#MSCOVID19: summertime

To me three swallows make a summer; one from Sweden, a second from Iran and now a third from Italy. I have little doubt more will emerge soon.

A few weeks’ ago I explained that having asymmetrical information is never a good thing. Tragically I have known about the data published yesterday on the Lancet’s pre-publication archive for several weeks.

The new data shows that ocrelizumab-treated Italian pwMS were more likely to get COVID-19 and severe COVID-19 compared to other DMTs. This now supports the Swedish rituximab data presented by Jan Hillert on the iWiMS COVID-19 webinar in May and the Iranian survey data on rituximab (see Safavi et al. below). The message across these three data sets is now quite consistent; anti-CD20 therapies affect the biology of COVID-19 differently to other DMTs. 

How anti-CD20 therapy increases your chances of getting COVID-19 suggests it either (1) increases your exposure to the SARS-CoV-2 virus, which to me is not plausible unless it is due to increased exposure to the virus as a result of attending hospitals for infusions, or (2) it reduces your chances of having an asymptomatic infection. To me, the latter seems most likely and is meanable to study.

The immune responses to other human coronaviruses, the ones that cause the common cold, may cross-react with SARS-CoV-2 and help keep the virus in check and explains why some people get asymptomatic or mild infections. Having had a common cold in the recent past has given you some built-in protection against getting COVID-19 and severe COVID-19.  

I hypothesise that if you were B-cell depleted from being on an anti-CD20 when you had that common cold your immune system doesn’t make the necessary high-quality or high-affinity cross-reactive antibodies that you now need to protect yourself from getting symptomatic COVID-19 and potentially severe COVID-19. 

Should this data on anti-CD20 therapy change clinical practice? If you are already on an anti-CD20 therapy there is little you can do about your preexisting immunity to community-acquired coronaviruses; you either have immunity or you don’t. Similarly, you can’t simply revere the action of anti-CD20 therapies as it takes months to years to reconstitute your peripheral B-cell pool. Therefore I would simply recommend that if you are on an anti-CD20 therapy being extra-vigilant when it comes to trying to avoid being exposed to SARS-CoV-2 (social isolation, personal hygiene and avoiding high-risk environments). 

What about starting an anti-CD20 therapy? The decision to do this must be individualised and weighed against the risk of getting COVID-19. In countries where this risk is very low anti-CD20 therapies will be safe. 

The issue of vaccine readiness may affect your decision to be treated with anti-CD20 therapy.  People who are B-cell depleted, as a result of anti-CD20 therapies, make blunted vaccine responses. This is not surprising because anti-CD20 treated patients lack germinal centres in their lymph nodes and spleen. Germinal centres are the immunological equivalent of a university. It is in the germinal centres that T-cells help B-cell mature, class switch their antibodies, i.e. go from IgM to IgG for example, and to then undergo affinity maturation of the antibody genes to produce high-quality antibodies. Without germinal centres, your immune system can’t educate your B-cells to make high-quality antibodies and hence vaccine response are poor. 

For people on anti-CD20 therapies, if they want to maximise your chances of responding to a vaccine you are going to have to pause your treatment to allow your immune systems to recover before receiving a coronavirus vaccine. When should you do this? Not now. I would not recommend this until an effective vaccine emerges. Only cross bridges when they are built and only if you need to cross them. 

There is still a relatively high chance that all of the 150+ SARS-CoV-2 vaccine candidates will fail; vaccine development for respiratory viruses is notoriously difficult.

These data is likely to be relevant to ofatumumab and other anti-CD20 therapies. 

Not surprisingly interferon-beta which is an antiviral protects you from COVID-19 and exposure to high-dose methylprednisolone in the last 4 weeks increased your chances of severe COVID-19. The latter supports our current policy of asking patients to shield for 2 weeks after steroids and to be extra-vigilant. 

Interestingly, there is a strong trend in the Italian data suggesting that natalizumab-treated patients may be at increased risk of COVID-19. Whether this is a real signal or not waits further data, but again the Swedish data supports this. This observation would not be surprising as we know natalizumab reduces trafficking of lymphocytes to mucosal membranes, which may be relevant in early anti-coronavirus immunity.

I suspect these observations will have implications for other infectious diseases. I would not be surprised when we study the immune responses and outcomes to other viral infections, for example, seasonal influenza the same patterns will emerge. Now that we have set-up COVID-19 registries I would urge the MS community to keep them open so that we can study what happens with the next influenza epidemic emerges, which is only months away. 

Sormani et al. Disease-Modifying Therapies and COVID-19 Severity in Multiple Sclerosis. The Lancet Preprint 8-Jul-2020.

Background: Immunosuppressive and immunomodulatory therapies are a major issue during the current coronavirus disease 2019 (Covid-19) pandemic, and in anticipation of possible next waves. 

Methods: In a nationwide study we retrospectively collected data of persons with Multiple Sclerosis (PwMS) with suspected or confirmed Covid-19. We assessed the association of therapies for MS with Covid-19 by comparing their observed frequency with the one expected in non-pandemic conditions (expressing the association by Odds Ratios [OR]). We evaluated baseline characteristics and MS therapies associated to a severe Covid-19 course by multivariate logistic models.

Findings: Of 784 PwMS with suspected (n=593) or confirmed (n=191) Covid-19 and a median follow-up of 84 days (range=30-135), 13 (1·66%) died: 11 of them were in a progressive MS phase, and 8 were without any therapy. Thirty-three (4·2%) were admitted to an Intensive Care Unit; 90 (11·5%) had a radiologically documented pneumonia; 88 (11·2%) were hospitalized. We found an excess of patients treated with Ocrelizumab (OR=1·84,95%CI=1·31-2·56, p<0·001) and a reduction of patients treated with Interferon (OR=0·47,95%CI=0·33-0·67, p<0·001) as compared to the frequency of use of these DMTs in the Italian MS population. After adjusting for region, age, sex, progressive MS course and recent methylprednisolone use, the therapy with an anti-CD20 agent (Ocrelizumab or Rituximab) was significantly associated (OR=2·59,95%CI=1·43-4·67, p=0·002) with an increased risk of severe Covid-19 course. Recent use (<1 month) of methylprednisolone was also associated with a worse outcome (OR=6·0,95%CI=2·2-16·5, p=0·007).

Interpretation: This study showed an acceptable level of safety of therapies with a broad array of mechanisms of action. However, the study detected elements of risk and protection with respect to Covid-19 in MS. These will need to be considered in countries where the pandemic is persisting and in preparation for post-pandemic scenarios.

Funding: Roche donated the web-Platform and funded a fellowship to the University of Genoa.

Safavi et al B-cell depleting therapies may affect susceptibility to acute respiratory illness among patients with multiple sclerosis during the early COVID-19 epidemic in Iran. MSARDS Published:May 12, 2020.

Objective: To determine whether the course of COVID-19 is more severe in patients with MS and if MS disease-modifying treatments (DMTs) affect the risk of contracting the disease.

Methods: 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. Being on B-cell depleting antibodies (as compared to non-cell depleting, non-cell trafficking inhibitor DMTs) was associated with a 2.6-fold increase in the risk of being in the COVID-19-suspect group. (RR: 3.55, 95%CI: 1.45, 8.68, p-value=0.005).

Conclusions: The course of infection in patients with MS 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.

Shen et al. Delayed Specific IgM Antibody Responses Observed Among COVID-19 Patients With Severe Progression. Emerg Microbes Infect. 2020 Dec;9(1):1096-1101.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has spread rapidly worldwide since it was confirmed as the causative agent of COVID-19. Molecular diagnosis of the disease is typically performed via nucleic acid-based detection of the virus from swabs, sputum or bronchoalveolar lavage fluid (BALF). However, the positive rate from the commonly used specimens (swabs or sputum) was less than 75%. Immunological assays for SARS-CoV-2 are needed to accurately diagnose COVID-19. Sera were collected from patients or healthy people in a local hospital in Xiangyang, Hubei Province, China. The SARS-CoV-2 specific IgM antibodies were then detected using a SARS-CoV-2 IgM colloidal gold immunochromatographic assay (GICA). Results were analysed in combination with sera collection date and clinical information. The GICA was found to be positive with the detected 82.2% (37/45) of RT-qPCR confirmed COVID-19 cases, as well as 32.0% (8/25) of clinically confirmed, RT-qPCR negative patients (4-14 days after symptom onset). Investigation of IgM-negative, RT-qPCR-positive COVID-19 patients showed that half of them developed severe disease. The GICA was found to be a useful test to complement existing PCR-based assays for confirmation of COVID-19, and a delayed specific IgM antibody response was observed among COVID-19 patients with severe progression.

CoI: multiple

20 thoughts on “#MSCOVID19: summertime”

  1. Thank you for a great summary 🙂 In light of these developments, will you be updating your excellent DMD in ‘COVID-19 times’ summary table? Particularly in reference to Natalizumab? Thanks

  2. When I saw your title “Summertime” I thought oh good a post on MS and body temperature. Even though it isn’t that, I wanted to reiterate at some point that the functions of lipids in the body are to regulate and signal. Myelin is a fine lipid and requires respect. The brain is incredibly sensitive to thermoregulation relying on it to effect well-ordered maturation and etch cell function i.e. signal, signal signal. In terms of the chicken and the egg, try making a baby chicken without specific temperature regulation on that fatty yolk and the cues which ensue. MS triggers tell us that temperature (too hot and too cold) is an active player in an attack. I have long thought that MS is a condition expressed by messed up regulation and signalling at its most basic and earliest receptor development level. Don’t forget about leptin. It may be boring but basics always are.

  3. As always thank you for keeping us up to date. I am due my third round of Ocrelizumab at the end of August. I am then due to return to a teaching assistant post in an Infant school with 4 and 5 year olds. In the last month or so I have seen improvements in my strength, a returned ability to be able to run and dance again after many years. I have been following daily HIT classes (in the form of Joe Wicks with my family) and pushing myself during lockdown something I would never have dreamed and I’m now following a 5:2 diet. (Diagnosed 2007 previously on Rebif and Copaxone.) Would you define working in a school a high risk environment? Would you consider delaying the next infusion?

  4. Thanks much for the information. What is the consensus amongst Neuros when it comes to redosing ocrelizumab for a PWMS living in a large metropolitan city with considerable infection rates?

  5. Thanks for the summary and interpretation of the data. Question: both studies from Italy and Iran as well as the covid data from Sweden show statistically increased risk for more severe covid with anti-cd20 when they rely on suspected covid cases. The data from Italy do not show any significantly higher risk when they look at confirmed cases. The authors claim it is because of low power but data from Sweden have shown an increased risk for hospitalized and non hospitalized upper respiratory infectios with rituximab when compared with interferons in the procovid era. How do the authors control for this in the suspected cases? Maybe the anti-cd20 suspected cases include other viruses and bacteria.

    1. The swedes have to publish their data and I am sure they will put alot of thought into the explanation and the possible biases

  6. How do you define severe COVID-19?

    Does anti CD20 increase your risk of death from covid?

    1. Until the data proves me wrong I am not covinced there is enough info to show increased risk of death, in the cohort I found there were 7/435 deaths. Many of the deaths could be associated with older age and disability I however say one 31 year old

  7. I feel like I need MD to come along and reassure me as usual!

    I’m hanging onto the positives – seems like risk of death for pwMS is still related to age and disability and comorbidities and not to the anti CD20.

    On reading the info 80% of anti CD20 patients did not get severe covid.

    The risk of severe covid seems higher the longer you have been on anti CD20 particularly over 12 months (have I interpreted that correctly?) but not particularly related to how recently you had it.

    Lastly I will ask my usual question which is what do you class as a high risk environment. As a HCP gone back to work with patients but avoiding aerosol generating procedures I am very interested to know!!!

    1. I am also interested to know. I am an allied HCP and trying to explain risk is proving difficult. I can avoid coming into contact with query or Known positives. My questions are regarding for example asymptomatic persons. My work involves being in very close contact with pts and it’s sometimes necessary for them to remove their face mask. Is this a situation I should avoid?

      1. Known positives are only a problem when they are shedding virus so only the PCR positives are a problem, the antibody positive are unlikely to be a positive

      2. I think you have to assume every one is aystomtomatic until proven otherwise, if you have a mask on when they don’t, you have more protection than having no mask. I went to the dentist with a broken tooth they had PPE. Maybe ProfG can give details of what we are doing

      3. You’ve magically brought up a truly relevant scenario that supports a point I tried to make. Being assured that it’s ‘OK’ because patients have all had their temp checked made me roll my eyes quite dramatically (as half my face was covered by a surgical mask I had to make my disbelief clear)
        Taking an X-ray isn’t an AGP of course but I wouldn’t say trying to put an X-ray film in the mouth of a potentially asymptomatic person with a poor gag reflex is ideal if they choke and spit on your face. I now wear goggles…………

      4. Temp is less than 50% of the symptom showers….we got this all so wrong in what it is and what is not covid-19.

        Governments did not react to this news and have spun a crock, such that the public are blishfully happy in their ignorance…..Shocking.

        E.g. the 1 week quarentine advice was always wrong

    2. Here I am…and the Swedish data did not show more severe disease although they found an increased risk of covid-19. The french registry data did not find a CD20 effect at all and of the 435 publically disclosed cases in my latest paper there were a total of 7 deaths and all bar 1 could be associate with age and disability..There was one stand-out for me and that was a 31 year old on rituximab…It was said that they were obese but what does that mean the 180kg obesity or something less.

      Yes you are correct that the longer you have been on anti-CD20 the higher the risk I have done a post called when the SH1 hits the fan and have tried to explain this in abit more detail than profG. This may be indicated by antibody levels in the blood. This increased risk has been seen to other infections….will Roche publish this data. I have the presentation. Should we start the clocking ticking before I disclose it.

      A high risk environment is when you have f-witts coughing and sneezing on you. The feeling I have is the more likely you are to have covid problems the aware and concerned you are. As a HCP can you get PPE that allows you to work but gives you some piece of mind, There are plenty of docs and nurses that are in the frontline and are still SARS-CoV-2 negative….I will have a look at the data

      1. Tick tok, tick tok, tick tok……..time is up! Better question, how long has Roche been holding the data hostage? How long has Roche known about the risk of drug failure due to the development of anti-drug antibodies?

      2. To be fair their data is that this chance is very low using the high dose they are using. I would not accuse them of hiding this data as it is quite easy to find and the early studies using lower doseses where the anti-drug antibodies are higher have been published.

        However it is now easy for use to check.now 😉

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