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Severe cutaneous adverse reactions

Nature Reviews Disease Primers volume 10, Article number: 30 (2024) Cite this article

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Abstract

Severe cutaneous adverse reactions (SCARs), which include Stevens–Johnson syndrome and toxic epidermal necrolysis, drug reaction with eosinophilia and systemic symptoms (also known as drug-induced hypersensitivity syndrome), acute generalized exanthematous pustulosis, and generalized bullous fixed drug eruption, are life-threatening conditions. The pathogenesis of SCARs involves T cell receptors recognizing drug antigens presented by human leukocyte antigens, triggering the activation of distinct T cell subsets. These cells interact with keratinocytes and various immune cells, orchestrating cutaneous lesions and systemic manifestations. Genetic predisposition, impaired drug metabolism, viral reactivation or infections, and heterologous immunity influence SCAR development and clinical presentation. Specific genetic associations with distinct SCAR phenotypes have been identified, leading to the implementation of genetic screening before prescription in various countries to prevent SCARs. Whilst systemic corticosteroids and conventional immunomodulators have been the primary therapeutic agents, evolving strategies, including biologics and small molecules targeting tumour necrosis factor, different cytokines, or Janus kinase signalling pathways, signify a shift towards a precision management paradigm that considers individual clinical presentations.

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Fig. 1: Pathophysiological mechanisms in SCARs.
Fig. 2: Cell death mechanisms in SJS/TEN: pathogenesis of keratinocyte death.
Fig. 3: Mechanistic models for T cell recognition and activation and systemic factors contributing to SCARs.
Fig. 4: Global representation of HLA risk alleles linked to SCARs.
Fig. 5: Cutaneous manifestations of severe cutaneous adverse reactions.
Fig. 6: Treatment strategies for SJS/TEN based on disease stage.
Fig. 7: Treatment strategies for DRESS based on disease stage.

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Acknowledgements

S.-I.H. and W.-H.C. acknowledge C.-C. Lee and S.-L. Lee for their help in preparing Tables 2 and 3, Figs. 1–3 and 6, and the manuscript.

Author information

Authors and Affiliations

  1. Cancer Vaccine and Immune Cell Therapy Core Laboratory, Department of Medical Research, Chang Gung Memorial Hospital, Linkou Branch, Taoyuan, Taiwan

    Shuen-Iu Hung

  2. Department and Institute of Pharmacology, National Yang Ming Chiao Tung University, Taipei, Taiwan

    Shuen-Iu Hung

  3. Dokumentationszentrum schwerer Hautreaktionen (dZh), Department of Dermatology, Medical Center and Medical Faculty, University of Freiburg, Freiburg, Germany

    Maja Mockenhaupt

  4. Division of Rheumatology, Allergy and Immunology, Department of Internal Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA

    Kimberly G. Blumenthal

  5. Division of Dermatology, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan

    Riichiro Abe

  6. Department of Ophthalmology, Kyoto Prefectural University of Medicine, Kyoto, Japan

    Mayumi Ueta

  7. Dermatology Department, AP-HP, Henri Mondor Hospital, Reference Centre for Toxic Bullous Diseases and Severe Drug Reactions TOXIBUL, Université Paris Est Créteil EpiDermE, Créteil, France

    Saskia Ingen-Housz-Oro

  8. Center for Drug Safety and Immunology, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA

    Elizabeth J. Phillips

  9. Department of Dermatology, Drug Hypersensitivity Clinical and Research Center, Chang Gung Memorial Hospital, Taipei/Linkou branches, and Chang Gung University, Taoyuan, Taiwan

    Wen-Hung Chung

  10. Department of Dermatology, Chang Gung Memorial Hospital, Xiamen branch, Xiamen, China

    Wen-Hung Chung

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  1. Shuen-Iu Hung
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Contributions

Introduction (W.-H.C. and S.-I.H.); Epidemiology (M.M., K.G.B. and S.-I.H.); Mechanisms/pathophysiology (S.-I.H., R.A. and M.U.); Diagnosis, screening and prevention (M.M., W.-H.C., S.-I.H. and E.J.P.); Management (W.-H.C.); Quality of life (S.I.-H.-O. and W.-H.C.); Outlook (W.-H.C., S.-I.H., M.M., K.G.B., R.A., M.U. and E.J.P.).

Corresponding author

Correspondence to Wen-Hung Chung.

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Competing interests

E.J.P. has received royalties from Uptodate and consulting fees from Janssen, Biocryst, Regeneron, Novavax, AstraZeneca and Verve. The other authors declare no competing interests.

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Nature Reviews Disease Primers thanks T. Shiohara, L. Naldi & J. H. Lee who co-reviewed with H. R. Kang and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Hung, SI., Mockenhaupt, M., Blumenthal, K.G. et al. Severe cutaneous adverse reactions. Nat Rev Dis Primers 10, 30 (2024). https://doi.org/10.1038/s41572-024-00514-0

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