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Review
. 2022 Sep 8;12(9):1474.
doi: 10.3390/jpm12091474.

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

Theodoros Mavridis  1 , Nikolaos Papagiannakis  1 , Marianthi Breza  1 , Georgios D Vavougios  2   3   4   5 , Kostas Patas  1 , Ariadne Daponte  1 , Achilleas Laskaratos  6 , Paraschos Archontakis-Barakakis  7 , Ioannis Pantazopoulos  8 , Dimos D Mitsikostas  1
Affiliations
Review

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

Theodoros Mavridis et al. J Pers Med. .

Abstract

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; I2 = 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; I2 = 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.

Keywords: B-cell targeted therapies; cladribine; headache incidence; ocrelizumab; ofatumumab; purinergic signaling; rituximab; ublituximab.

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Conflict of interest statement

T.M. received travel grants from Merck and Sanofi-Genzyme. M.B. received travel grants from Merck, Teva-Specifar, Genesis Pharma and Pfizer. N.P. declares no conflict of interest. K.P. declares no conflict of interest. A.D. declares no conflict of interest. A.L. declares no conflict of interest. G.V. declares no conflict of interest. A.B.P. declares no conflict of interest. I.P. declares no conflict of interest. D.D.M. 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.

Figures

Figure 1
Figure 1
PRISMA Flow Diagram.
Figure 2
Figure 2
Forest plot for the association of headache with B-Cell modifying therapies. NCT: clinicaltrials.gov registration number, CLA: Cladribine, OCR: Ocrelizumab, RTX: Rituximab, OFA: Ofatumumab, RR: Risk Ratio, CI: Confidence Interval.
Figure 3
Figure 3
Forest plot of sub-group analysis for the association of headache with Cladribine treatment. NCT: clinicaltrials.gov registration number, RR: Risk Ratio, CI: Confidence Interval.
See this image and copyright information in PMC

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