I am being asked why I have moved ocrelizumab and other anti-CD20 therapies into the low-risk categories of DMTs in my latest version of my DMT table.
The reasons I use to justify the change are several-fold.
Anti-CD20 therapies deplete B-cells and only have a small impact on T-cell counts and innate immune cell function. This is important because anti-viral responses don’t seem to be affected to a great extent on ocrelizumab and other anti-CD20 therapies. In the phase three ocrelizumab trial programme apart from seeing a small herpes zoster signal there was no clear viral infection signal. When viral infections occurred they tended to be mild or moderate. The severe infections were bacterial (pneumonia, UTIs and cellulitis).
We are seeing an increasing number of patients who have been treated with anti-CD20 therapies who have had COVID-19 doing well. We have just published a case report in MSARDs of a man with PPMS treated with ocrelizumab who did well (see below). This has to be good news for patients on anti-CD20 therapies.
Ocrelizumab also blunts antibody responses, which may be important in severe COVID-19. This may delay or prevent damage to the COVID-19 lung as some of the damage seems to be mediated by complement activation and microthrombi. The latter is indicative of damage consistent with IgG3 anti-viral responses and IgG antibody-dependent cellular cytotoxicity by macrophages and in some instance neutrophils. Antibody production against the SARS-CoV-2 spike protein may promote cytokine production that activates macrophage to become more destructive. Blunting these antibody responses with an anti-CD20 therapy may actually be beneficial, which is why we are predicting that anti-CD20 treated patients will have a lower risk of getting severe COVID-19.
What about hypogammaglobulinaemia then?
Yes, this does occur with anti-CD20 therapies but occurs at a relatively low level. As SARS-CoV-2 is a new human pathogen and hence we don’t have immunological memory against the virus this makes little difference to the risk of becoming infected with SARS-CoV-2. Hypogammaglobulinaemia may, however, put you at risk of getting secondary bacterial infections. Fortunately, these can be treated with antibiotics.
What about vaccine responses?
Yes, anti-CD20 and other immunosuppressive therapies can blunt antibody responses to some vaccines. And yes, contrary to the dogma patients on anti-CD20 therapies do make antibodies to viruses and vaccines. I assume this happens because we still have B-cells in secondary lymphoid organs and/or there may be CD20 negative B-cells that can takeover antibody production. Please note that the latter is a hypothesis.
Antibody responses to glycoproteins (sugar antigens) are particularly affected by anti-CD20 therapies and this may be important in the context of coronavirus immunity as the spike protein is heavily modified with sugar molecules. However, all these arguments are theoretical; until a vaccine emerges I would focus on getting MS treated. We can cross the vaccine bridge if and when it gets built. I am still of the opinion that the government’s strategy is herd immunity and hence the majority of us will at some point become infected with SARS-CoV-2. Waiting for a vaccine that never arises is going to be difficult for individuals; how long can you realistically self-isolate and/or shield?
We are very keen to do an anti-SARS-CoV-2 seroprevalence study in pwMS to see how many have been exposed to the virus and have not developed COVID-19 and to also look at antibody responses to SARS-CoV-2 in patients on different DMTs. We hypothesise that patients on anti-CD20 therapies will have as good an antibody response to SARS-CoV-2 as patients not on anti-CD20 therapies. This hypothesis refers to qualitative antibody responses, i.e. neutralising or protective antibody responses.
For the reasons above I have not stopped offering patients with active MS anti-CD20 therapies during the pandemic. This refers to both starting and retreatment. Some patients have chosen to delay their treatments until the pandemic is over and others have taken my advice and gone ahead with their treatments; this is their choice. But as I have said before the pandemic won’t be over anytime soon; the tail is likely to extend for 18-24 months and possibly longer. Therefore all the guidelines that have recommended delaying or postponing treatment with depletion therapies, i.e. the anti-CD20s, cladribine, alemtuzumab, mitoxantrone, cyclophosphamide and HSCT will have to be reviewed. We can’t stop treating MS or offering patients less effective options for the next 18-24 months. If we do what will be the consequences?
How many swallows does it take to make a summer? I am aware that one case report is not much, but there are an increasing number of patients being reported on social media who have been treated with an anti-CD20 and have had gotten through COVID-19 without a problem.
I would urge all the national register studies to be please report your data on COVID-19 outcomes in pwMS as soon as possible. We need the data to formalise our treatment guidelines and to help allay the fears of our patients. Please use one of the archive repositories to get your data out to the MS community as soon as possible. Thank you.
Giovanni Novi et al. COVID-19 in a MS Patient Treated With Ocrelizumab: Does Immunosuppression Have a Protective Role? Mult Scler Relat Disord 2020 Apr 15;42:102120.
Background: Coronavirus disease 19 (COVID-19) is a novel disease entity that is spreading throughout the world. It has been speculated that patients with comorbidities and elderly patients could be at high risk for respiratory insufficiency and death. Immunosuppression could expose infected patients to even higher risks of disease complications due to dampened immune response. However, it has been speculated that overactive immune response could drive clinical deterioration and, based on this hypothesis, several immunosuppressants are currently being tested as potential treatment for COVID-19.
Methods: In this paper we report on a patient that has been treated with ocrelizumab (a B-cell depleting monoclonal antibody) for primary progressive multiple sclerosis who developed COVID-19.
Results: Despite complete B cell depletion, patient symptoms abated few days after hospitalization, and he was discharged to home-quarantine. Phone interview follow-up confirmed that, after 14 days, no new symptoms occurred.
Discussion: This report supports the putative role of immunosuppressive therapy in COVID-19 affected patients.
CoI: multiple
Thanks as always Prof G. I’ve sent this to my MS nurse to ask her for her thoughts and my neurologist’s. They say that they are taking guidance from you so I’ll see what they say. I’m due my 2nd ocrelizumab in May but it’s been postponed. The shielding letter I received says it can be delayed for up to 24 months but at what cost to my MS. Like you said COVID-19 will be around for a while so how long will they be happy to delay my treatment for?
Ask then for the evidence for the 24 month delay…I can see a logic for this, but this is not evidence based.
P.S. FYI.
In this individual (58 years old) they had ocrelizumab dose in August 2019 and was due a dose in Feb 2020 but that didn’t happen for non-important reasons. Thei CD19 were still flatlined but recovering from 1 CD19 cell/microlitre to 8 cells per microlitre. Normal range is about 103-581 cells per microlitre. They got PCR confirmed covid-19 and had fever, cough in March 2020. They got symptoms for a week went to hospital with breathing issues and they were out 3 days later ….There is not report of COVID antibody levels, I have written to authors
Did the patient receive the Feb 2020 dose or not ? I was not sure if the patient did or not. As well, I think the goal with RTX or OCR is to keep the CD 19 cell count to < 5/uL , if I am not mistaken and therefore 8/uL is already showing an uptick which tells me that the patient perhaps did NOT receive the Feb infusion.
Jay Avasarala
U of Kentucky Med Ctr
When he was admitted with COVID-19 his B-cell count was 1/uL so he was B-cell depleted. The report states that the February infusion was delayed to Marck and doesn’t make it clear whether or not he had his March infusion. He also had moderate IgG hypogammaglobulinemia (6.5g/L) on admission for COVID-19.
I spoke to Gavin ahead of my 6 monthly Ocrevus infusion on 16 March and decided to continue with my treatment – I am pleased that I followed his advice.
Thanks Prof G. Superising given b cells importance in orchestrating the immune response. Also given Aubagio’s anti viral effect. Do you think this is safe to take and may even protect you against COVID 19? I am have asked my Ms care provider t9 be put on aubagio as maintenance therapy after 2 doses of alemtuzumab. They have refused so far and thinking of self medicating with a generic version for arthritis. My last scan showed cervical spinal cord lesions are more conspicuous on the STIR sequences. With definite no abnormality signal. Otherwise no change for last 4 years and want to keep it that way.
This is an interesting question, do you trust alemtzumab has done its job and disease has gone away or do you want the comfort of an induction therapy follwed by maintainence therapy. ProfG may have opinions on this as I know this trial design has been thought about, but the question I have, is have the immune system repopulated after alemtzumab and if not what effect would teriflunomide/leflunomide do to this? It blocks nucleotide synthesis and so can stop deviding cells so would it block repopulation
Do I trust Alemtuzumab has done the job? I feel alot better. But have I been cured? I feel no! Its been 1-2 years since my last dose and repair mechanism are kicking in but not completely fixed. Aubagio beat cd20 therapies in preserving brain volume. And is relatively safe and does not immuno suppress. Also after alemtuzumab depletion the effects of aubagio are going to be magnified.
This is the type of study that I imagine Genzyme want to do, ProfG may have more to say on this and there is evidence that teriflunomide is better as a second line than as a first line. In rheumatoid arthritis it (leflunomide) is a better anti-memory B cell agent, we don’t have data we asked a lab for this but they never showed us the data
Thank you for this. Prof G do you agree therefore that patients with no co morbidities on ocrelizumab do not need to be shielded? I will tell my neuro who has blanket told everyone on a DMT to shield.
Also – I think I had covid in March (on ocrevus) – I wish I could be part of that study but I have no way of knowing if I even had it!
The essential thing is to know if you have made antibodies. It says you have been infected if they are there. Ocrelizumab may blunt this response
Read the posts below
That case report gives a glimmer of hope, however slight. Obviously, there are a lot of unknowns, but it is interesting to note that anti-CD20 therapies, for example, are NOT uniformly safe in that the underlying disease is EQUALLY relevant. Consider RTX use in RA and PML causation. Conversely, RTX use in MS (off-label) and PML; to the best of my knowledge, none have been reported. JCV is neurotropic but strangely the same drug used in MS vs RA behaves differently as far as PML causation is concerned. So that is one aspect of PML and medications that is still a question mark. In a similar vein, anti CD20 therapies in CoVID19 may not have any antiviral properties and in fact may have a beneficial effect by suppressing Ab mediated lung injury but is CoVID19 a neurotropic virus and could it cause some delayed demyelinating syndromes worsening MS ? Is SARS-CoV2 neurotropic ? In the brain, strokes are much more evident with SARS-CoV2 as we are finding out. What is the cellular expression in of the ACE2 receptors ?
Coming to CoVID19 and the use of OCR, blunting Ab mediated lung disease with anti CD20 treatment options may not be a bad idea if the hypothesis holds. It may be EVEN be recommended ! Meanwhile, the ONLY class of drugs that I know have been shown to have an effect on SARS-CoV virus, per se, are beta-inteferons and I am NOT sure why they are not the BEST option for newly diagnosed MS patients. I wrote a piece (editorial/opinion piece) and submitted it to various journals and was summarily shown the exit. Everyone wants ‘cases’. Looking to the past for answers is NOT ‘cool’ (for want of a better word), I suspect. Can beta-interferons be given with OCR ??
In an in vitro study published on beta-interferons and SARS-CoV replication it was shown that the virus was inhibited by beta-interferon-1a. Vero E-6 cells were treated with concentrations (5,000 to 500,000 IU/mL) of IFN-β 1a either 24 h before or 1 h after inoculation with the SARS-CoV and monitored for cytopathic effect and production of infectious SARS-CoV at 24, 48, and 72 h post-infection. Inhibition of the SARS-CoVs by IFN-β 1a was dependent on both time of drug administration and time of culture sampling after SARS-CoV infection. Production of infectious SARS-CoV was inhibited (≥99.5% or 2.00 log10 PFU/mL) at 24 h post-infection ( Hensley LE, Fritz EA, et al. Interferon-beta 1a and SARS Coronavirus replication. Emerg Infect Dis. 2004; 10(2): 317-319. 10.3201/eid1002.030482.).
I think your article brings up a ton of queries because there are many patients on OCR needing their inescapable 6 month infusions.
Jay Avasarala, MD
U of KY Medical Center
Thanks for your input
There have been are studies on alpha, beta and lamda interferons, however will beta iterferon do the trick if the virus has already replicated as
Please read review below…it will answer some of your questions…4 cases of COVID encepalitis reported yesterday
PML and anti-CD20 in MS have been reported. Arthritis typical treatment also involved methorexate so more immunosuppression
Stroke perhaps you can publish your data quick to counter claims
The Baffling Case of Ischemic Stroke Disappearance from the Casualty Department in the COVID-19 Era.
Morelli N, Rota E, Terracciano C, Immovilli P, Spallazzi M, Colombi D, Zaino D, Michieletti E, Guidetti D.
Eur Neurol. 2020 Apr 14:1-3. doi: 10.1159/000507666. [Epub ahead of print]
Could COVID-19 represents a negative prognostic factor in patients with stroke?
Siniscalchi A, Gallelli L.Infect Control Hosp Epidemiol. 2020 Apr 20:1-4. doi: 10.1017/ice.2020.146. [Epub ahead of print]
Cellular expression of ACE2 is widespread but it is not the only way SARS gets in cells CD147, etc
“Looking to the past for answers is NOT cool”…but surely is sensible…as you can learn from your mistakes.
P.S. We also know on one death in the Italian cohort from someone treated with rituximab
Can I ask could ‘when’ you had your Ocrevus infusion influence how your body deals with Covid? Is there a point after the infusion when patients are at increased risk or due to this being a maintenance therapy is the number of months from the last infusion not so much of an issue? I made decision to go ahead with first full dose in early March and now trying to plan my Covid exit strategy to going back to working in a school.
That’s really interesting – thank you.
But whilst reassuring, I’d quite like to know if there have been other cases and how they resolved. I personally wonder about the risk of secondary bacterial infection. I have now had 2 infections in 2 months requiring antibiotics to clear. And I’m fairly sure didn’t have a pneumococcal (?) vaccine before I started treatment. Plus I was only switched to ocrelizumab due to low lymphocytes caused by DMF, I have no idea what my level is now!
I’m not shielding but am not going to shops myself and trying to get food delivered whenever I can get a delivery slot!
I’d be very interested to hear your thoughts about the risk to MSers having kids going back to school if they do decide to reopen them. Would that also be treatment dependent?
Thanks!
Yes, there have been more cases and we expect the Italian series to be published in the next week or so.
As you have DMF-induced lymphopenia and now B-cell depletion you are not the same as someone who has simply been treated with ocrelizumab. Being T-cell, in particular CD8 T-cell, depleted is a risk factor for viral infections.
Yes, the kids going back to school with vulnerable parents or household contacts is a big issue. This is the same issue we have with carers coming into the home of vulnerable. Children returning to school will clearly increase the risk of vulnerable people in the home. Will it be feasible to socially isolate from children as a parent? I suspect not. This is more reason for you to prepare yourself for being infected with SARS-CoV-2 and potentially getting COVID-19.
Have these other cases on ocrelizumab also done ‘well’ Prof G?
We know of one death in Italy of the 5 reports about two weeks ago
MouseDoctor was this a person with comorbidities or severe MS, or otherwise fit and well on ocrelizumab?
I’m in the same boat, lymphocyte depletion due to DMF (.68 lowest whole on therapy, average .76 over 2.5 years of treatment). Since discontinuing DMF and initiating ocrevus, average lymphocytes .81. I acknowledge that the covid/MS data will likely not address my particular situation, but am curious what benchmarks are being looked at: obviously mortality but what about severity of infection, duration, viral shedding, etc. I can understand the conclusion being drawn that immunosuppression could be protective against ARDS but what about all the other issues we see cropping up: renal failure, hepatic injury, blood clots, etc. I’m curious what kind of data is being solicited.
The lungs are an obvious problem because you cant breathe and you notice it, but ACE2 is all over the place and the prettiest staining I have seen is in the kidneys, my wifes friends brother has just had a blood test and their kidney function is down alot, they thought they had an asthma attack and that is why bloods were taking. So what happens in the lung happens else where, people are dying because it hits the heart too. This it’s just a fever and cough thing is tosh
I suspect “body count” is what will be recorded.
Very interesting and positive news. Thank you
I think more caution is needed here.
I currently have a patient who has had 4 doses of B-Cell treatment/CD20 who has now been in ITU for 15 days with COVID-19 pneumonitis. B cells 0, immunoglobulins within normal range. Even if B cells do not fight COVID they may be of relevance in secondary bacterial infections.
Beyond this I had another CD20 patient with bad non-COVID pneumonia and cellulitis earlier this year.
Was the non-COVID pneumonia viral or bacterial? I suspect it was more likely to be bacterial and more likely to due to an encapsulated bacterium (pneumococcus, haemophilus influenzae, etc.)
Bacterial I believe
Interesting case studies from Italy on two patients with X‐linked agammaglobulinemia who develop pneumonia as COVID‐19 manifestation but recovered.
https://onlinelibrary.wiley.com/doi/10.1111/pai.13263
Neurologist101 – does this patient have any other risk factors? What type of MS etc
PPMS
No other known risk factors. Relatively young. Edss 5
Interesting discussion. I have safety concerns about OCR during pandemic and the difficult balance between risks of infection vs delaying treatment. It was important to read these comments.