Severe Cutaneous Adverse Drug Reactions: Presentation, Risk Factors, and Management
- 721 Downloads
Purpose of Study
Immune-mediated adverse drug reactions occur commonly in clinical practice and include mild, self-limited cutaneous eruptions, IgE-mediated hypersensitivity, and severe cutaneous adverse drug reactions (SCAR). SCARs represent an uncommon but potentially life-threatening form of delayed T cell-mediated reaction. The spectrum of illness ranges from acute generalized exanthematous pustulosis (AGEP) to drug reaction with eosinophilia with systemic symptoms (DRESS), to the most severe form of illness, Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN).
There is emerging literature on the efficacy of cyclosporine in decreasing mortality in SJS/TEN.
The purpose of our review is to discuss the typical presentations of these conditions, with a special focus on identifying the culprit medication. We review risk factors for developing SCAR, including HLA alleles strongly associated with drug hypersensitivity. We conclude by discussing current strategies for the management of these conditions.
KeywordsSevere cutaneous adverse drug reaction (SCAR) Acute generalized exanthematous pustulosis (AGEP) Drug reaction with eosinophilia and systemic symptoms (DRESS) Stevens-Johnson syndrome (SJS) Toxic epidermal necrolysis (TEN) HLA-associated drug hypersensitivity
Compliance with Ethical Standards
Conflict of Interest
The authors declare no conflicts of interest relevant to this manuscript.
Human and Animal Rights and Informed Consent
This article does not contain any studies with human or animal subjects performed by any of the authors.
Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance
- 11.Rzany B, Hering O, Mockenhaupt M, Schroder W, Goerttler E, Ring J, et al. Histopathological and epidemiological characteristics of patients with erythema exudativum multiforme major, Stevens-Johnson syndrome and toxic epidermal necrolysis. Br J Dermatol. 1996;135(1):6–11.CrossRefPubMedGoogle Scholar
- 20.• Peter JG, Lehloenya R, Diamini S, Risma K, White KD, Konvinse KC. Severe delayed cutaneous and systemic reactions to drugs: a global perspective on the science and art of current practice. J Allergy Clin Immunol Pract. 2017;5(3):547–63. A review on SCAR focusing on global epidemiology, clinical phenotypes, diagnostic considerations, and special considerations, including drug re-challenge and SCAR in pregnancy. CrossRefPubMedGoogle Scholar
- 31.•• White KD, Abe R, Ardern-Jones M, Beachkofsky T, Bouchard C, Carleton B, et al. SJS/TEN 2017: building multidisciplinary networks to drive science and translation. J Allergy Clin Immunol Pract. 2018;6(1):38–69. A review on SJS/TEN discussing global epidemiology and pharmacogenomics networks of SJS/TEN, management, with a focus on special populations, including children, pregnant women, and the elderly, and potential focus of future research. CrossRefPubMedGoogle Scholar
- 36.•• Mallal S, Phillips E, Carosi G, Molina JM, Workman C, Tomazic J, et al. HLA-B*5701 screening for hypersensitivity to abacavir. N Engl J Med. 2008;358(6):568–79. Double-blind, prospective, randomized trial that showed HLA-B*57:01 screening decreased the risk of drug hypersensitivity to abacavir. This was a key study leading to the recommendation of genetic screening prior to the administration of certain medications. CrossRefPubMedGoogle Scholar
- 45.Paulmann M, Mockenhaupt M. Severe drug-induced skin reactions: clinical features, diagnosis, etiology, and therapy. English online version of J Dtsch Dermatol Ges. 2015;13(7):625–45.Google Scholar
- 46.• Guegan S, Bastuji-Garin S, Poszepczynska-Guigne E, Roujeau JC, Revuz J. Performance of the SCORTEN during the first five days of hospitalization to predict the prognosis of epidermal necrolysis. J of Investigative Derm. 2006;126(2):272–6. Study showing the validity of the SCORTEN score, a severity-of-illness tool to predict mortality in SJS/TEN. CrossRefGoogle Scholar
- 60.• Sharma N, Thenarasun SA, Kaur M, Pushker N, Khanna N, Agarwal T, et al. Adjuvant role of amniotic membrane transplantation in acute ocular Stevens-Johnson syndrome: a randomized control trial. Ophthalmology. 2016;123(3):484–91. Prospective, randomized, controlled trial showing amniotic membrane transplantation improves ocular outcomes in the acute phase of SJS/TEN. CrossRefPubMedGoogle Scholar
- 73.• Paradisi A, Abeni D, Bergamo F, Ricci F, Didona D, Didona B. Etanercept therapy for toxic epidermal necrolysis. J Am Acad Dermatol. 2014;71(2):278–83. Case series of ten patients with TEN treated with a tumor necrosis factor α antagonist (etanercept). Despite a predicted mortality of 50%, all patients responded promptly to a single treatment. The use of anti- TNF α agents therefore warrants further study in TEN. CrossRefPubMedGoogle Scholar
- 75.• Gonzalez-Herrada C, Rodriguez-Martin S, Cachafeiro L, Lerma V, Gonzalez O, Lorenta JA, et al. Cyclosporine use in epidermal necrolysis is associated with an important mortality reduction: evidence from three different approaches. J Invest Dermatol. 2017;137(10):2092–100. By comparing outcomes in TEN at different centers using predominately different forms of immunomodulatory therapy (typically cyclosporine versus IVIg), cyclosporine was consistently shown to improve mortality in TEN. CrossRefPubMedGoogle Scholar
- 76.•• Zimmerman S, Sekula P, Venhoff M, Motschall E, Knaus J, Schumacher M, et al. Systemic immunomodulating therapies for Stevens-Johnson syndrome and toxic epidermal necrolysis, a systematic review and meta-analysis. JAMA Dermatol. 2017;153(6):514–22. A review and meta-analysis of systemic immunomodulating therapies in SJS/TEN that shows cyclosporine to have the most promise in decreasing mortality. CrossRefGoogle Scholar
- 77.• Roujeau JC, Mockenhaupt M, Guillaume JC, Revuz J. New evidence supporting cyclosporine efficacy in epidermal necrolysis. J of Invest Derm. 2017;137(10):2047–9. A review of recently published literature and presentation of expert opinion that cyclosporine is effective in decreasing mortality in TEN and should possibly considered as first line systemic therapy in this life threating condition. CrossRefGoogle Scholar
- 83.• Creamer D, Walsh SA, Dziewulski P, Exton LS, Lee HY, Dart JK. UK guidelines for the management of Stevens-Johnson syndrome/toxic epidermal necrolysis in adults. Br J of Derm. 2016;174(6):1194–227. Guidelines from the United Kingdom on the diagnosis and management of SJS/TEN. CrossRefGoogle Scholar