Ocular safety signals of sphingosine-1-phosphate receptor modulators in postmarketing surveillance.

BACKGROUND

Sphingosine-1-phosphate (S1P) receptor modulators are used for immune-mediated diseases, and macular oedema is an established ocular adverse effect. However, ocular-focused, class-wide postmarketing reporting across all five approved agents remains incompletely characterized.

METHODS

We analyzed U.S. Food and Drug Administration Adverse Event Reporting System (FAERS) data from 2004 Q1 through 2026 Q1 using report-level deduplication, approval-aligned windows, and primary-suspect exposure. Ocular events were assessed using a curated set of 52 Preferred Term (PT) strings. Sensitivity analyses included report-level macular/retinal oedema aggregation, same-indication active comparators, temporal and sparse-data analyses, restricted empirical-Bayes assessment, and external validation in Canada Vigilance. Exact-date time to onset was assessed for the aggregated phenotype.

RESULTS

The primary cohort included 98,843 primary-suspect reports, of which 8,812 (8.9%) were ocular, representing 12,088 unique ocular report-PT pairs. At the class level, 21 ocular PTs met primary signal criteria; macular oedema showed the strongest anatomically specific signal (n = 947; reporting odds ratio [ROR], 48.18; 95% confidence interval [CI], 44.84-51.76). Fingolimod had the broadest signal spectrum; macular oedema was the principal anatomically specific signal for siponimod and ozanimod. No ponesimod PT met primary criteria, and the etrasimod macular oedema estimate was sparse (n = 11). Of 36 primary drug-PT signals, 13 were High, 22 Moderate, and one Low. Report-level aggregation yielded a class-level ROR of 29.47 (95% CI, 27.62-31.45). In indication-restricted multiple sclerosis analyses, the association remained elevated versus all non-S1P disease-modifying therapies (ROR, 43.85; 95% CI, 35.75-53.78), while ulcerative colitis/inflammatory bowel disease analyses were sparse and exploratory. For fingolimod, the association persisted after exclusion of the first two post-approval years (ROR, 45.79; 95% CI, 37.26-56.26). Median time to onset was 93.0 days for fingolimod and 15.5 days for siponimod. Canada Vigilance showed a concordant class-level association (ROR, 74.00; 95% CI, 59.30-92.35).

CONCLUSION

Macular/retinal oedema was the most consistent ocular reporting pattern in the S1P receptor modulator class. The association remained evident after phenotype aggregation and indication-restricted analysis and was also observed in Canada Vigilance. Sparse data for newer agents and residual confounding limit comparative interpretation.