Abstract
A recent review by Egea et al. presents a compelling case for adding allopurinol to standard beta-blocker/ARB therapy in Marfan syndrome (MFS) aortopathy, drawing on consistent preclinical evidence and the drug's recent European Medicines Agency orphan-drug designation. This letter identifies two gaps that are genuinely absent from that review and could materially affect the safety and interpretability of any future allopurinol trial in MFS. First, the review discusses allopurinol hypersensitivity syndrome, toxic epidermal necrolysis, and Stevens-Johnson syndrome only as background toxicology, without proposing pre-treatment pharmacogenomic (HLA-B*58:01) or renal-function screening, despite targeting a population typically treated from childhood for years or indefinitely; real-world data show that guideline-recommended testing is not reliably performed even where quality-improvement measures exist. Second, the review's own preclinical data reveal a sex-dimorphic allopurinol treatment effect and sex-dependent aneurysm severity that are never translated into a recommendation for sex-stratified trial design, a concern reinforced by recent evidence of sex-specific, sometimes opposing, vascular responses to comparable Marfan pharmacotherapies and by sex-specific patterns in the serum urate-cardiovascular outcome relationship. Both gaps are correctable at the design stage rather than reflecting flaws in the underlying rationale. We recommend that future allopurinol-MFS trials incorporate risk- or ancestry-based pharmacogenomic screening alongside renal-function assessment, together with prospective balanced enrollment, stratified randomization, and prespecified sex-by-treatment interaction analyses, to ensure a safe and conclusive test of allopurinol's role in Marfan aortopathy management.