Over the past years, anti-CD20 treatments such as Ocrevus have quickly superseded other DMTs on the first and second line treatment shelf. This is good news, because Ocrevus has a high efficacy in controlling MS-related inflammation. The MRI results are very impressive, and pwMS treated early with this drug will definitely do better in the long run. However, the most logical outcome of solving one problem is…. creating a new problem. One of the questions that keeps the MS community busy at night – especially given the fact that night starts at 5 pm these days – is when to stop treatment in pwMS. There is namely no way around the fact that Ocrevus is an immunosuppressive treatment and that our world is full of bugs.
Before the MS community establishes rational evidence rather than age-based stopping criteria and before we have blood biomarkers at our disposal that can guide the stopping decision, there is – as always – a middle way: derisking CD20 treatments. This means that you continu with Ocrevus infusions for several years without knowing it is really still necessary to control the disease (the current situation) but that you take all possible precautions to avoid drug-related side effects.
Therefore, we outlined in a recent review five steps that need to be taken when derisking anti-CD20 treatments for long-term use:
- Screening for chronic infections: It is for example important to screen for latent hepatitis B infection as there is a considerable risk for flare ups after starting anti-CD20 mAbs.
- Vaccinations: Anti-CD20 treatment makes you a little bit more susceptible to bladder, lung and skin infections. Vaccinations exist to protect you from certain lung infections. Therefore it is wise to have your flu, COVID-19 and pneumococcal vaccine before starting treatment. There is also emerging evidence that a vaccination against human papilloma virus or varicella zoster vaccine before starting immune suppressive treatment might be useful.
- Family planning: It is important to discuss family planning with female pwMS, as it is not advisable to try falling pregnant if there were new lesions or relapses in the previous year. Moreover, pwMS need to be aware that it is necessary to wait at least 3-4 months (could be longer depending on the guideline) after an anti-CD20 infusion before trying to conceive.
- Reduce Infusion reactions: pwMS might feel miserable after an anti-CD20 infusion as all B cells are killed at the same time and spill their content in the peripheral blood. This could be managed upfront with appropriate hydration and during the infusion by adding steroids, paracetamol and antihistaminics.
- Pharmacovigilance: As pwMS become more susceptible to infections with more longstanding use of anti-CD20, it is important to try and mitigate the infection risk. This could be done by measuring immunoglobulin levels annually, reviewing vaccination status and counselling pwMS about adequate fever management. It is easily overlooked that many pwMS on anti-CD20 wait too long before starting antibiotics when they are febrile. Moreover, there is still uncertainty about whether anti-CD20 might facilitate the development of certain breast cancers. Therefore, female pwMS should be actively encouraged to participate in local breast cancer screening programs.
Following the steps above as a pwMS and clinician requires a preventive mindset. In practice, prevention means that clinicians spend time explaining hundreds of pwMS about fever management and the need for annual flu vaccinations while there is no tangible immediate benefit for both. Admittedly, it is so much easier to avoid these topics and treat infections with antibiotics. If the infection turns out to be more severe, we know that in the Western World there is always the luxury a well-equipped respiratory medicine department. These fail-safe options do not take into account the individual burden of infections. Many pwMS experience worsening of existing disability during and after a severe infection, infections always mess with personal and professional plans, and many feel stressed when having an infection as they know they are immune suppressed. Hence, a derisky Tom Cruise would say: “What the fuck, make your preventive move!”
Disclaimer: Please note that the opinions expressed here are those of dr. Ide Smets and do not necessarily reflect the position of the Barts and The London School of Medicine and Dentistry nor Barts Health NHS Trust.
Derisking CD20-therapies for long-term use
Anti-CD20 have quickly become the mainstay in the treatment of multiple sclerosis (MS) and other neuroinflammatory conditions. However, when they are used as a maintenance therapy the balance between risks and benefits changes. In this review, we suggested six steps to derisk anti-CD20. Firstly and secondly, adequate infectious screening followed by vaccinations before starting anti-CD20 are paramount. Third, family planning needs to be discussed upfront with every woman of childbearing age. Fourth, infusion reactions should be adequately managed to avoid treatment interruption. After repeated infusions, it becomes important to detect and prevent anti-CD20-related adverse events. Fifth, we recommended measuring immunoglobulin levels and reviewing vaccinations annually as well as counselling adequate fever management. For female patients, we emphasised the importance to engage with the local breast cancer screening programs. Sixth, to fundamentally derisk anti-CD20 therapies, we need evidence-based approaches to reduce dosing intervals and guide retreatment.
At ECTRIMS there was a discussion on long term use of anti-CD20 treatments. One of the arguments made is that the risk of severe infection whilst on anti-CD20 is cumulative with time. Do you think there is a limit to the time it is safe to be on an anti-CD20 therapy for (in time or in immunoglobulin levels)?
Personally, I think there is although we don’t know when exact the balance shifts between benefits vs harm. Therefore we would need biomarkers. One possibility would be to measure immunoglobulin levels but there’s no good correlation between the levels and infection risk. Another strategy would be to define biomarkers for MS disease activity so that we know when it’s not necessary anymore to continue.
Perhaps the best strategy would just be to make induction therapy the standard for MS care? Just give everyone alemtuzumab?
Maybe or alternative IRTS?
Regarding 4, aren’t steroids and antihistamines part of the official ocrelizumab infusion protocol? I definitely always got them and remember reading about it even beforehand.
Never got or needed paracetamol.
Never had any reactions outside this weird tired but wired state that comes from combining steroids with antihistamines…
Yes, but it’s possible to futher optimize the protocol by recommending hydration the day before + antihistaminic
Thank you for the post.
What is the current information and thinking about blood markers and criteria for stopping or continuing with anti-CD20?
Does Sweden have any guidelines for rituximab?
One strategy would be to measure when B cells repopulate and to delay the time between dosing intervals. Because now we administer ocrevus when b cells are still at zero. But it would be better to have biomarkers available to measure ms disease activity. If you stop, you are able to measure whether ms disease activity reappears and whether it is safe to keep your drug stopped.
I dont know sorry
What if we pair IVIG with CD20 for longer-term use? Would it cause additional safety concerns and how often would one require a top-up IVIG infusion?
That would be theoretically a good option, but IVIG is very expensive and needs to be administered every 10 weeks which is not very convenient
Thank you Ide, I kept imagining with memory B-cells knocked out, an IVIG not only helps raise antibody levels but also provides an opportunity to fix immune defects using antibodies from healthy donors.
One idea is it gives antibodies it also blocks FC receptors on natural killer cells, macrophages, neutrophils and blocks innate immunity and killing mechanisms of antibodies
Thank you MD, is there an article I can read about this idea?
Dear Anon Below
Could you comment on this please
This article came up in a Google Alert just now
They cant find a rituximab link to hospitalisation
“There is also emerging evidence that a vaccination against human papilloma virus or varicella zoster vaccine before starting immune suppressive treatment might be useful. ”
Can you post a source please. I am interested in reading more about this.