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

Background: Multiple sclerosis (MS) treatment with B-cell targeted therapies, such as rituximab, ocrelizumab, ofatumumab and cladribine may be associated with an increased incidence of headache, thus proper management of a possible adverse effect may be necessary. We aimed to find, if any, 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 till 6th of June 2020: Pubmed/MEDLINE, ClinicalTrials.gov, EU Clinical Trials Register. No limits were applied to publication year, sex or race. 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 metanalysis. Two reviewers independently extracted individual study data and evaluated studies for risk of bias using Cochrane Risk of Bias version 2 tool (ROB-II). PRISMA guidelines were followed at all stages of the systematic review. Random effects meta-analysis to derive confidence intervals and to assess heterogeneity were conducted. The primary outcome was all-cause headache during the administration of B-cell targeting therapy in patients with multiple sclerosis. Findings: Nine randomized clinical trials (3785 participants) were included. Compared with placebo, treatment with B-cell targeting therapies was not associated with a statistically significant increase in headache risk (RR 1·12 [95% CI 0·96 – 1·30]; p=0·15; I2 = 9·32%). In a subgroup analysis, cladribine was statistically significant for an increase in headache risk (RR 1·20 [95% CI 1·006 – 1·42]; p=0·042; I2 = 0%; 3 studies with 2107 participants). Interpretation: Even though a trend is shown, B-cell targeted therapies do not correlate with an increased incidence of headache as an adverse effect. Further sub-analyses revealed a significant association between cladribine alone and increased incidence of headache. Further research is needed to unravel the underlying pathogenetic mechanism of headache induction, as well as, to establish headache prevention strategies. Funding statement: The authors declare no funding applied for this study Declaration of Interests: T.M. has received travel grants from Merck and Sanofi-Genzyme. M.B. has received travel grants from Merck, Teva-Specifar, Genesis Pharma, Pfizer. N.P. declares no conflict of interest. K.P. declares no conflict of interest. A.L. declares no conflict of interest. G.V. declares no conflict of interest. N.G. declares no conflict of interest. N.F. has received honoraria, consultation fees and/or research grants from Actelion, Amgen, Biogen, Celgene, Genesis Pharma, Eli Lilly, Merck Serono, Novartis, Receptos, Roche, Sanofi-Genzyme and Teva-Specifar. D.D.M. has received consulting, research, speaking fees and/or travel grants from Allergan, Amgen, Bayer, Biogen, Cefaly, ElectroCore, Eli-Lily, Genesis Pharma, Merck-Serono, Merz, Mylan, Novartis, Roche, Sanofi Genzyme and Teva -Specifar