Someone said that my last long-post was not an “Easy read”. I suggested that in the Post-G era, I could’nt be bothered with ProfG-invented categories after all, what is “Thought-4-the-day” and “clinicspeak”? However, if you feel it helps ,I will continue to report the reading level from easy to super scientific
Clinical trials are important human experiments that can uncover alot about biology of disease. The results of these studies have to assimilated into your World knowledge.
One of the biggest shake-ups to affect MS, was the finding that CD20-depleting antibodies are on the whole, very effective at treating relapsing MS and active progressive MS. How do you explain this?
One way is to stick your head in the sand and peddle the old World view, another is to embrace the New World view. Eventually, the majority see the light and slowly change their World view, leaving the Ostriches to become DoDos
Therefore, some birds will say…”Ocrelizumab works in MS because it is depleting a special kind of T cell”. One can ask “Where is the proof? But I admit there is some circumstantial evidence. I say “Time will tell”. Remember, five years ago, most people could not care less about B cells, many still don’t but…the tide is turning and you have to explain CD20-depleting therapy.
One approach was to move T cells off the top spot and have a look at B cells and challenge people….It is evidence science people do not like speculation.
However, if you focus on B cells you can try and make a new story
We have made a story of the importance of the memory B cell subsets, which can be generated by the action of Epstein Barr Virus that is involved in the development of MS. If you seperate and look at the “wheat and not the chaff” you can perhaps forsee things. However the B memory cell view is not an easy sell particularly in certain places and you get “why not look at CD20 T cells or double negative naive B cell derived cells”. The memory B cell idea is being tested and is still standing over the course of a few years and getting stronger as the ostriches become more Dodo like.
The B memory idea suggests that it is possible that for many people with MS who are taking CD20 depleting antibody infusions on a 6 monthly dosing schedule, it is more frequent than is necessary to control MS.
Baker D, Pryce G, James LK, Marta M, Schmierer K. The ocrelizumab phase II extension trial suggests the potential to improve the risk: Benefit balance in multiple sclerosis. Mult Scler Relat Disord. 2020 Sep;44:102279.
This is possibly because the cells being controlled are in the memory cell pool and their progeny and these are depleted for a long, long time and much longer than the naive B cells making new antibody responses. These naive B cells are depleted for at least 6 months and dictate the dosing interval for the CD20-antibody. Memory B cells may be depleted for 18 months or more.
However, we have shown that for some people naive B cell depletion is much longer than 6 months and based on trial data this can be up to 175 weeks. This would suggest that’s why dosing every six month with riituximab or ocrelizumab means that people being vaccinated againt COVID-19 often don’t make an effective antibody response. This is because there are no B cells present. The longer you are on the drug the more of a clear out of your B cells. We know that on the whole this has been seen in MS and every other condition where rituximab is used.
The thought that the generation of antibody responses are inhibited by CD20-depletion has been repeated over and over again in MS and other conditions. In fact it has been repeated so many times that you could do a meta-analysis (analysis of the many studies) of the meta analysis studies. But here is a recent one and it tells us what we have seen in MS and other conditions, over and over again.
Schietzel et al. Humoral and cellular immune responses on SARS-CoV-2 vaccines in patients with anti-CD20 therapies: a systematic review and meta-analysis of 1342 patients. RMD Open. 2022; 8(1):e002036.
Abstract.Ninety studies were assessed (Ninety studies on the same subject…do we need more? But they keep coming). Inclusion criteria were met by 23 studies comprising 1342 patients (Remember this a variety of conditions and not just MS). Overall rate of humoral response was 0.40 (95% CI 0.35 to 0.47). (That’s 40% of people make an antibdy response) Overall rate of cell-mediated immune responses was 0.71 (95% CI 0.57 to 0.87) (That’s 71% of ppeople make a T cell response). A time interval of greater than 6 months since last anti-CD20 therapy was associated with higher humoral response rates with 0.63 (95% CI 0.53 to 0.72) versus less than 6 months 0.2 (95% CI 0.03 to 0.43); p=0<01 (So if you have vaacine less than 6 months after infusion you have a 20% chance of making an antibody response and a 63% chance if you wait more than 6 months before having the jab). Similarly, patients with circulating B cells more frequently showed humoral responses (if you have B cells you have a greater chance of making an antibody response). Interpretation: Those with very recent therapy and depleted B cell are at high risk for non-seroconversion and should be individually assessed for personalised SARS-CoV-2 vaccination strategies.
Antibody responses help to stop you developing symptomatic COVID-19. Some people have inferred that a COVID-19 vaccine responses occurs in the majority of people, but that sort of depends on the test and the gap between infusion and vaccination. We have the weight of data. More arrives every week
The studies say that a delay in therapy also known as an extended dosing interval (EID) is needed to try and get a better antibody response. Antibody responses are increased with boosting in some people.
COVID-19 can teach us about MS biology
However, this has not been particularly adopted as there has been paper after paper showing that CD20-depletion does not block T cell responses, leading many neuros to recommend jab, jab, jab to get a protective T cell response from COVID-19 vaccination., especialy as many people taking anti-CD20 do not have the risk factors for severe COVID-19.
However this info raises a question of biology.
So, the first question we must ask is “If CD20-depletion does not inhibit (vaccine) T cell responses how come it inhibits T cell responses in MS?”. You can’t have it both ways. Can you?
Does it say the anti-CD20 inhibitor effect is not due to a direct effect on T cells? After all CD19 depleting antibodies inhibit MS just like CD20 depleting antibodies and B cells do not express CD19 and so a major roll for CD20 T cells cannot explain the effects of CD19-depleting antibody. The Ostriches have not explained this one they just ignore it and made a “sigh a relief” that anti-CD19 was not developed further in MS, otherwise its mechanism of action would need explaining.
Can the effect really be at the level of the T cell as the difference between targeting the brain or the SARS-CoV-2 is mainly the T cell antigen receptor? However, a T cell action is being supported by opinion leaders so it is a dominant thought
People may argue CD8 responses give the anti-viral response and CD4 T cells cause the autoimmunity, But CD8 T cells are the dominant T cells in MS and CD8 T cells express more CD20 than CD4 T cells importantly both CD4 and CD8 T cell responses are not inhibited by vaccination. So COVID-19 vaccination is teaching us something fundemental about MS. If it is not T cell mediating the effect, the CD20 positive B cells are doing something different. What is it?
Do you have any thoughts? or Maybe you don’t you care?
Are the B cells presenting the cause of MS? What is it?
There are possibly more plausible explanations. But it is clear that COVID-19 can teach us about MS.
Extended Interval Dosing
At the beginning of the COVID-19, neuros were in favour of using extended interval dosing as they were frightened of the consquences of immunomodulation and COVID-19 and they did not want people entering hospital for infusions there was no vaccine and no anti-virals. So people stopped taking or stopped giving CD20-depletion infusions.
Did MS return? On the whole no and thus proving the point that EID could be of benefit.
How long could you wait and not get MS returning? Was it no time at all and you need to dose at 6 months or 9 months, 12 months, 18 months, forever? . The studies were not done in a definative way and were unlikely to be adopted.
However EID showed that more people could get a vaccine response if they delayed infusion to allow their naive B cells to recover. This is important as there can be no doubt that vaccination has benefitted people by protecting them against symptomatic COVID-19 infection and severe COVID-19 if people have become symptomatic. In doing so some neuros realise that standard dosing at 6 monthly intervals in more than is needed.
So how long would you wait between infusion and vaccination to get antibody response? At least 6 months in some conditions?
Fendler A et al. the CAPTURE study. Nat Cancer. 2021;2:1305-1320.
This a cancer study so I wont bore you with the details but they say ” anti-CD20 treatment ≤12 months before vaccination was associated with reduced NAbT against SARS-CoV-2 ……after first and second vaccine doses. I guess we say NSS what’s new here? But they say 12 months delay and the response is poor, so how long would you wait?
In MS more data surfaces
Extended B-cell depletion beyond 6-months in patients receiving ocrelizumab or rituximab for CNS demyelinating disease.AbdelRazek MA, Casasola M, Mollashahi R, Brodski A, Morin S, Augustynowicz A, Jassim S, Matiello M, Sloane J.Mult Scler Relat Disord. 2022; 59:103505. doi: 10.1016/j.msard.2022.103505.
Objectives: To investigate the duration of B-cell depletion in a cohort of patients receiving ocrelizumab or rituximab for multiple sclerosis (MS) or neuromyelitis optica spectrum disorders (NMOSD).
Methods: We retrospectively searched our database for patients diagnosed with MS or NMOSD, who were receiving ocrelizumab or rituximab and had available CD19 measurements. We collected demographic data, infusion doses, infusion dates, CD19 absolute counts and percentages, and their collection dates. We paired each infusion with the subsequent CD19 measurements recorded before the next infusion, discarding measurements done during a washout period of 30 days after each infusion. We applied three definitions for B-cell depletion, the most stringent of which was an absolute B-cell count ≤20 cells/uL.
Results: From 695 patients with demyelinating diseases in our database, over the period of January 1st 2010 to March 1st 2020, we identified 188 patients (178 with MS and 10 with NMOSD), who had received ocrelizumab or rituximab and had available CD19 measurements. 1054 CD19 measurements were captured. B-cell depletion, as defined above, was recorded as far out as 22.8 months after an ocrelizumab infusion, and 22.3 months after a rituximab infusion. Out of 90 B-cell measurements done ≥ (greater or equal) 8 months (>210 days) after ocrelizumab infusion, 45(50%) measurements showed B-cell depletion. Similarly for rituximab, out of 113 measurements, 49(43%) showed B-cell depletion.
Conclusions: This study demonstrates that B-cell depletion after ocrelizumab and rituximab continues beyond the traditional 6-month re-infusion interval in many patients. Our report provides data that can support clinical trials testing increasing the interval of re-infusion with ocrelizumab and rituximab beyond 6-months guided by B-cell measurements.
So don’t forget to have aread of this paper
Baker D, MacDougall A, Kang AS, Schmierer K, Giovannoni G, Dobson R. CD19 B cell repopulation after ocrelizumab, alemtuzumab and cladribine: Implications for SARS-CoV-2 vaccinations in multiple sclerosis. Mult Scler Relat Disord. 2021 Dec 4;57:103448. doi: 10.1016/j.msard.2021.103448.
In the time of rising infections and knowledge of protective T cell responses not being inhibited and the development of anti-virals, we have had the Jab, jab, jab ethos. Many people say I don’t want to wait. It is not in the interests of the pharmaeutical industry to do these studies and without pharma and regulatory guidance many neuros say I don’t want to change. Booster will give more peple a response, it remains to be seen what levels are important for the variant of interest circulating
To make any change we need informed studies to know if it is ready and without pharma support it will be difficult and it depends on whether there are any academic neuros interested in attempting change. During COVID19, neuros delayed treatment and it is clear to me that it is likely that you won’t get an optimal protective antibody response without a delay, but by the time one works this it out, the necessity for this has probably passed. The landscape has changed and we have anti-virals. we also have options that are not problematic. In the UK we have had the booster cycle and for many people on ocrelizumab/rituximab it will not have worked to increase antibody response and it has not boosted the T cell response, but we have not learned anything before it is too late to enact change for most people.
Maybe we don’t need a change and we simply need more jabs. This is the basis of booster immunizations. I had 6 hepatitis B vaccinations when most people only get three. In Israel we have had round 4 of jabs for some people, but again it is too late for the extremely vulnerable as they have already been offered and had round four or three primining jabs and a booster.
Whilst I think the future for anti-CD20 infusion it will eventually be with a personalised EID, can we do a study to show its safety? If EID gets adopted into clinical practise it will be difficult to do a study. Maybe all we can do is use a registry and hope that the MS registry or MSBase come up with the answer. But will a registry make a difference to induce change?
CoI: Multiple but not considered relevant.
Disclaimer. The views expressed are those of the author and do not represent the views of any institution