#MSCOVID19 It’s not all good news for anti-CD20

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ProfG has written about the the effect of continous B cell depletion and the the influence of B cell depletion.

However, this posts asked if continous B cell depletion can put you at risk of catching SARS-CoV-2 virus. Although B cells are important in fighting off bacteria, there is a small increased risk of catching some viral infections (Hauser et al. 2019). CD20 is expressed by the B cells that will form new B cell responses to new infections(Immunology 101). In MS we know that the response to vaccination is blunted with ocrelizumab and rituximab (Stokmaier et al. 2018; Kim et al. 2013). So maybe it could increase risk of COVID infection.

Of all the MS DMT, we have heard the most about rituximab. Much of this has been from the International Women in MS meetings and congrats to them for keeping this initiative going. This could be simply due to B clldepletion deemed as a useful treatment

Looking a the Biology we have made the case that B cells and antibody may not be absolutely necessary based on:

  • Genetic B cell deficient people can recover from COVID Infection (Soresino et al. 2020; )
  • In animals models B cells are a minor population in COVID-19 Lesions (Boa et al. 2020a)
  • In animal models the virus can be cleared before a notable antibody response is produced (Boa et al. 2020a, Boa et al. 2020b).
  • Humans can recover before a significant anti-viral response develops (Thevarajan et al. 2020)
  • Humans can recover in the apparent absence of anti-COVID19 antibody responses (Wang et al. 2020; Wu et al. 202)
  • B cells are a minor population in the covid lesion in humans (Christine et al. 2020)
  • Humans with depleted with B cells can recover and that is not just anti-CD20 B cell depleting drugs (Somarni et al. 2020)
  • Importantly people with MS provide most news for this statistic (Novi et al. 2020; Louapre et al. 2020 Montero-Escribano et al. 2020; Somarni et al. 2020).

Although there have been COVID-19-related deaths in people taking CD20 antibodies, there have been deaths in people not taking anything and based on infromation presented at the iWiMS meetings older people and people with co-mordibities like hyper tension; diabetes and other cardiovascular issues are at risk as reported in the General Population (Xhu et al. 2020) and todate the vast majorit of people treated have recovered (Novi et al. 2020; Louapre et al. 2020 Montero-Escribano et al. 2020; Somarni et al. 2020). This is also the case in this new report involving 50 people taking anti-CD20. So thats good news in my book.

Blocking B cells from generating antiboides could be good news as:

  • High levels of antibodies can be associated with more severe disease (Liu et al. 2019; Zhoa et al. 2020).
  • Anti-viral antibodies may be destructive as evidenced by activated complement (Hole-producing molecules) and complement inhibitors may have value (Mastaglio et al. 2020; Magro et al. 2020)
  • Antibodies can cause cells like neutrophils and macrophages to act get activated to destroy virus but if exaggerated could destroy tissues (Barnes et al. 2020; Magro et al. 2020).
  • Antibodies can induce antibody inducted macophagee enhancement, where by antibodies bind to virus and take it to macrophages via the Fc receptor (Iwaski & Yang 2020) and help cause the

However, there is also evidence that B cells are of value in COVID-19

  • Theorectically B cells can activate T cells for immunity (Immunology 101. Jelic et al. 2019)
  • SARS-CoV2 antibodies can be detected within a few days of symptom on set and some can neutralize the virus (Guo et al. 2020; Xiang et al. 2020; van der Heide et al. 2020;Okba et al. 2020; de Assis et al. 2020)
  • SARS-CoV2 antibodies can clear the virus in humans (Zeng et al. 2020)
  • SARS-C0V2 antibodies can facilititate recovery in some people (Rajendran et al. 2020; van der Heide et al. 2020 )
  • SARS-CoV2 may limit re-infection (Boa et al. 2020b)
  • Genetically impaired B cells may associate with more severe disease (Quinti et al. 2020) .
  •  Rituximab use may be associated with a higher risk of catching COVID-19

B-cell depleting therapies may affect susceptibility to acute respiratory illness among patients with Multiple Sclerosis during the early COVID-19 epidemic in Iran,Farinaz Safavi, Bardia Nourbakhsh, Amir Reza AzimiPublication stage: Multiplesclerosis and related disorder In Press Journal Pre-Proof.

Highlights

  • 4.8% of MS patients fulfilled defined criteria for COVID-19-suspect group. (There was no viral testing)
  • Two patients required hospitalization; no intubation or ICU admission was reported
  • Patients on B-cell depleting agents had three times higher risk of being in COVID-19 group

In a cross-sectional survey, data were collected by sending a questionnaire to 2000 patients with a demyelinating disease through an online portal system. Collected data included the current MS DMT and patient-reported disability level, history of recent sick contact, recent fever, respiratory symptoms, diagnosis with COVID-19 and the disposition after the diagnosis. We defined a COVID-19-suspect group as patients having fever and cough or fever and shortness of breath, or a presumptive diagnosis based on suggestive chest computed tomography. We calculated the proportion of COVID-19-suspect patients and compared their demographics, clinical characteristics, and DMT categories with the rest of survey-responders, using univariable and multivariable models.

Results

Out of 712 patients, 34 (4.8%) fulfilled our criteria for being in the COVID-19-suspect group. Only two patients required hospitalization. No patient required intensive care. In a multivariable model, disease duration (p-value=0.017), DMT category (p-value=0.030) and history of sick contact (p-values<0.001) were associated with the risk of being in the COVID-19-suspect group. Patients on B-cell depleting antibodies had 3.6 times higher risk of being in the COVID-19-suspect group as compared to patients on none-lymphocyte-depleting and non-cell trafficking inhibitor DMTs (95%CI: 1.45, 8.68, p-value=0.005).

Conclusions

The course of infection in MS patients suspected of having COVID-19 was mild to moderate, and all patients had a full recovery. B-cell depleting antibodies may increase the susceptibility to contracting COVID-19.

There are many explanations of why this view may not be right, but as we know…SH1 sticks. First you have to determine how blocking CD20- cells could make a problem. In this sample there was 21/285 people taking rituimab with suspected COVID-19, but 0/12 taking ocrelizumab.

However, last night Professor Jan Hillert from Rituxiland…Oops I mean Sweden, gave International women in multiple sclerosis a taster of the data of COVID-19 infection and their view was associated with more infection. Now does this blow my ideas into touch. Not really because again even if there was more infection, one the whole people were recovering from the infection.

If you want to hear ProfB’s presentation and those of Prof Hillert, plus French and US updates watch youtube from the IWiMS. As you can see there was a cock-up at the start. ProfB thought he would pre-record a video to keep too time, but it was done live.

Anyone can make suggestions after the event, but we have put our necks out tomake some suggestions. However, we will eat humble pie when we are proved wrong.

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13 comments

  • So people on ocrelizumab more likely to catch it but not more likely to be severe/die is that what this is saying?

    And Rituximab and ocrelizumab – are they exactly the same drug?

    • More likely to catch is the inference, there does not appear to be a death signal from any DMT as far as I can see at the moment.

      Are rituximab and ocrelizumab the same….no they differ by a few grand….only joking……the both target CD20 antigen but I would say that at the clinical dosing that ocrelizumab is abit more active…..I base this on the way that the B cells repopulate, it is slower with ocrelizumab based on my reading

  • The study is weak sans RT-PCR testing. Secondly, recovery was good in almost all patients.

    BTK inhibitors which block BCR and Fc receptor and play into this downregulation of B cell responsiveness, may be the ideal drug to study and this class of drugs is used in RA and SLE. Therefore you can look at data from the rheumatology world.

  • It is very nice to have so many articles on B-cell depletion therapies, but I am missing one tiny bit of information: Who with PPMS really benefits from the use of Ocrelizumab or Rituximab considering both risks and benefits? Ocrevus is not without risk (serious infections, malignancies, hypogammaglobulinaemia, neutropenia, PML, etc.).

    To me it seems that the Ocrevus trial was loaded with PPMS patients whose MRI showed disease activity (133 patients (27.5%) in the Ocrevus arm had GD+ lesion, they had activity at the baseline). As Ocrevus has a strong anti-inflammatory effect, it is very effective in RRMS patients with disease activity and the trial was loaded with PPMS patients with disease activity, doesn’t the effect of the drug mostly come from PPMS patients who have disease activity confirmed by MRI? Would Ocrevus pass a clinical trial in pure PPMS patients with no activity? If not, why do we recommend Ocrevus also to PPMS patients with pure progression? By the way, Rituximab failed in the clinical trials for PPMS patients.

    • MD here
      In Europe Ocrelizumab is not approved for all PPMS. By the way the ocrelizumab trial that showed positivity because it used the information from the so called failed rituximab trial. I am sure if they had loaded the trial with young active people with PPMS you would have got a positive trial

      • What if we put it the other way around? If they hadn’t loaded the trial with young active people with PPMS they wouldn’t have got a positive trial with Ocrevus. 🙂 Isn’t Ocrevus approved for all PPMS patients in the US? In Europe, did they limit the approval for Ocrevus because of risks/benefits reasons or more because of financial reasons?

        Now, more and more studies (likely pharma sponsored) are coming out which argue for the use of Ocrevus even for old patients with non-active PPMS. It boggles my mind for what reasons. The best I can read out of the clinical trials is that it helps patients with active PPMS. Loading the clinical trials with likely responsive patients with active PPMS seems a nasty old trick to get approval for the whole PPMS population and making big bucks this way. I am just wondering what Prof G’s take on the use of Ocrevus in PPMS. What is your view, Prof G?

        • Nasty trick or simply learning from past errors. His view, I suspect, was to get a positive trial in PPMS you need to treat people who will respond the best…hence a postive result….I think he may have been on the steering committee. However he is not the regulator and what they do with the information is beyond his control.

          • I didn’t know Prof G was involved in the trial in any capacity. I was just interested in finding out his view. Sorry, if I touched a sensitive issue. 🙂

            Regarding the trial design: I agree with you, “to get a positive trial in PPMS you need to treat people who will respond the best”. In my view, this is not what happened. If we expect patients with MRI activity to be responsive and they are the ones who most likely benefit, why don’t we limit the trial to these patients (with GD+ lesions or several new non-enhancing lesions per year in regular MRI follow-ups)?

            What happened: The trial was not powered enough to be certain that patients with GD+ lesions are the ones who benefit (statistically there was only a trend). However, they included enough of these patients in a population of non-active PPMS patients to pass the trials and get approval. Consequently, ocrelizumab is approved in the US for PPMS without any guidelines or restrictions from the FDA. Based on the FDA approval, most neurologists in the US say that progression in PPMS in a still ambulatory individual with no contradictions should probably treated with ocrelizumab. Now, patients are very hard put to make a decision about a therapy which might be offered by their neurologists. Now, Ocrelizumab is offered by neurologists to everyone and even their neighbors. I don’t know the European situation, but restrictions can happen also for financial reasons. I suspect that is what happened in Europe. So, that is why I was asking who with PPMS can benefit from ocrevus if we consider both risks and benefits???

          • Nothing sensitive at al….I would see it as a plus point 3 years ago there was no option and now there is one. You didnt know that profG was involved but the authors of the paper are : Montalban X, Hauser SL, Kappos L, Arnold D1, Bar-Or A, Comi G, de Seze J, Giovannoni G, …….et al.

            The trials was not powered….I would say this was on purpose because it was the first most obvious question that EVERYONE would ask. I remember seeing this trial reported and thinking why wasn’t this done….but it was obvious dont do it in such a way that it would show that non actives did not respond.

          • thank you. However, one things is still not clear to me: should we treat progressing non-active PPMS patients with ocrelizumab or not? Should progressing non-active PPMS patients get ocrelizumab or not? (of course, in countries where it is legal)

  • I’ll bite. I am a 59-year-old woman living in the United States and overdue by three months for my second Ocrevus infusion. I have progressive disease, so the infusion is slowing further profession. I have been reading your blogs on B cell depletion and COVID-19 with great interest. What would you do? Thank you.

    • Hi Kathleen,
      May I ask if you have PPMS or SPMS? Time since onset of MS symptoms and diagnosis? Have you had Gadolinium-enhancing lesions before starting treatment? What was your EDSS when starting treatment? Have you noticed anything since the first infusion?

      Wishing you all the best and thanks.

    • MD
      With regard to to infusions we too note of the British Neurology guidelines, but I know the neuros have been discussing this issue , but they need to report their views

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