The most common questions about Rituximab and SARS-CoV-2

Questions from the COMBAT-MS members

1. How does Rituximab work?

Answer: Rituximab is an antibody that attaches to the surface of a type of white blood cell called B cells. When they do, the body's own immune system is activated so that the B cells are eliminated from the blood. Since these B cells have been shown to be very important in maintaining certain autoimmune reactions, the inflammatory activity in MS is greatly reduced and with it the risk of new relapses. This is roughly, in reality it is much more complex…

2. What is the risk benefit of using RTX?

Answer: For most people, the treatment has significantly more benefit than it involves risks. The most important risk is that you become more susceptible to infections, but for most people this is not a problem. Serious infections that lead to hospitalization are very rare, from our studies about 2 per 100 treated per year. For some individuals, however, the risk of MS disease leading to problems is so low that it does not motivate the risk either, especially in slightly older people where the risk of MS relapse is very low. The most important question we are working on now is whether the risks increase if you treat for several years, which is important for assessing the risk over time.

3. What do I need to think about / know before I start my treatment (vaccinations, other medications, diet, exercise, pregnancy)?

Answer: It is good to make sure that you have good vaccination protection against the infections you want protection against, because it is more difficult to get good protection if you from vaccination if you do not have any B cells in the blood. The vaccinations I think you should prioritize are SARS-CoV-2, TBE (tick encephalitis) and pneumococci.

4. Will I feel bad after my treatment?

Answer: Most people do not feel very bad either during or after an infusion. Some people get side effects when you get the actual infusions (allergy-like reactions, feeling sick) that can last for a couple of days, but after that most people usually do not feel anything different at all.

5. Can you use RTX for life?

Answer: In MS, it is not relevant to keep rituximab for life partly because the reduced in disease activity with years for everyone and partly because several years of treatment with rituximab probably leads to that the disease is "slowing down". We estimate that most people can discontinue their treatment somewhere between the ages of 50 - 60 without the risk of relapse increasing, possibly they can stop or take longer breaks earlier.

6. Why do I feel worse in my MS when it is "time" for a new infusion with RTX?

Answer: It is very difficult to answer. It's not very common to feel that way, but I know some people do. It is important to know that rituximab should not be used to 'feel good' but to reduce the risk of MS inflammation.

7. Is there a greater risk of being treated with RTX if you are older? Can you be too old for treatment?

Answer: You are always more sensitive to medication when you are older, but there are many who are treated with rituximab in old age for other diseases, especially rheumatism. However, it is very rare that it is justified to treat with rituximab up to old age for MS, very rarely after the age of 60.

8. When should you not take RTX?

Answer: You should not take rituximab during an ongoing infection or if you are pregnant. It is unclear if there is any effect on a baby being breastfed by a woman who has recently been treated with rituximab. It is probably risk-free, but in the absence of good studies, we advise against breast-feeding during concomitant treatment with rituximab.

9. Why does my treatment end even though I feel so good about it?

Answer: Most likely it is because your doctor has judged that you no longer need the treatment, which is the most common reason for discontinuing the treatment. You should get the exact answer from your treating neurologist.

10.What is the best time interval between infusions?

Answer: We do not know as there are few controlled studies that shed light on this. Every 6 months leads to a very good protection that seems to remain when sparse until every 12 months. I personally think that we treat "too much" rather than "too little". There is room for both sparser intervals than annually and longer treatment breaks. Then I think you get the maximum effect of the drug without exposing anyone to any unnecessary risks.

11.What is the best dose?

Answer: As above, we do not know. You can probably go down quite a bit in dose compared to what we use today with a preserved effect. The standard schedule to start with 1000 mg and then 500 mg every 6 months for a couple of years is a very effective regimen. After that, you can probably sparse out or take longer breaks.

12.What premedication should I take before treatment and for how long should I take it?

Answer: Standard premedication is paracetamol 1000 mg, antihistamines and cortisone, preparations and doses of the latter vary and probably do not matter much.

13.Because my B cells disappear during treatment, when will they return?

Answer: It varies a lot but usually it takes 6 - 12 months but can go both faster or take longer

14.Can B cells disappear forever?

Answer: Basically no. There are individual cases in the literature where it is described, but then there is almost always some other reason that can explain it.

15.How many B cells should I have before treatment and after?

Answer: We have no answer to that. After a treatment, they are always zero. If you ask me, I think there may be benefits to seeing the B cells recover a bit between infusions, especially if you have had a few. But there is no science evidence that can answer that question well.

16.What should my IgG level be after infusion before infusion?

Answer: You should have normal IgG levels at all times. An individual treatment does not affect the levels, but for some people, repeated infusions lead to a slow decrease in IgG. Then you should sparse the intervals or take a break in the treatment so as not to risk getting too low values.

17.What can be done to reduce the risk of infections (viruses, bacteria and fungi)?

Answer: The most important thing is to try to have good vaccination protection before starting treatment and otherwise the same applies as for everyone else, live healthy, sleep properly, and avoid with reasonable means to meet people who are obviously infected. Overall, however, there is no reason to live differently from how you did before starting treatment.

18.What is considered low IgG in relation to treatment with rituximab and when can it be justified to treat with IVIG to reduce the risk?

Answer: Each lab has its own limits, but a common limit in Sweden is 6.7 g/L. However, one should strive not to fall below that limit and one sees a clear trend that the IgG values fall below the limit value, one should extend the dose interval or take a break.

19.How long can we go in-between infusions and still be protected from progression or relapse?

Answer: No one knows! Protection against relapse occurs effectively after a couple of infusions and the more you get, the longer the protection will lasts (probably!) Protection against progression is probably mostly due to starting the treatment as early as possible, there is no way to know.

20.Why do you stop treating patients with RTX? After how many years?

Answer: It is individual. We now strive to not provide more treatment than is required to be relapse-free. It can vary from a few years (if you are a little older) to many years. We have a lot to learn about this.

21.Is there anything I can do about my progression?

Answer: This is a very difficult question and we have no sure answers. We hope that some of the new drugs that are being tested can have a positive effect on progression. In all probability, however, there are certainly gains to be made from being physically active with both strength training and aerobic training. You should stop smoking if you do so and make sure you take care of your health in the best way possible. It's almost impossible to say how much it can do, but I'm convinced it matters.

22.Is there any research on autophagy , Trehalose and MS?

Answer: Nothing that I know of, at least not that can be applied to anything practical.

23. Are there any studies or guidelines on having pets (such as dogs) while being immunocompromised on B-cell depleting treatments? I am concerned about the risk of infections and disease transmission.

Answer: There are not many diseases that are transmitted from animals to humans, so in general it should not be a problem. However, you should be vaccinated against TBE because many pets attract ticks that can become infected. Borrelia is also difficult to diagnose if you do not have any B cells because the body does not then form antibodies and the diagnosis then becomes very difficult.

24.Any comments on the use of Astra Zenca's drug to prevent COVID-19 in people with weakened immune systems who have not been adequately protected by vaccines?

Answer: Sorry, have no knowledge about that.

25.Are COVID vaccine side effects common when treated with RTX?

Answer: In all probability no increased risk of side effects. However, the vaccine response is less efficient if you do not have any B cells.

26.What is the recommended interval for COVID vaccination and booster shots?

Answer: There are no recommendations about it. Most suggest that you need a certain amount of B cells in the blood to get a good response to the vaccine. So I always measure the level of B cells before I decide whether to recommend a new dose. If it is zero, I recommend waiting and then I measure B-cells again in about 3 months. When the B cells have reached about 30 - 40 / uL (0.03 - 0.04 x 10 9 / L), there are good conditions for a good vaccine response. However, we know that you still get an answer among the so-called T cells against SARS-CoV-2 when vaccinated, even if you do not have any B cells. It probably protects against more severe infection but not from becoming infected. Now we know that even 3 vaccinations in completely immune-healthy individuals are not enough to not get Omikron, but the disease does often not become so serious.

27.Will there be guidelines?

Answer: The MS Society continuously updates information about this. One must be aware that there will never be any "truth" about how one should do. The virus is constantly changing and our immune response is changing with vaccinations. All "guidelines" are fresh and there are always exceptions for certain people. But for most people with MS, you can apply the general recommendations issued by the authorities. When it comes to vaccination and when it should be taken is an issue that is much discussed and therefore there are no "strong" guidelines. However, we have data that strongly suggest that you need certain levels of B cells in the blood to get a good antibody response and this means that you can not give general recommendations of the type "take the vaccine a certain time after rituximab infusion". However, it requires extra sampling and the resources are not available everywhere. In that case, it can be applied that "the longer after infusion the better", preferably longer than 6 months. The risk of relapse is very low even if you wait up to a year after the last infusion and at the moment my opinion is that it is better to prioritize getting good vaccine protection than to take your rituximab infusion exactly as previously planned. This is true for most people, everyone needs to discuss this with their neurologist.

28.What is a good amount of antibodies?

Answer: It is not possible to say because the values are different for different tests. The higher the better, I would say, but if you get to "medium" levels based on the values that apply to the current test, it shows that the immune system has reacted really well.

29.Fully vaccinated and has T cells. Is that enough?

Answer: If you have measurable antibodies, it sounds great! Then surely the vaccination protection must be improved for everyone over time

30.What about vaccine side effects?

Answer: Usually a little pain in the arm and feeling sick, maybe fever, a few days. Very rare more than that.

31.Should patients who do not have antibodies or T cells continue to be isolated?

Answer: Very few can measure their T cells against SARS-CoV-2, this is done only in scientific studies as far as I know. I do not recommend anyone to isolate themselves, because it will be unbearable in the long run. The situation is still considerably much better than it was for everyone when the pandemic started. Then no one had any T cells or antibodies and the early virus strains were much more dangerous than Omikron which now dominates. You have to make a much broader risk assessment to give concrete advice, but if you are otherwise healthy and relatively young (<50 years), the risk is extremely low that you will get such severe COVID-19 that you would end up in IVA and almost non-existent that you would die of it. I would primarily see if you can time the next vaccination so that you get it when you have good levels of B cells and then you will surely get a completely OK answer. If you have other diseases, it must be taken into account, but isolation is not a solution regardless. Wear good masks when you are among people you do not know, wash with alcohol and avoid meeting people who are obviously ill.

32.Are T cells sufficient protection after two different episodes of COVID-19, but no antibodies?

Answer: It depends on what you mean by "enough". You will be susceptible to infection, as it is primarily determined by having antibodies, but you will most certainly have an immunological memory as a result of your infections, which clearly reduces the risk of serious illness. Try to get a vaccination when you have B cells back so that the protection will surely be improved.

33.Does everyone who has been vaccinated or has had COVID form T cells?

Answer: We do not know if everyone does, but most people do. If you have other diseases or drugs that inhibit the immune system, it can certainly affect how well you form T cells.

34.What do the death rates from COVID -19 look like when taking RTX?

Answer: I have no recent or reliable figures on this, but all the data we have seen so far have not indicated any increased risk of dying from COVID-19 as a direct result of being treated with rituximab. Other risk factors seem to be much more important. Most important is, as you know, old age, then comes overweight, diabetes, smoking and that men have a higher risk than women. However, the risk increase for men does not seem to be as clear in infection with Omikron.

35.How many have ended up at IVA so far?

Answer: I do not have any figures on that either. Previous data showed that the risk was almost doubled compared to others if you were on rituximab, but it is unclear whether this applies any longer, perhaps an effect of Omikron and that most are vaccinated. The risk of ending up on IVA of COVID-19 years is now considerably lower than at the beginning of the pandemic and most people who have ended up there have been completely unvaccinated. So by getting vaccinated, you have an enormously low risk of needing IVA care due to COVID-19 today.

 

A bit of general information about COVID in MS and rituximab

Knowledge about COVID-19 is constantly increasing and it is virtually impossible to write "guidelines" that stay current for more than a month. Below is some information and "advice" based on the experience we have today and what it looks like in healthcare:

- Everyone should be vaccinated against SARS-CoV-2 as it is by far the best way to reduce the risk of becoming seriously ill with COVID-19. There is virtually no one who can be advised against this and anyone who receives a vaccination with 2 or 3 doses will reduce the risk of getting severe COVID-19.

- You probably need to have a certain amount of B cells in the blood to get a complete response with both antibodies and T cells during vaccination, but most people get at least a good response in their T cells, which most likely reduces the risk of severe COVID-19.

- By waiting to take your next dose of rituximab and letting the B cells come back, the chance of a good antibody response to the vaccination increases significantly. There is rarely a great risk of waiting to take your rituximab dose from an MS perspective, in most cases it is better to prioritize a good vaccine response.

- The risk of severe COVID-19 is determined by what we know today mainly by general risk factors where old age is the most important and in addition the risk of other serious diseases, smoking and obesity increases.

- Now Omikron dominates and it clearly gives a generally milder disease, which is good to keep in mind when making your own values about what "risks" you want to take.

- If you have a very severe MS with pronounced disabilities, the risk is greater that you get a more severe COVID-19, especially if the breathing is affected by the disease. In my opinion, it is then more important to prioritize getting a good vaccine response than to take rituximab exactly where it was intended before.

 

About "monoclonal antibody therapy" against COVID-19 in MS :
It is a treatment that gives monoclonal antibodies to SARS-CoV-2 intravenously to help the immune system fight the virus. The vast majority of people treated with rituximab will be able to fight the infection, but it may take a little longer to get rid of it. There is currently a great shortage of these monoclonal antibodies against SARS-CoV-2 and it is therefore completely impossible to promise such treatment to different groups, but it must always be decided on a case-by-case basis if this is going to be the case. The deficiency of the drug is so great today that it is mainly used by people with very severely weakened immune systems, for example due to cancer and chemotherapy or if you have recently been transplanted with a vital organ. There are very few people who have MS and are on rituximab who have such a weakened immune system that it is directly dangerous to get COVID-19, which is why it takes very special circumstances for it to become relevant and must always be preceded by discussion with the local infection clinic.

The following factors may suggest treatment with monoclonal antibodies to SARS-CoV-2 in MS :
1. Severity of MS: - Illness that in itself leads to difficulty in breathing and already known problems with recurrent respiratory infections may come into question.

2. MS treatment:
- Treatment with autologous stem cell transplantation or Lemtrada last six months should lead to discussion about offering monoclonal antibodies to SARS-CoV-2. - Treatment with rituximab in a person who has been vaccinated and has been shown to have their own antibodies will not be offered monoclonal antibodies to SARS-CoV-2 as their own antibodies in principle do the same as the intended treatment effect. - Treatment with rituximab in people with MS who are vaccinated but have not developed their own antibodies. In the case of a person who is otherwise relatively young and healthy, the conditions are very good that the infection will pass in an uncomplicated manner without monoclonal antibodies to SARS-CoV-2. Given the large deficiency that exists, it is extremely unusual for monoclonal antibodies to SARS-CoV-2 to be relevant in these cases. It can be considered if the infection develops into a more serious course with high fever that does not go away in a few days, but the decision is always made by the infection specialist and not by the treating neurologist. However, a person with MS is on rituximab and that has neither B cells nor antibodies in the blood and has a serious illness with severe functional impairment of his/her MS (whether vaccinated or not) may be eligible for treatment, but it should always be first discussed with an infection specialist.