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Granulomatous Cutaneous Drug Eruptions: A Systematic Review

  • Systematic Review
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Abstract

Background

Granulomatous drug eruptions are rare entities, where granuloma formation occurs as an attempt to contain an exogenous or endogenous inciting agent. Granulomatous drug eruptions may be localized to the skin or may include major systemic involvement, and their characteristics depend both on the properties of the causative irritant and host factors. Because of the overlapping features amongst noninfectious granulomatous diseases, granulomatous drug eruptions are challenging to diagnose and distinguish both histologically and clinically.

Objective

The objective of this article is to provide a review and summary of the current literature on the five major types of cutaneous granulomatous drug eruptions: interstitial granulomatous drug reaction, drug-induced accelerated rheumatoid nodulosis, drug-induced granuloma annulare, drug-induced sarcoidosis, and miscellaneous presentations.

Methods

A systematic review was conducted through PubMed using the search terms “granulomatous drug eruption” and “cutaneous” or “skin”. English full-text studies that included human subjects experiencing a cutaneous reaction comprising granulomatous inflammation as the direct result of a drug were included. Of 205 studies identified, 48 articles were selected after a full-text review. Evidence was evaluated using the Tool for evaluating the methodological quality of case reports and case series.

Results

Polypharmacy and a prolonged lag period from drug ingestion to rash onset may create diagnostic challenges. Ruling out tuberculosis is imperative in the endemic setting, particularly where anti-tumor necrosis factor therapy is the presumed cause. Interstitial granulomatous drug reactions and granuloma annulare are often localized to the skin whereas accelerated rheumatoid nodulosis and sarcoidosis may sometimes be associated with systemic features as well. Granulomatous drug eruptions typically resolve on discontinuing the offending medication; however, the decision for drug cessation is dependent on a risk–benefit assessment. In some situations, supplementation of an additional agent to suppress the reaction may resolve symptoms. In some cases, granulomatous drug eruptions may be pivotal in the successful outcome of the drug, as in cases of melanoma treatment. In all situations, the decision to continue or withdraw the drug should be carefully based on the severity of the eruption, necessity of continuing the drug, and availability of a suitable alternative.

Conclusions

Granulomatous drug eruptions should always be considered in the differential diagnosis of noninfectious granulomatous diseases of the skin. Further research examining dose–response relationships and the recurrence of granulomatous drug eruptions on the rechallenge of offending agents is required. Increased awareness of granulomatous drug eruption types is important, especially with continuous development of new anti-cancer agents that may induce these reactions.

Clinical Trial Registration

PROSPERO registration number CRD42020157009.

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Author notes

  1. Nidhi Shah and Monica Shah contributed equally to the article.

Authors and Affiliations

  1. Department of Dermatology and Venereology, BP Koirala Institute of Health Sciences, Dharan, Sunsari, Nepal

    Nidhi Shah

  2. Faculty of Medicine, University of Toronto, Toronto, ON, Canada

    Monica Shah

  3. Division of Dermatology, Department of Medicine, University of Toronto, Toronto, ON, Canada

    Aaron M. Drucker & Neil H. Shear

  4. Division of Dermatology, Department of Medicine, Women’s College Research Institute, Women’s College Hospital, Toronto, ON, Canada

    Aaron M. Drucker

  5. Division of Dermatology, Department of Medicine, Sunnybrook Health Sciences Centre, Toronto, ON, Canada

    Neil H. Shear & Roni P. Dodiuk-Gad

  6. Department of Dermatology, Ha’emek Medical Center, Afula, Israel

    Michael Ziv & Roni P. Dodiuk-Gad

  7. Ruth and Bruce Rappaport Faculty of Medicine, Technion Institute of Technology, 1 Efron St. Bat Galim, Haifa, 3525433, Israel

    Roni P. Dodiuk-Gad

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  1. Nidhi Shah
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Correspondence to Roni P. Dodiuk-Gad.

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Funding

No funding was received for the preparation of this article.

Conflicts of Interest/Competing Interests

Nidhi Shah, Monica Shah, Aaron Drucker, Neil Shear, Michael Ziv, and Roni Dodiuk-Gad have no conflicts of interest that are directly relevant to the content of this article. In the last 3 years, Aaron Drucker has been a consultant for Sanofi, RTI Health Solutions, Eczema Society of Canada, and the Canadian Agency for Drugs and Technology in Health. He has received honoraria from Prime Inc., CME Outfitters, and the Eczema Society of Canada. His institution has received educational grants from Sanofi and research grants from Sanofi and Regeneron. Neil Shear is a consultant to AbbVie, Amgen, Bausch Medical, Celgene, Janssen, Leo Pharma, Lilly, Novartis, Sanofi-Genzyme, and Sun Pharma.

Ethics Approval

Not required by our institution for this systematic review.

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Not applicable, none required by our institution for this systematic review.

Consent for Publication

Not applicable, none required by our institution for this systematic review.

Availability of Data and Material

This systematic review follows Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. The data reported in this manuscript were obtained from openly available, previously published articles in the literature found through the PubMed database, and were cited accordingly.

Code Availability

Not applicable, no custom code or mathematical algorithm deemed central to the conclusions was used.

Authors’ Contributions

NS, MS and RPD-G made substantial contributions to the design of the work, analysis, interpretation of data, drafting and critical revision of the work. AMD, NHS and MZ made substantial contributions to the design and critical revision of the work.

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Shah, N., Shah, M., Drucker, A.M. et al. Granulomatous Cutaneous Drug Eruptions: A Systematic Review. Am J Clin Dermatol 22, 39–53 (2021). https://doi.org/10.1007/s40257-020-00566-4

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