A comprehensive review of immunosuppressive drugs in pediatric dermatoses: Part I - Corticosteroids, azathioprine, and cyclosporine-A

Pediatric dermatoses constitute an array of varied diseases, a few of which may require long-term treatment with immunosuppressants in the form of corticosteroids (CS) and steroid-sparing agents such as azathioprine, cyclosporine, and methotrexate. There are numerous articles mentioning long-term adverse effects of these immunosuppressants in adults, but just a few mentioning the same in the pediatric age group. This concise review focuses on the immunosuppressants commonly used for dermatoses in children and gives a comprehensive list of the various indications for use in each and associated adverse effect on long-term use. A comprehensive search was done using PubMed, Google, EMBASE, Cochrane, and MEDLINE on studies published till date on immunosuppressant use in pediatric dermatoses with special emphasis on the safety and adverse effects on long-term therapy. Only English language articles were considered. Thirty-eight articles were found, of which only 28 were selected after removing duplication and articles having no relevant information. Clinical as well as randomized double-blinded or single-blinded controlled trials, open-label studies, retrospective studies, case series, reviews, and case reports on the use of immunosuppressants in pediatric age group, including their long-term adverse effects were screened and a documented evidence was prepared, analyzed and presented in a narrative fashion to highlight the important pediatric indications for the use of the respective immunosuppressant, with special emphasis on the adverse effects on prolonged usage. The review has been divided into two parts for the reader's benefit. Part I consists of CS, azathioprine, and cyclosporine, whereas, Part II consists of methotrexate and mycophenolate mofetil.

[1]  E. Kechichian,et al.  Pediatric lichen planus: a systematic review of 985 published cases , 2021, International journal of dermatology.

[2]  R. George,et al.  Update on Management of Morphea (Localized Scleroderma) in Children , 2020, Indian dermatology online journal.

[3]  S. Kamphuis,et al.  European consensus-based recommendations for diagnosis and treatment of immunoglobulin A vasculitis-the SHARE initiative. , 2019, Rheumatology.

[4]  D. Buckley,et al.  British Association of Dermatologists guidelines for the safe and effective prescribing of oral ciclosporin in dermatology 2018 , 2019, The British journal of dermatology.

[5]  J. Kammermeier,et al.  Azathioprine dosing and metabolite measurement in pediatric inflammatory bowel disease: does one size fit all? , 2019, Annals of gastroenterology.

[6]  Y. Fujisawa,et al.  Juvenile case of multiple morphea profunda resulting in joint contracture that was successfully treated with cyclosporin A: A case report and review of the published works , 2019, The Journal of dermatology.

[7]  C. Caffarelli,et al.  Clinical features, outcomes and treatment in children with drug induced Stevens-Johnson syndrome and toxic epidermal necrolysis , 2019, Acta bio-medica : Atenei Parmensis.

[8]  T. Oranges,et al.  Clinical Use and Molecular Action of Corticosteroids in the Pediatric Age , 2019, International journal of molecular sciences.

[9]  L. Scherrer,et al.  Efficacy and safety of cyclosporine in Stevens–Johnson syndrome and toxic epidermal necrolysis , 2018, Dermatologic therapy.

[10]  A. Berrebi,et al.  Acute steroid myopathy: a highly overlooked entity. , 2018, QJM : monthly journal of the Association of Physicians.

[11]  K. Kridin Emerging treatment options for the management of pemphigus vulgaris , 2018, Therapeutics and clinical risk management.

[12]  C. Flohr,et al.  Use of systemic corticosteroids for atopic dermatitis: International Eczema Council consensus statement , 2018, The British journal of dermatology.

[13]  Luan-Yin Chang,et al.  The prevention of coronary arterial abnormalities in Kawasaki disease: A meta-analysis of the corticosteroid effectiveness. , 2017, Journal of microbiology, immunology, and infection = Wei mian yu gan ran za zhi.

[14]  M. Panda,et al.  Extensive childhood alopecia areata responding to combination of oral cyclosporine and corticosteroid therapy – clinical experience in four patients , 2018 .

[15]  D. Švecová Current Therapy in Autoimmune Bullous Diseases , 2017 .

[16]  R. Salomon,et al.  Clinical outcomes in children with Henoch–Schönlein purpura nephritis without crescents , 2017, Pediatric Nephrology.

[17]  M. Seager,et al.  Corticosteroids for the treatment of Kawasaki disease in children. , 2017, The Cochrane database of systematic reviews.

[18]  M. Krucoff,et al.  Coronary Artery Complication in Kawasaki Disease and the Importance of Early Intervention : A Systematic Review and Meta-analysis. , 2016, JAMA pediatrics.

[19]  C. Guarneri,et al.  Effectiveness and safety of cyclosporine in pediatric plaque psoriasis: A multicentric retrospective analysis , 2016, The Journal of dermatological treatment.

[20]  A. Bitton,et al.  Thiopurines in the Management of Crohn's Disease: Safety and Efficacy Profile in Patients with Normal TPMT Activity—A Retrospective Study , 2016, Canadian journal of gastroenterology & hepatology.

[21]  C. Wouters,et al.  Prednisone versus prednisone plus ciclosporin versus prednisone plus methotrexate in new-onset juvenile dermatomyositis: a randomised trial , 2016, The Lancet.

[22]  Y. L. Lim,et al.  Retrospective Study on Autoimmune Blistering Disease in Paediatric Patients , 2015, Pediatric dermatology.

[23]  V. Kinsler,et al.  The adverse effect profile of oral azathioprine in pediatric atopic dermatitis, and recommendations for monitoring , 2015, Journal of the American Academy of Dermatology.

[24]  A. Papp,et al.  Retrospective review of Stevens-Johnson syndrome/toxic epidermal necrolysis treatment comparing intravenous immunoglobulin with cyclosporine. , 2014, Journal of the American Academy of Dermatology.

[25]  R. Goldman,et al.  Henoch-Schönlein purpura in children: limited benefit of corticosteroids. , 2014, Canadian family physician Medecin de famille canadien.

[26]  A. Griffiths,et al.  Consensus guidelines of ECCO/ESPGHAN on the medical management of pediatric Crohn's disease. , 2014, Journal of Crohn's & colitis.

[27]  M. Malathi,et al.  Management Of Childhood Lichen Planus , 2014 .

[28]  Gaurang Gupta,et al.  Steroid pulse therapies in dermatology , 2014 .

[29]  E. A. Greene,et al.  Propranolol vs prednisolone for symptomatic proliferating infantile hemangiomas: a randomized clinical trial. , 2014, JAMA otolaryngology-- head & neck surgery.

[30]  M. Levin,et al.  Management of Kawasaki disease , 2013, Archives of Disease in Childhood.

[31]  T. Torres,et al.  Maintenance treatment of psoriasis with cyclosporine A: comparison between continuous and weekend therapy. , 2013, Journal of the American Academy of Dermatology.

[32]  H. Gollnick,et al.  Therapy of psoriasis in childhood and adolescence ‐ a German expert consensus , 2011, Journal der Deutschen Dermatologischen Gesellschaft = Journal of the German Society of Dermatology : JDDG.

[33]  P. Leadbitter,et al.  Pharmacologic Therapies for Infantile Hemangioma: Is There a Rational Basis? , 2011, Plastic and reconstructive surgery.

[34]  A. Menter,et al.  The use of cyclosporine in dermatology: part I. , 2013, Journal of the American Academy of Dermatology.

[35]  A. Menter,et al.  The use of cyclosporine in dermatology: part II. , 2010, Journal of the American Academy of Dermatology.

[36]  G. Ganzetti,et al.  A non‐responsive chronic autoimmune urticaria in a 12‐year‐old autistic girl treated with cyclosporin , 2009, Journal of the European Academy of Dermatology and Venereology : JEADV.

[37]  C. Chow,et al.  Efficacy and tolerability at 3 and 6 months following use of azathioprine for recalcitrant atopic dermatitis in children and young adults , 2009, The Journal of dermatological treatment.

[38]  C. Grattan,et al.  Guidelines for evaluation and management of urticaria in adults and children , 2007, The British journal of dermatology.

[39]  C. Deshmukh Minimizing side effects of systemic corticosteroids in children. , 2007, Indian journal of dermatology, venereology and leprology.

[40]  J. Schmitt,et al.  Cyclosporin in the treatment of patients with atopic eczema – a systematic review and meta‐analysis , 2007, Journal of the European Academy of Dermatology and Venereology : JEADV.

[41]  G. Elion,et al.  The purine path to chemotherapy , 1989, In Vitro Cellular & Developmental Biology.

[42]  P. Woo,et al.  Evaluation of methotrexate and corticosteroids for the treatment of localized scleroderma (morphoea) in children , 2006, The British journal of dermatology.

[43]  Akash A. Patel,et al.  Azathioprine in dermatology: the past, the present, and the future. , 2006, Journal of the American Academy of Dermatology.

[44]  J. Fernandes,et al.  Cyclosporin A treatment in severe childhood psoriasis , 2006, Journal of the European Academy of Dermatology and Venereology : JEADV.

[45]  N. Reynolds,et al.  Azathioprine dosed by thiopurine methyltransferase activity for moderate-to-severe atopic eczema: a double-blind, randomised controlled trial , 2006, The Lancet.

[46]  C. Romano,et al.  Alopecia areata in Down syndrome: a clinical evaluation , 2005, Journal of the European Academy of Dermatology and Venereology : JEADV.

[47]  A. Gedalia,et al.  Chronic Steroid and Immunosuppressant Therapy in Children , 2004, Pediatrics In Review.

[48]  N. Reynolds,et al.  Guidelines for prescribing azathioprine in dermatology , 2004, The British journal of dermatology.

[49]  M. Sticherling,et al.  Juvenile pityriasis rubra pilaris: successful treatment with ciclosporin , 2003, The British journal of dermatology.

[50]  P. Friedmann,et al.  Traditional therapies: glucocorticoids, azathioprine, methotrexate, hydroxyurea , 2002, Clinical and experimental dermatology.

[51]  R. Sundel,et al.  Aggressive management of juvenile dermatomyositis results in improved outcome and decreased incidence of calcinosis. , 2002, Journal of the American Academy of Dermatology.

[52]  D. Atherton,et al.  A retrospective evaluation of azathioprine in severe childhood atopic eczema, using thiopurine methyltransferase levels to exclude patients at high risk of myelosuppression , 2002, The British journal of dermatology.

[53]  A. Fleischer,et al.  Oral corticosteroid use is effective for cutaneous hemangiomas: an evidence-based evaluation. , 2001, Archives of dermatology.

[54]  U. Wahn,et al.  Low‐dose cyclosporin A microemulsion in children with severe atopic dermatitis: Clinical and immunological effects , 2001, Pediatric allergy and immunology : official publication of the European Society of Pediatric Allergy and Immunology.

[55]  D. Várszegi,et al.  Complete Recovery from Juvenile Pemphigus Vulgaris , 2001, Pediatric dermatology.

[56]  J. Bystryn,et al.  Ineffectiveness of cyclosporine as an adjuvant to corticosteroids in the treatment of pemphigus. , 2000, Archives of dermatology.

[57]  A. Finlay,et al.  Cyclosporin for severe childhood atopic dermatitis: short course versus continuous therapy , 2000, The British journal of dermatology.

[58]  S. Wananukul,et al.  Childhood pemphigus , 1999, International journal of dermatology.

[59]  B. Kirschner,et al.  Safety of azathioprine and 6-mercaptopurine in pediatric patients with inflammatory bowel disease. , 1998, Gastroenterology.

[60]  A. Finlay,et al.  Cyclosporine in severe childhood atopic dermatitis: a multicenter study. , 1996, Journal of the American Academy of Dermatology.

[61]  K. Verma,et al.  Azathioprine as a corticosteroid-sparing agent in air-borne contact dermatitis. , 1996, Indian journal of dermatology, venereology and leprology.

[62]  D. Faulds,et al.  Cyclosporin. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic use in immunoregulatory disorders. , 1993 .

[63]  C. Munro,et al.  Severe lichen planus clears with very low‐dose cyclosporin , 1992, The British journal of dermatology.

[64]  W. Weston,et al.  Systemic Glucocorticosteroid Therapy of Skin Disease in Children , 1984, Pediatric dermatology.

[65]  G. Elion Significance of azathioprine metabolites. , 1972, Proceedings of the Royal Society of Medicine.