The wearing off effect also known to some as the “CRAP gap” is something that occurs when you get to the end of your treatment cycle. But what is it?
AI says “The “wearing-off” effect (WOE) of monoclonal antibodies (MAbs) is a commonly reported phenomenon where therapeutic benefits subside before the next dose is administered. Symptoms often increase and include fatigue and cog-fog and others.
It is a difficult to say what it is, there have been studies and when it has been assessed formally as a trial, they can’t show differences in return to disease activity, but there are too many comments on it to ignore it…One person said to me they knew when they had to have their next hit of Coke…another their word for natalizumab. Here they call it “woe” but it is a bit sad they look and fail to find a difference. Here they look at binding of natalizumab to T cells and α4-integrin receptor saturation levels across T-lymphocyte subset and conclude there is no difference between the ~40% of people reporting their “woe” and fewer without the crap gap. You say hang on the abstract says 57.3% experienced WOE….In the paper it says Sixty-seven (57.3 %) of the 117 included patients reported having previously experienced WOE, while 50 (42.7 %) reported never having experienced it….but the analysis was actually done when, 70 did not experience a WOE, whereas 47 did (40%). They say “no relation was found between α4-integrin receptor saturation in any T-lymphocyte subset and the occurrence of WOE at the time of sampling. Those with extended interval dosing more than 4 weeks between doses had lower levels of natalizumab saturation of the but in both cases this level of receptor binding is above 80% which is enough to stop lymphocytes binding to and crossing the blood brain barrier. This needs to drop to about 50-60% percent to allow entry of cells……However, have they missed a trick here?
They have not looked at macrophages or importantly B cells. So the B cell message continues to fall on deaf ears:-(. So if T cells are not the important cell to look at, then the study misses the point.
If you look at lymphocytes, it is changes in B cells that really show you that the drug is working, as they increase above normal levels. Most circulating T cells do not express beta 1 integrin (CD29) so they do not express the alpha 4, beta 1 integrin pair required for movement into the inflammed brain. So they are not sensitive to natalizumab. They did look at memory T cell subsets that do express CD29 and CD49d (Target for natalizumab).
There was a study that was presented years ago looking at movement of cells across blood vessel walls after normal and extended dosing which maintains disease control but reduces the risk of PML. Surprise surprise at the extended interval dosing it was found that CD4 T cells and macrophages were entering the CNS, where as memory B cells were not. Therefore standard and extended interval dosing stops MS but only extended interval dosing avoids PML risks. This also says that CD4 T cells are not the cells mediating the problems in MS.
Alarm bells ring-Scientists have been wasting their time…Therefore, I suspect that this paper is having problems with (T cell biologist) reviewers not wanting people to hear this message…It will be buried in the journal written on toilet paper:-(.
However, it says this paper has missed an opportunity to focus on T cells, they are ignoring things. So if monocytes/macrophages start to enter the CNS they could be mediating a sickness behaviour due to the release of cytokines. So it is not about return of disease activity in terms of relapsing attacks but things that can cause symptoms.
Freeman SA, Rual C, Biotti D, Lepetit M, Le Berre J, Ferrara K, Treiner E, Ciron J. No association between the wearing-off effect and α4-integrin receptor saturation in natalizumab treated patients with relapsing-remitting multiple sclerosis. Neurotherapeutics. 2026 Mar 20;23(2):e00888.
Approximately half of patients with relapsing-remitting multiple sclerosis treated with natalizumab (NTZ) report transient symptom worsening – particularly fatigue – toward the end of the dosing interval. This phenomenon, commonly referred to as the wearing-off effect (WOE), has been hypothesized to result from a decrease in α4-integrin receptor saturation on circulating leucocytes. However, existing evidence is inconsistent, considering either small samples studied or conflicting results derived from previous studies. Our study aimed to investigate the association between α4-integrin receptor saturation and the WOE in a large prospective cohort of NTZ treated patients. We conducted a prospective observational study collecting demographic and clinical data, including WOE assessment via a structured questionnaire, treatment interval data, and α4-integrin receptor saturation levels across T-lymphocyte subset. Among 117 participants, 57.3 % reported experiencing WOE. WOE was significantly associated with higher disability (EDSS score) and longer NTZ treatment duration. However, no significant correlation was found between WOE and α4-integrin receptor saturation in any T-lymphocyte subset. Our findings suggest that WOE is not related to reduced α4-integrin receptor saturation and thus does not reflect diminished pharmacodynamic efficacy of NTZ. These results provide reassurance regarding the continued therapeutic effect of NTZ in patients experiencing WOE.
CoI None really although we did speak to the manufacturers of natalizumab about something else.
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Source: multiple-sclerosis-research.org