Science is not a religion and hence scientific advice, unlike beliefs, change as new evidence emerges. When the COVID-19 pandemic started we had to formulate advice on DMT use and their impact on SARS-CoV-2 infection and COVID-19 based on scientific principles and evidence of other viral infections. I created a table to summarise my opinions and as evidence has emerged I have updated the table accordingly. I have also added in new columns for example on advice about shielding/quarantine and on vaccine readiness. I have just updated the table for a sixth time changing the risk category of rituximab and other anti-CD20 therapies with a warning that it appears that this class of therapy increases your chance of getting COVID-19 and possibly severe COVID-19. This change is based on data from the Swedish MS registry and the survey below done in Iran. In short being on rituximab doubles your risk of getting COVID-19 and there is a suggestion that it increases your risk of getting severe COVID-19. At the moment there is not enough evidence to be firm about the latter or to comment on mortality risk.
How rituximab 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. The latter seems most likely and is meanable to study.
It now seems that 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. So just maybe having had that common cold last winter or the year before has given you some built-in protection against getting COVID-19 and severe COVID-19. However, 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. Please note this is a hypothesis, but it can be tested by studying people with MS and other condition on anti-CD20 therapies and screening them for antibodies against coronaviruses and comparing them to age-matched controls and patients on other DMTs. I am prepared to bet you the anti-CD20ers don’t have these cross-reactive antibodies or if they do they are at a lower level (titre) and are non-neutralizing.
Another possibility is that anti-SARS-CoV-2 antibody responses, in particular IgM antibodies, help clear the virus and aid in a more rapid recovery from COVID-19 and milder disease. Therefore, if your anti-SARS-CoV-2 antibody response is delayed or blunted by being on an anti-CD20 therapy this will increases your chances of getting more severe COVID-19. Whether this contributes to you being less likely to have asymptomatic SARS-CoV-2 infection is unknown, but again this can be studied in carefully designed studies.
Should this emerging data on rituximab 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 it takes months to years to reconstitute your peripheral B-cell pool. This is why I am now recommending that if you are on an anti-CD20 therapy you be extra-vigilant when it comes to trying to avoid being exposed to SARS-CoV-2 (social isolation, personal hygiene and avoiding high-risk environments). The good news is that the risk to individuals is low as a result of acquiring SARS-CoV-2 infection falls rapidly in most countries where anti-CD20 therapies are widely used to treat MS. I am still not recommending shielding because even though there is about a doubling of the risk of getting severe COVID-19 (hospitalization) the affected people with MS have been making a good recovery. The main determinants of death from COVID-19 in people with MS are older age, advanced disease and comorbidities and not the DMT they are on.
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 other issue that is emerging is vaccine readiness, i.e. having a peripheral immune system that is ready to respond to a SARS-CoV-2 vaccine if and when one emerges.
We know that 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 will be 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? I would not recommend this until a vaccine emerges; only cross bridges when they are built and if you need to cross them. There is still a relatively high chance that all of the 100+ SARS-CoV-2 vaccine candidates will fail; vaccine development for respiratory viruses is notoriously difficult.
At the moment the data we have from the Swedish registry and Iran is limited to rituximab but is likely to be relevant to ocrelizumab, ofatumumab and other anti-CD20 therapies. If you are conservative you may want to wait for the evidence base for these other anti-CD20 therapies to mature before incorporating the emerging evidence into your clinical decision-making. The good news is that there are several big data initiatives underway and we should report out within the next 1-2 months to confirm if this is a real signal, how robust the signal is and whether or not it applies to ocrelizumab and potentially other anti-CD20 therapies.
Does this have implications for other infectious diseases? I don’t know but I would not be surprised when we study the immune responses and outcomes to other viral infections, for example, seasonal influenza the same patterns may 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 that is only months away. The scary thought is what will happen if next season’s flu strain is a bad one? The impact of a more virulent flu strain on top of the tail of a SARS-CoV-2 pandemic is a scenario that makes me shudder. Do black swans ever emerge as twins?
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.
Addendum
The following slides show some of the data I refer to above:
If you want to watch the iWiMS Webinar it is on YouTube; the relevant section starts at about 21 minutes.
CoI: multiple
What about Roche’s ocrelizumab data? Is it consistent with the rituximab data and do they have an update?
Yes, this is consistent with their data, i.e. 26% had severe disease (hospitalisation) which may be higher than expected considering the population of ocrelizumabers is likely to be younger than the general population with COVID-19. However, on the other side of the coin, the Roche data is likely to be contaminated with reporting bias.
At the moment we don’t have enough data to make a call about ocrelizumab as there are too few patients reported; even the published Italian cohort and French data presented on iWiMS did not have a signal. Maybe with more cases a signal may emerge or on the other hand it may not.
I had this comment on the last post but thought I would ask here…
I have 2 questions!
1) Is everyone who doesn’t have these cross cover antibodies destined to get severe disease? Or can you still fight it fine without them? Perhaps this is where risks such as co morbidities come in etc
2) Why then are children not more infected? (Haven’t had as much exposure and therefore antibodies to many other colds)
Re: 1) Is everyone who doesn’t have these cross cover antibodies destined to get a severe disease? Or can you still fight it fine without them? Perhaps this is where risks such as comorbidities come in etc.”
I don’t know, but I doubt it as most younger people have benign or mild COVID19 and they can’t all have cross-reactive anti-coronavirus antibodies.
Re: “2) Why then are children not more infected? (Haven’t had as much exposure and therefore antibodies to many other colds)”
We don’t know this. Younger children get many more colds and coughs than older peoples; anybody who has children knows this. Whether or not the are coronavirus colds and coughs need study.
Please note it highly unlikely that cross-reactive anti-coronavirus antibodies are the only mechanism for having benign or mild COVID-19; biology is never that simple and there are likely to many other factors at play.
Your table states that for alemtuzumab “live vaccine safe post immune reconstitution “. My patient guidance notes for alemtuzumab tell me never to have a live vaccine. Can you please clarify? Many thanks.
The SmPC is based on data submitted to it from Genzyme. There is no reason why post-immune reconstitution alemtuzmabers can’t have live vaccines. We have given live vaccines to several of our patients with no safety concerns. Please note that post-HSCT many units readminister all childhood vaccine including live vaccines. HSCT is much more aggressive than alemtuzumab and there has not been a safety signal with vaccine including live vaccines post-HSCT. The important thing is patients have to have reconstituted their immune systems.
One of the pros of IRTs is the ability to have vaccines including live vaccines.
What is the latest thinking regarding cladribine because cladribine is often used for those in the progressive category and this will be particularly true for your chariot trial.?
You surely will not be wanting to expose those very people who are less likely to be able to deal with covid
B-cell depletion with cladribine is only about 90% and rapidly reconstitutes with all treated subjects having normal B-cell levels by about 120 weeks. Please note the B-cells that return are naive from the bone marrow and not memory B-cells. Unpublished data indicate no risk of hypogammaglobulinaemia. Once reconstitution occurs post cladribine treated patients will be vaccine ready.
Many thanks for clear reply.
But forgetting about the vaccine does cladribine make a patient more susceptible to covid-19 and further more to a more severe case of covid 19?
Not based on the current data. However, there are too few patients who have developed COVID-19 after cladribine for this to be evidenced-based.
B cells back to normal levels witin 30 weeks for cladribine, 49 weeks for ofatumumab (anti-CD20), and 62-72 weeks for ocrelizumab, alemtuzumab abit quicker
MERS, SARS, now COVID-19, all in recent years. Extra incentive for MS treatments that don’t just hammer the immune system?
What about seasonal flu? I think we need to study this in more detail as well.
So then what to do about continuing ocrelizumab? My 2nd full due due in May has been rescheduled for July. Should I continue or look to switch DMT? I thought that Prof G has continued to dose his patients throughout. To give some context my MS is relatively mild with only sensory symptoms and I’m 51.
I’ve had MS since 1993 when I was 21. It has been very mild. I did my infusion in May, but am avoiding high risk situations (ie moving my daughter into her college dorm) for a month or so. Per my doctor, not forever.
I remember in the Italian data (232 pwMS with COVID-19, 6 critical (5 of whom died). Most were over 60 (some well over) males with comorbidities. One lady who died was only 53, no comorbidities, treated with rituximab. Has always bothered me a bit.
Sorry, can’t find a link to the paper. Stand to be corrected if have remembered wrong!
Had also understood ARS worsened by virus infected cells in lung being coated with antibody and activating cytokine storm? Hence fingolimod trial in China? Ie at later stage COVID-19 not a bad thing to be low in B cells?
But totally understand better to have IgG to be ready for subsequent infection…
Ok here’s the link on this blog:
https://multiple-sclerosis-research.org/2020/04/mscovid19-asymmetry/
Woman aged 54, SPMS, EDSS 7, treated with rituximab. No comorbidities.
EDSS 7 is hardly advanced.
54 is young.
No surprise treated with rituximab, she wouldn’t have qualified for anything licensed. Must have had a fantastic neurologist, willing to keep treating her even though SPMS and EDSS 7.
Notice no mention of anyone smoking. Is being a smoker routinely recorded as a comorbidity?
RE: “Notice no mention of anyone smoking. Is being a smoker routinely recorded as a comorbidity?”
It should be recorded. Smoking is interesting in that it appears to reduce your chances of getting COVID-19 at a population level, but when you get COVID-19 it seems to increase severity. Based on the former the French are doing a trial of nicotine in COVID-19.
Maybe less chance of being infected as less lung (from smoking) and therefore smaller surface area for virus to enter body? But also less lung and therefore smaller area for gas exchange once decompensated from COVID-19 pathological process??
To me, looking at the hazard ratio is misleading in this case:
1) Absolute risk was still small (in Sweden and Iran, of all places) and the Covid patients seem to have recovered without ICU visits
2) Exposure to SARS-COV-2 can be managed to some degree (how much obviously depends on life circumstances) even if a second wave were to hit us
3) Without anti CD20 treatments there is a definite increase in the risk of disease progression that is hard to otherwise manage (under the assumption that switching to Cladribine or alemtuzumab is hardly an option right now)
To me, the choice is obvious. Given all the reports of infusion delays, it sadly seems it is not for all neurologists. I would very much appreciate a post on how to constructively discuss this decision with our HCPs as ultimately it is – as always – the PwMS who bear the risk of whichever decision we take.
Yes, a very insightful comment. At our centre, we think the risk is manageable and low, which is why we are redosing and starting patients on anti-CD20 therapies as before COVID-19. MS is a bad disease and needs to be treated that way.
I second this, it would be so helpful for people at hospitals that are more risk averse how to have these discussions. These comments from you are reassuring and I am so glad to be at Royal London on Ocrevus but its very sad that treatment is so varied across the country and not all hospitals are as forward thinking as you at Barts. I wish my sister was at RL 🙁
Could you elaborate when you advise that anti-CD 20 patients do not need to shield but do need to be extra-vigilant, what exactly does this mean? I fear the course of the pandemic is not well controlled here in the US and I want to make sure I am making best practice decisions for avoiding infection. Thank you in advance!
In a strict sense, shielding/quarantine is no contact with other people to prevent exposure to the virus. The UK government has relaxed that recently and states you can meet one person, but you need to do it outdoors, with social distancing (2m apart) and they imply wearing a face mask.
Extra-vigilance is being very careful about social distancing and hygiene and to avoid high-risk work. The latter and only really applies to healthcare workers. In London, you would want to avoid public transport where it may not be possible to socially distance yourself from fellow passengers.
Prof G – so health care workers on anti CD20 shouldn’t be working? This has been 12 weeks now and still can’t do my job properly. And now with no end in sight…
This is an HR issue that you need to discuss with your employers. I would think you could return to work but I would not advise working on the COVID-19 frontline with patients who are infectious.
What do we do about children returning to school? Both of my children have started back part time but I am having my infusion imminently. Would it be wise to keep them at home and if so for how long?
Many thanks
how can i see or print the chart? it’s so hard to read on iphone and pc
https://docs.google.com/spreadsheets/d/1GqEoeXod4CLTBsa6ke0TWmiJ7_I77HiBQ_rvFrmouOA/edit?usp=sharing
Prof G
EDSS 0 – fit and very well. But on ocrelizumab. You have changed advice to strict social distancing, what are your thoughts on children in school? Mine are all in school now.
Government advice says those in clinically vulnerable category should/can put children in school. I’m assuming you’re not saying anti CD20 are extremely clinically vulnerable and therefore the children are ok to go to school…
Yes, that is correct. You simply need to include in your risk assessment that you are at about twice the risk of getting COVID-19 and severe COVID-19 compared to say someone else with MS on another DMT. Doubling a small risk remains a small risk.
Thanks for quick reply!
Is my risk of severe covid not smaller as I am female under 40 normal BMI and with no comorbidities?
Yes, low risk but as always not zero and double that of a group of matched people with MS who are on another DMT, but not an anti-CD20.
What about 45 female, but WITH comorbidities (PCOS/metabolic syndrome BMI>40 borderline T2) 3rd dose Ocrevus in December 2019 due again June 2020 but delayed …however likely to go ahead July/August once SGH catch up with backlog….surely my risk is higher and should consider shielding? Suspending next dose…
Unfortunately, we don’t have a COVID-19 risk calculator analogous to the PML risk calculator Biogen developed for PML risk on natalizumab. I think you have implied in your question that you think your risk is too high. Some would consider it too high regardless of ocrelizumab treatment.
Doubling a small risk remains a small risk.
Thanks for the reminder to keep this in perspective. Have a good weekend 🙂
Thank you for all that you do! I’m still confused though! Are we (Ocrevus folks) 2x the risk as *anybody* for contracting COVID and developing more severe disease or just compared to other pwMS on other DMTs. And if the former (which I think is the case) does this make us only slightly more at risk compared to the general population? Seems to be the case – But I’m very confused about conflicting statements on this site and many others. No significant impact of DMTs… Then other statements saying there are. I’m thinking the distinction is DMT versus DMT? and not OCREVUS versus general population?
the study was ocrelizumab MS verses MS I think
Blogging clearly has the upper hand over vlogging in the MS space. I uploaded a vlog on this topic yesterday and it has generated very little interest, which says a lot.
Given the choice, I strongly prefer reading – I am much faster that way and just skimming familiar parts is much easier, too. Often articles are better structured, too (although I found your vlogs to be very good on that front [1]).
I do wonder which format creates more work for you?
[1] The before and after natalizumab one finally made it click what natalizumab actually does and how, so kudos for that part in particular!
I will have my 6th infusion on 22 June , my doctor told me there is no need to postpone the same , what do you recommend Prof G?
Im on Ocrelizumab
Living in Sweden, i know that Rituximab as MS treatment has been overrepresented in Stockholm, where we also have had the highest rate of people with covid 19. Also as I understood the Swedish report, our doctors didn’t see an increased risk of serious disease even if they saw a higher risk of getting it. Is the overrepresentation of Rituximab use in Stockholm taken into account and why do you reach a different conclusion reguarding the severity of the disease?
I have added an addendum to the post.
Thank you for continuing to analyze and report/share.
Ocrevus here – 50y, female, healthy, active, no comorb.. just the MS for 2 yrs. 5 wks ago had an infusion round & was vigilant 4 wks post infusion (family was too). Now still very very careful but family (teens) going out a wee bit to be with a friend or 2 outside.
Trying to parse thru this update and figure out what it means for how I should act day-to-day. Trying to figure how high is the risk for going to an outside space (a park, beach) where I can be physically 6 ft apart from others but most people will not be masked? (US). Oy vey…
How many cases are there in your region?
FWIW I did go the beach on Friday but in my area daily casesöl.kjuzhtgrfedwsqa
FWIW, on ocrelizumab myself (late thirties tho), I do that every now and then.
In my view, it depends on the number of cases in your area. We have on the order of 5 new confirmed cases per million of population per day where I live so I feel comfortable doing that as I’d estimate the number of active cases at something like 50 times that number, so fairly unlikely that you run into any of them. I stayed home when we were at 10+ times the rate (and less data on just how bad cd20 depletion could be).
I am more wary about indoor space but when density is low enough, I sometimes risk that, too (mostly for the occasional work meeting that is hard to do online or shopping). I have also once or twice walked out of a shop when I thought the density was too high.
I think we are talking small risk and as you are thinking about things, you are being cautious…As for going out maybe start coughing alot and you will soon get a 6ft space around you:-)
As for going out maybe start coughing alot and you will soon get a 6ft space around you:-)
Haha love this!
I have found doing some exaggerated breathing when I am running and someone is coming towards me does make them give me a lot more distance 😆
Oh I needed that laugh! ‘Start coughing a lot‘ = 6 feet
Thank you 🙂
Thanks for the continuous update. I have a difficult question. How would you treat a highly active patient (5 relapses in the past 18 months) that has failed to natalizumab (1 multifocal relapse and 20gd enhancing lesions after the 5th infusion) considering the pandemic context? Alemtuzumab or Ocrelizumab? I would very much appreciate your feedback.
Iam not a neuro and cant give advice. There are cases of people doing well with covid on both these and cladribine