Mavridis T, Papagiannakis N, Breza M, Vavougios GD, Patas K, Daponte A, Laskaratos A, Archontakis-Barakakis P, Pantazopoulos I, Mitsikostas DDB-Cell Targeted Therapies in Patients with Multiple Sclerosis and Incidence of Headache: A Systematic Review and Meta-Analysis. .J Pers Med. 2022 Sep 8;12(9):1474. doi: 10.3390/jpm12091474.

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. 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.

A trend means there is no proven difference and data hacking means you trawl through the information until you find something, by chance do it twenty times and you will find something. Now I have no issue with the suggestion that there is an increased chance of headache, but what is the biology that explains it. But they do not find anything with anti-CD20, but there is a suggestion that there is an effect with cladribine . Is it the dreaded non CD20 T cell that makes the difference or is it a chance finding and even if is real the increased risk of 1.2 is small. I would argue that all MS drugs are B cell depleters why not look at alemtuzumab and the others and indeed the introduction talks about headaches in fingolimod. There should be a hierarchy of effects from the good to the weak inhibitors. In addition there are headaches and there are headaches, as one who generally stays clear of paracetemol and asprin etc. I got the headache from hell with COVID, but I am sure this is chicken-feed to any one who gets migraine. However remember when you get an antibody infusion you expect to get infusion reactions and you are given all sorts of preventative agents like anti-histamines and guess what? Yep often paracetemol, so is it a fair fight? I will let the manufacturers of cladribine explain this one to me.

What is you experience?

There are people out there who have taken both c;asses of agent. I know people some people have had rituximab, ocrelizumab and cladribine.

COI Multiple

Disclaimer. This represents the authours view only

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  • If there are no true correlations and you consider 20 subgroups, one will demonstrate ‘statistical significance’ where no true significance exists. Unless they have prospectively decided to look at Cladribine and Cladribine alone, this can be ignored and taken as an example of data trawling and bad scientific technique. People who truly understand meta analysis should understand this, and editors should refuse to publish, unless they are shamelessly headline seeking and ignorant of scientific technique. Sadly, because the primary endpoint failed to achieve statical significance, this may have been an unscientific attempt to avoid publication bias (which shouldn’t exist, but does).

  • Seriously, at the risk of sounding callous, who cares about that “trend” (eyeroll) in slightly increased headache risk from an infusion med? I mean, what HASN’T at some time, been implicated in causing headaches? Alcohol, caffeine, spicy food, stress, lack of sleep, the list is nigh endless. And considering the high prevalence of headaches in general among pwMS, I’m surprised they could even find enough people who could actually note a significant difference just from having an infusion of med. For instance, I just had a covid shot yesterday, and today I have a super bad headache. Is it worse than my “normal” daily headache? A bit. But if I didn’t know I’d had that shot yesterday, I would say the such a bad headache this morning is not out of the range of the headache severity I experience fairly often all without covid shots. Unless the headache lingers without end until the NEXT infusion, take your NSAID of choice, it’ll go away in a bit, and we can get back to worrying about the more serious side effects of those meds and how to treat those.

  • It’s a sledgehammer to crack a nut that’s barely and poor science. Mark and Karen are right. We don’t need redundant science and it may upset pwMS who are spooked into thinking they should not be taking OCR etc., because of “another risk factor “. I know a recently diagnosed young woman who’s terrified of everything. Thinks OCR is harming her and on the brink of changing her clinic yet again. This kind of thing encourages her insecurities.
    Glad you avoid Aspirin, Paracetamol etc., MD. A glass of water often does the trick.

  • Interesting.

    I have experienced headaches daily, for at least the past 15 years. Most days the headaches are mild, but every once in awhile I will get a debilitating migraine. I have rescue meds to help with the migraines.

    I have had both OCR and CLAD (most recently), and I cannot say I noticed worsening of my headaches on either drug. Honestly, the I feel the headaches have somewhat subsided over the past few years on CLAD.

    However, my PPMS symptoms have naturally gotten worse over the same time, so new pains have replaced old pains, my “pain scale” gets readjusted with each day and new symptom, and I am also on a lot more various pain meds these days.

    I believe all the above factors may impact the way I would describe how headaches impact my current daily life. But if someone did a meta-analysis, they would find my medical chart does say I have headaches. For whatever value that is worth 🤷‍♂️

  • Anecdotal: I thought my head was going to explode because it hurt so much when I started the 2 doses of Tecfidera (one of the reasons that made me change the medication, was to take the medication 2 times a day and an unbearable headache would appear)

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