Higher Circulating IL-6 levels as a predictor for poor outcome after migraine preventive treatment: a prospective study

Clinical and preclinical evidence suggests an association between higher levels of IL-6 and migraine. The present study aimed to determine whether pretreatment serum IL-6 levels were associated with headache outcomes at month 3 following migraine preventive treatment. In this prospective study, newly diagnosed migraine patients without current or recent use of preventive medications within 3 months were recruited, and were dichotomized as having higher or lower IL-6 serum levels according to the median at baseline among all of the patients who started preventive treatment with flunarizine. Primary and secondary outcomes were the mean change from baseline in the number of monthly headache days (MHDs) at month 3 based on headache diaries, and the percentage of non-responders, i.e., patients without ≥ 50% MHD reduction at month 3 compared to baseline, respectively. Logistic regression analysis was performed to estimate the odds ratio (OR) and 95% confidence interval (CI) for the association between higher IL-6 levels and treatment non-response, which were further controlled for demographics, headache profiles, disability (measured by Migraine Disability Assessment), psychiatric comorbidities (measured by Hospital Anxiety and Depression Scale), and sleep quality (measured by Pittsburgh Sleep Quality Index). In total, 236 migraine patients (187 F/49 M, mean age ± standard deviation 37.1 ± 10.3 years) were analyzed. At baseline, the median IL-6 level was 0.79 pg/mL, and a higher IL-6 level was associated with an older age (mean age 39.5 ± 10.6 vs. 34.6 ± 9.5 years, p < 0.001) and female sex (85.6% vs. 72.9%, p = 0.016), and a trend toward more MHDs (17.1 ± 8.1 vs. 15.0 ± 8.1 days/month, p = 0.050). After preventive treatment, patients with higher baseline IL-6 levels had less improvement in headache frequency (-5.7 vs. -8.2 MHDs, p = 0.004), and were more likely to be non-responders (72.0% vs. 44.9%, p < 0.001) (adjusted OR = 2.90, 95% CI = 1.61–5.25, p < 0.001). The results were consistent in sensitivity analysis across different subgroups. There was an independent association between higher pretreatment IL-6 levels and poorer response to preventive treatment with flunarizine at month 3 in this large cohort of migraine patients. Whether this finding could be generalizable to other preventives and whether such patients could benefit from preventives of immunomodulatory properties need to be further explored. ClinicalTrials.gov. NCT02747940, NCT04702971.