Frontiers in pharmacology · 2026
Ocular safety signals of sphingosine-1-phosphate receptor modulators in postmarketing surveillance.
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Fu Mei, Wang Jue, He Qingyi, Ma Nan, Zhang Jie, Li Yangjun, Han Jing
Аннотация
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.
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.