B-Cell Targeted Therapies in Patients with Multiple Sclerosis and Incidence of Headache: A Systematic Review and Meta-Analysis

Background: Multiple Sclerosis treatment with B-cell targeted therapies may be associated with an increased incidence of headache. We aimed to find and compare the association of B-cell targeted therapies with the incidence of headache in patients with Multiple Sclerosis. Methods: In a systematic based approach, the following databases were searched from inception until the 6th of June 2020: Pubmed/MEDLINE, ClinicalTrials.gov, EU Clinical Trials Register. Only randomized clinical trials (RCTs) enrolling patients with Multiple Sclerosis comparing B-cell targeted therapies (Rituximab, Ocrelizumab, Ofatumumab, Ublituximab or Cladribine) with placebo were selected for the systematic review and further meta-analysis. PRISMA guidelines were followed at all stages of the systematic review. The primary outcome was an all-cause headache of B-cell targeting therapy in patients with Multiple Sclerosis. Results: Nine RCTs were included. Compared with placebo, treatment with B-cell targeting therapies revealed a trend in headache risk, but it was not statistically significant (Relative Risk 1.12 [95% Confidence Interval 0.96-1.30]; p = 0.15; I-2 = 9.32%). Surprisingly, in a sub-group analysis, Cladribine was statistically significant for an increase in headache risk (RR 1.20 [95% CI 1.006-1.42]; p = 0.042; I-2 = 0%; 3 studies with 2107 participants). Conclusions: Even though a trend is shown, B-cell targeted therapies do not correlate with an increased incidence of headache as an adverse effect. Sub-analyses revealed a significant association between Cladribine alone and an increased incidence of headache. Whereas a purinergic signaling cascade is proposed as a mechanism of action, further research is needed to unravel the underlying pathogenetic mechanism of headache induction and establish headache prevention strategies.