, Brown AE, Armstrong D. Pneumocystis carinii pneumonia without acquired immunodeficiency syndrome. More patients, same risk. Arch Intern Med 1995; 155: 1125–1128. Aberg J, Powderly W. HIV: primary and secondary prophylaxis for opportunistic infections. Clin Evid (Online) 2010; 2010: 0908.
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32 LaBerge L, Pratt M. Immediate and delayed hypersensitivity to systemic corticosteroids: 2 case reports. Dermatitis 2012; 23: 288–290. 33 Carnahan MC, Goldstein DA. Ocular complications of topical, peri-ocular, and systemic corticosteroids. Curr Opin Ophthalmol 2000; 11: 478–483. 34 Fardet L, Kassar A, Cabane J, et al. Corticosteroidinduced adverse events in adults: frequency, screening and prevention. Drug Saf 2007; 30: 861–881. 35 Warrington TP, Bostwick JM. Psychiatric adverse effects of corticosteroids. Mayo Clin Proc 2006; 81: 1361–1367. 36 Hengge UR, Ruzicka T, Schwartz RA, et al. Adverse effects of topical glucocorticosteroids. J Am Acad Dermatol 2006; 54: 1–15. 37 Shaw M. When is perioperative steroid coverage necessary? Cleve Clin J Med 2002; 69: 9–11.
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