(22) Immune checkpoint inhibitors induced Miller Fisher Syndrome: A disproportionality analysis in USFDA adverse event reporting system database

Background: Immune checkpoint inhibitors(ICI’s) are widely used in the treatment of several malignancies and various immune-related adverse events have been reported with them. Among the reported adverse events, the possibility of developing miller-fisher syndrome has not yet been explored.

OBJECTIVES: To detect the possible safety signal of ICI’s associated with Miller-Fisher Syndrome(MFS) through disproportionality analysis in the FDA Adverse Event Reporting System (FAERS) Database.

METHODS: Open Vigil 2.1 was utilized for the case/non-case retrospective disproportionality analysis in the publicly accessible FAERS database (2004Q1-2022Q3). The preferred term used for the study was "Miller Fisher Syndrome," and the drugs included in the analysis were pembrolizumab, ipilimumab, nivolumab, atezolizumab, avelumab, and durvalumab. The data mining algorithm used for the analysis was Reporting Odds Ratio (ROR) and Proportional Reporting Ratio (PRR). The threshold for a signal was defined as ROR-1.96SE >1 and PRR ≥2 with an accompanying X² value of 4 or above.

Results: FAERS database had a total of 100 reports associated with Miller-Fisher Syndrome, out of which 17 reports (17%) were associated with ICI.  A cumulative signal strength of ROR 28.646 (95% CI 16.999; 48.272) was obtained for all ICI’s and MFS. The median age of patients was 66 (65.5-72) years, hinting at a risk among elderly patients. It was also observed that the adverse event was reported only in males, suggestive of a possibility of genetic association with these drugs. Amongst the ICI’s, the highest number of cases and signal strength was obtained for pembrolizumab [(ROR 57.52 (95%CI=30.74; 107.628); followed by nivolumab [(ROR 16.49 (95%CI= 6.708; 40.532). Hospitalization was reported as an outcome in 60% of the patients with nivolumab.

Conclusion: Our analyses of the spontaneous reporting data revealed a positive signal for MFS with pembrolizumab, nivolumab, and ipilimumab, while a causal relationship cannot be established. Hence, further epidemiological studies with a defined population is required to validate these findings.