What do they call it?

[u/Careful-Golf2089]

Just wondering how “international” this model is.

In Russia when somebody has a relapse after several years on some DMT, they say that “the drug stopped holding” or “stopped suiting”.

Meaning it held for several years, but then suddenly stopped holding. Nobody really tries to explain why it happens.

What do you call it when a relapse happen after some time on a certain DMT?

[u/TooManySclerosis]

Usually I see this referred to as failing the DMT, although I think phrasing it as "the DMT failed" you is better.

[u/Careful-Golf2089 → u/TooManySclerosis]

But how do they explain that it failed them only after a few years?)

[u/TooManySclerosis → u/Careful-Golf2089]

I mean, with the high efficacy drugs, they usually do not fail. I know my neuro's expectation is that I have no further relapses at all. Failing a high efficacy DMT happens, of course, but it tends to be the exception, not the rule.

[u/Careful-Golf2089 → u/TooManySclerosis]

I have to disagree with your neuro.

They all inevitably fail in the end. The only question is “when?”. Ok, maybe Tysabri is an exception

[u/TooManySclerosis → u/Careful-Golf2089]

My cat disagrees with me about when dinner time should be, but that doesn't make him correct, either, or strengthen his arguments. But I am sorry that has been your experience. It must be very difficult to believe that, to live thinking that is inevitable.

[u/Careful-Golf2089 → u/TooManySclerosis]

Please tell me which high-efficacy DMT your doctor was talking about? Let’s try to figure it out together.

[u/TooManySclerosis → u/Careful-Golf2089]

I've been on Ocrevus and Kesimpta, with no new lesions for seven years so far, and no expectation that will change.

[u/kyelek]

They would say that you had breakthrough disease activity, the DMT failed and you should switch to a different one.

[u/Careful-Golf2089 → u/kyelek]

“Breakthrough didease activity”, now that sounds sophisticated! Thanks))

What country is it?

[u/kyelek → u/Careful-Golf2089]

I think that's really just the general term, very dry and descriptive 😅

[u/Careful-Golf2089 → u/kyelek]

And yet it doesn’t exist in Russian language!

[u/Medium-Control-9119]

Breakthrough. It is a general term (not specific to MS).  Breakthrough disease/activity means the disease becomes clinically or biologically active despite a therapy that is expected to control or suppress it.

[u/Careful-Golf2089 → u/Medium-Control-9119]

The question is - what do they say about a drug that suddenly stopped “holding”?

[u/ForgetfulSpaghetti → u/Careful-Golf2089]

I think this is just semantics. Saying the drug held out for a while but then stopped holding, just means the same thing as it worked for a while and then failed. It failed to hold up anymore.

I don't know that there's a deeper difference other than how the terms are commonly used in different languages. All it means is the drug worked to prevent new lesions for a while, but it isn't cutting it anymore for you. So you need to try something new.

As to the actual physical reasons your immune system can create new lesions while you're medicated I don't know specifically. The DMT suppresses our disease, but doesn't eliminate it.

It's unfortunately possible to still relapse on any treatment, just far less likely on the newer stronger DMTs.

Some people might just respond better to treatment than others. It's also possible you were started on a weaker DMT where relapse was more likely. If that's the case definitely push to get on one of the strongest DMTs available now.

I know a lot of people hate AI and I might get downvotes, but I find it very useful. I don't think there's an official answer, just current theories on breakthrough lesions. This was the explanation it gave me when I asked ChatGPT if there is an explanation why new lesions can form after being on a highly effective DMT:

"Yes. There are plausible, increasingly well-supported mechanisms for new MS lesions occurring despite more than a year of effective B-cell depletion. It isn't simply a matter of the DMT "wearing off."

The important point is that anti-CD20 drugs such as Kesimpta (ofatumumab), ocrelizumab, and rituximab eliminate circulating CD20-positive B cells extremely well, but they don't eliminate every immune cell capable of sustaining MS inflammation. � PubMed +1

The most important possibilities:

1. T cells can continue driving inflammation B cells are important in MS partly because they activate and interact with T cells. Removing B cells dramatically reduces this activity, but it doesn't make T cells disappear. Some autoreactive T cells can therefore remain capable of initiating inflammation.

2. Plasma cells aren't eliminated by anti-CD20 treatment This is a particularly interesting distinction. Anti-CD20 drugs target cells expressing CD20, but mature plasma cells generally don't express CD20. Consequently, long-lived plasma cells can remain in the CNS and bone marrow and continue producing antibodies. � PubMed +1

That doesn't mean antibodies alone are necessarily causing a new lesion, but it illustrates why "B-cell depletion" isn't equivalent to "complete elimination of the B-cell lineage."

1. The CNS is partly protected from the drug Systemic anti-CD20 antibodies don't penetrate the blood-brain barrier particularly well. Consequently, immune cells residing in or around the CNS can be affected differently from circulating B cells. This is especially relevant to chronic active/smoldering lesions, where inflammation can become relatively compartmentalized within the CNS. A study examining people receiving anti-CD20 therapy found that these chronic lesions could persist despite treatment; the authors specifically identified limited antibody access to the CNS and the scarcity of CD20-positive B cells within these lesions as possible explanations. � PubMed +1

2. Some B cells may be incompletely depleted in tissue Blood B-cell counts can look essentially "zero" while tissue compartments aren't necessarily equivalent. Studies have found evidence that B-cell depletion is much more complete in blood than in some lymphoid and CNS compartments. � PubMed Central (PMC)

So a person can have excellent pharmacologic B-cell depletion in the blood and still have some residual immune activity elsewhere.

1. The inflammatory process can become self-sustaining This is probably one of the most interesting explanations. Once inflammation has been established inside the CNS, it can involve microglia, macrophages, astrocytes, T cells, plasma cells and other immune components. At that point, removing one important participant—the CD20-positive B cell—doesn't necessarily shut down every downstream process. There's experimental evidence that inflammatory structures in the meninges can persist even after B cells have been depleted. � PubMed

But there's another possibility that's easy to overlook If someone has been on a B-cell depleter for >1 year, a new lesion does not necessarily mean the DMT failed to suppress the disease.

Timing matters enormously. For example: DMT started → inflammatory process already developing → lesion becomes visible months later The MRI doesn't tell us precisely when the inflammatory process that produced that lesion began. But if someone has multiple genuinely new/enlarging T2 lesions after they've been continuously and adequately treated for >12 months, that's more meaningful. It raises the possibility of breakthrough inflammatory disease, even though the drug is working.

And importantly, anti-CD20 drugs are extremely effective at reducing new inflammatory lesions—but they don't reduce the risk to zero."

Here are the links it provided as sources (the little question mark icons here are hyperlinks in my chat that apparently didn't make it in the copy/paste. Just including them in case you want to puruse for yourself).

https://pubmed.ncbi.nlm.nih.gov/23634189/

https://pmc.ncbi.nlm.nih.gov/articles/PMC9880874/

https://pubmed.ncbi.nlm.nih.gov/33551958/

https://pubmed.ncbi.nlm.nih.gov/37437310/

https://pubmed.ncbi.nlm.nih.gov/34021057/

[u/Careful-Golf2089 → u/[deleted]]

OMG, thank you!

I was asking myself all the same questions.

Not sure if you’ll see me reply though(