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We appreciate the interest and comments by Quilis et al 1 on our recent publication.2 Quilis et al draw our attention to the incidence of cutaneous adverse reactions (CARs) with febuxostat in people who had already had reactions with allopurinol. In their study which included several practices in Spain from 2011 to 2018, 15% of people developed these reactions with febuxostat1 compared with the 9%–15% range reported previously for similar patient populations from the USA and France.3 4 CARs are frequent, and are associated with significant morbidity.5 Interestingly, the rate of CARs in people newly starting febuxostat and not previously exposed to allopurinol was 2.5% in the French study,4 similar to the rate of 31 per 1000 patient-years in our study.2 So why is the risk of CARs with febuxostat increased by four-fold to six-fold (2.5% to 9%–15%) in people with previous allopurinol-associated CARs compared with lower rate in the general population? Does allopurinol hypersensitivity increase the risk of hypersensitivity reactions to another urate-lowering therapy? Is there some cross-reactivity,6 despite some differences in the mechanism of action between these two medications? Are some allopurinol-associated CARs just adverse events and not hypersensitivity reactions that usually manifest as severe CARs (SCARs)7 8? These are important questions to answer.
Allopurinol-associated CARs and SCARs are uncommon adverse events, and intriguing from research perspective. Given the unpredictability in occurrence and a fatal outcome in some cases, ULT-associated CARs/SCARs are important clinically. Future studies need to examine this clinical problem using various innovative approaches. Systematic studies of gene–environment–comorbidity–medication interactions are needed to solve this puzzle.
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Footnotes
Handling editor Josef S Smolen
Contributors JAS wrote the first manuscript draft, revised, read and approved the final version.
Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Competing interests JAS has received consultant fees from Crealta/Horizon, Medisys, Fidia, UBM, Trio health, Medscape, WebMD, Clinical Care options, Clearview healthcare partners, Putnam associates, Focus forward, Navigant consulting, Spherix, Practice Point communications, the National Institutes of Health and the American College of Rheumatology. JAS owns stock options in Amarin pharmaceuticals and Viking therapeutics. JAS is on the speaker’s bureau of Simply Speaking. JAS is a member of the executive of OMERACT, an organisation that develops outcome measures in rheumatology and receives arms-length funding from 12 companies. JAS serves on the FDA Arthritis Advisory Committee. JAS is the chair of the Veterans Affairs Rheumatology Field Advisory Committee. JAS is the editor and the Director of the UAB Cochrane Musculoskeletal Group Satellite Center on Network Meta-analysis. JAS previously served as a member of the following committees: member, the American College of Rheumatology’s (ACR) Annual Meeting Planning Committee (AMPC) and Quality of Care Committees, the Chair of the ACR Meet-the-Professor, Workshop and Study Group Subcommittee and the cochair of the ACR Criteria and Response Criteria subcommittee.
Patient and public involvement Patients and/or the public were not involved in the design, or conduct, or reporting, or dissemination plans of this research.
Provenance and peer review Commissioned; internally peer reviewed.