The escalating approach to MS was based on failure. Failure drug 1 go to drug 2, fail go to drug 3 and hope that its not too late to limit progression occurring. This is a problem of the softly softly approach but the we’ll wait until I feel I have to do something type of old school Neurologists. Here the de-escalating approach supports our biological explanation hypothesised years ago.
First line high efficacy treatment as soon as possible is having benefit…even the sofly sofly numpties can see this…OK for some it has taken over a decade for the light bulb to come on. But better late than never. The revolution is occurring and this can occur because people are seeing the light but I suspect it is in part driven by laziness because the advent of CD20-depleting antibodies provided a tool that had high efficacy but required very limited monitoring and so the duffers at NICE said the neuros can use the high efficacy treatment first…The pyramid of treatment has been flipped.
Now we have a choice of a few CD20 antibodies and the real choice is injection every 6 months or every month to keep B cells from circulating in the blood…For some it it is home treatment compared to a trip to the hospital. This whole approach is based on destroy everything that is B cell…but a few people asked how does this work and a few bright sparks suggested that because of biology you can target what you need to target and you may not have to do so frequently to do this. The companies response was this hasn’t been tested and shown to work and this is not in the label, but once you put your neck on the block to suggest what is happening you can see that if you stop B cells doing their job forever there may be an infectious consequence and you could see that you will not be able to make full vaccine responses if you don’t have any B cells. So during COVID we had the freaked out Neuros trying to do nothing to keep you out of hospital which was a COVID-19 central and so extended interval dosing began and just as we and others predicted disease did not come screaming back…So there is overdosing at least for some people.
So do you have to go on forever can you stop or if you are less confident reduce the degree of of immunosuppresion created by B cell therapy. Here they used a lower dose of rituximab every 24 months rather than 1000mg every 6 months and guess what they found just what I told them would happen with ocrelizumab is that disease on the whole did not reappear. This repeats what has been shown in Scandiland with rituximab. It has been shown that you can wait for over 30 months in people who aren’t showing disease activity when they are first treated. Based on other studies we know that older people and those with more stable disease will benefit from this. So with a bit of reading, we can guess what will probably happen in the £3,500,000 UK study will find in about 3 years time.
The extension of the phase II study we showed that three dose cycles (i.e. 0,6, 12) over one year gives long term protection. Why should this surprise us we have been getting long term benefit after a year of treatment with alemtuzumab a B cell depleter and cladribine also a B cell depleter. We have given you a plausible mechanism and it is not about T cells or should I say a direct effect on T cells. I can take pleasure in this result and say yes we told you so even if we are air-brushed out of the the thought process.
Only 2.4% (n = 25, ITT) had a relapse and/or new MRI disease activity this is better than seen with alemtuzumab where about 50% of people had activity. Of course these studies were done in a different era and when alemtuzumab was tested disease was more active as there were no high-efficacy treatments first line that were available but it is a big difference. I could make a suggestion….but I won’t for now
During “follow-up, B-cell counts reached 80 cells/µL or higher in 72.8% of patients in the q18–24mo and 63.7% of patients in the q6–12mo group, respectively” and “There was no correlation between B-cell counts and relapses although patients who relapsed or had new MRI disease activity”…
So yet further replication of all the stuff we were saying years and years and years ago. What comes back is not the same as what was there in the first place…Get this and it is obvious why this extended interval dosing works. Explain the biology to people and it is obvious. But when the “Great and the Good” who dominate scientific thinking keep telling us that all is “unknown” as a preamble for their Nature/Science study down another garden path then there is no focus and without paying attention to the cry that the important stuff “is behind you” it takes time for the message to surface.
Soon we will get the dose and then watch and wait study and we can predict that too
Langer-Gould AM, Smith JB, Nielsen AS, Beaber BE, Brara SM, Amirova S, Su E, Li BH, Z Esfahani N, Torres F, Xu S. De-escalating low-dose rituximab up to every 24-month infusions and the risk of disease activity in people with relapsing multiple sclerosis who were stable the first year on therapy. Mult Scler. 2026 Mar 19:13524585261430130.
Background: Higher cumulative rituximab doses are associated with greater risks of infections. Therefore, we routinely extend low-dose rituximab (500 mg) intervals in people with relapsing multiple sclerosis (pwRMS) from every 6(q6mo) to 12 months(q12mo) to 18(q18mo) and/or 24 months(q24mo).
Objective: To determine whether q18-24mo extension increases disease activity risks compared to continuing q6-12mo intervals.
Methods: We conducted a retrospective cohort study of rituximab-treated pwRMS with no evidence of disease activity (absence of relapses, MRI disease activity and disability progression, NEDA-3, 96.6%) during the first year on rituximab.
Results: We identified 1052 patients (mean age = 38.5 years; 71.5% female). 467 (44.4%) pwRMS received at least one q18-24mo 500 mg interval and 585 never extended beyond q6-12mo. Relapses and/or MRI disease activity (2.4%) and failing NEDA-3 (2.9%) were uncommon. Extending dosing to q18-24mo was not associated with an increased risk of failing NEDA-3 in inverse probability of treatment weighting propensity-score adjusted intention-to-treat (hazard ratio [HR] = 0.57, 95%CI = 0.21-1.57, p = 0.275) or per-protocol analyses (HR = 0.56, 95%CI = 0.17-1.86, p = 0.348) over 3-5 years of follow-up.
Conclusion: Extending low-dose rituximab after at least 1 year of clinical and radiological stability up to q24mo was not associated with an increased risk of disease activity compared to continuing q6-12mo intervals in this large, population-based cohort.
Have a read of “Baker D, Marta M, Pryce G, Giovannoni G, Schmierer K. Memory B Cells are Major Targets for Effective Immunotherapy in Relapsing Multiple Sclerosis. EBioMedicine. 2017;16:41-50”. This said “this creates a unifying concept….. that is consistent with therapeutic, histopathological and aetiological aspects of MS” Meaning it gets to the root biology of MS but it says how we can manage pregnancy and all I can say it why haven’t the MS fraternity and pharma really bitten the bullet and definitely showed this.
COI Multiple
Disclaimer My views
Source: multiple-sclerosis-research.org