I saw several patients in clinic yesterday and had to speak to many on the phone about what to do about the next course of ocrelizumab and cladribine. It got me thinking.
According to the Italian society of neurology or SIN (Società Italiana di Neurologia) recommendations on the management of patients with MS during the COVID-19 epidemic we should stop dosing. However, the SIN guidelines don’t address the temporal sequence of the COVID-19 epidemic and how the epidemic may evolve. The SIN guidelines provide relatively straightforward, and I would argue arbitrary, advice on how to manage patients with MS in the short-term, but they don’t address how to manage these patients in the intermediate or long-term and in particular patients with highly active MS. If the public health measures flatten the peak of the epidemic, but extend its tail, the problem of community-acquired COVID-19 infection may be with us for many months and potentially years. Do we stop using these treatments for years?
Over the last few days, I have asked myself are the SIN guidelines compatible with the best interests of our patients or do they represent a knee jerk response to an undefined problem that may not be a problem at all?
I had a discussion about the COVID-19 epidemic with our renal transplant team who informed me that they are not taking any specific action about the levels of immunosuppression they are providing their transplant patients during the epidemic. Apart from informing their transplant patients to improve their hand and home hygiene, to avoid high-risk travel and unnecessary contacts, to self-isolate if necessary and to reduce contact with the hospital and other medical institutions as much as possible, because they are more likely to be sources of COVID-19. It is business as usual. Nor are they halting their transplant programme. Their argument is that transplanted kidneys and other transplanted organs are too precious not to protect them with relevant immunosuppressive drugs. Why would we not have the same attitude about the brains and spinal cords of our patients with active multiple sclerosis?
I would argue that solid-organ transplant patients are significantly more immunocompromised than pwMS on a DMT. Most transplant patients are on triple immunotherapy, compared to pwMS who are on monotherapy and even then the level of immunosuppression is generally low on MS DMTs. Hence, the mortality risk to an individual on a DMT, who is unfortunate to be infected with COVID-19, maybe actually quite low. Another hypothesis being considered is that moderate immunosuppression may prevent severe complications associated with COVID-19 infection. The severe pulmonary complications of COVID-19 infection appear to be consistent with ARDS (acute respiratory distress syndrome) caused by an over-exuberant immune response to the virus. As a result of this, several exploratory trials are currently being undertaken in China using immunosuppressants to try and dampen the immune response to the virus. Interestingly, fingolimod the S1P modulator, a licensed DMT for MS, is currently being tested as a treatment for COVID-19 associated ARDS.
Then there is the virology to take into account. COVID-19 is a new human pathogen, that is likely to have recently crossed species. COVID-19 will eventually become endemic and hence pose a seasonal risk to patients on immunosuppressive therapies. As it is a small RNA virus with low fidelity it is likely to mutate rapidly making a one-off vaccine only a partial solution. Vaccines take time to be developed, tested and introduced at a population level. Delaying treatment, de-escalating therapy by switching to immunomodulatory DMT, or interrupting dosing of DMTs to wait for a vaccine will delay the adequate treatment of MS. We, therefore, need a pragmatic response to how we manage the potential threat of COVID-19 in individuals with MS. If patients have active MS they need to be treated and managed based on the clinical evidence at hand and hence may need to be treated with higher efficacy DMTs. This will need to be done in the context of appropriate behavioural modifications to prevent exposure to the virus.
The potential risks posed by each DMT differ and, rather than imposing a blanket rule, decisions regarding treatment should be individualised. For some patients having their MS treated and controlled may be more important than the potential risk of being exposed to and acquiring a severe COVID-19 infection.
Based on the immunological principles that antiviral responses are mainly driven by T-cells, in particular CD8+ cytotoxic T-lymphocytes, and natural-killer cells and less so, at least initially, by B-cells. Based on these principles there is a hierarchy of immunosuppression of the DMTs. The highest risk will be the immune reconstitution therapies during the depletion phase of the treatment, i.e. HSCT, alemtuzumab (Lemtrada), mitoxantrone (Novantrone) and possibly cladribine (Mavenclad). However, post-immune reconstitution once the total lymphocyte counts have returned to normal the risk of severe viral infections are probably no higher than what would occur in the background population and would be associated with age and other comorbidities. Please note immune reconstitution takes months to years, so if the patient’s last course of treatment was in the last 12-24 months they may still be immunocompromised. As a rough guide if the total lymphocyte count is above 0.8 x 109/L or 800/mm3 they should be able to deal with viral infections reasonably well provided they have not other comorbidities and are relatively young.
Of the IRTs, cladribine (Mavenclad) should be classed as being of intermediate risk, because it is a relatively poor T-cell depleting agent. T-cells are only depleted post-cladribine by an average of 50% with the CD4+ population being more sensitive than the CD8+ population. In the Phase 3 CLARITY study, viral infections were uncommon post-cladribine and apart from herpes zoster, infections were only slightly more common in cladribine-treated subjects compared to placebo-treated subjects. When viral infections occurred post-cladribine they tended to be mild or moderate in severity. Therefore I think cladribine should be classified as relatively low-risk DMT.
Similarly, anti-CD20 therapies such as ocrelizumab have a minor impact on T-cell counts and are not associated with severe viral infections. In the Phase 3 relapsing-remitting and primary progressive trials infections were more slightly more frequent on ocrelizumab compared to comparator arms (interferon-beta-1a or placebo). Most of these infections were mild and moderate with the severe infections being bacterial in nature (pneumonia, urinary tract infections and cellulitis). Similar to cladribine there was a small risk of herpetic infections, which were mild to moderate and manageable with antiviral agents. I, therefore, feel that anti-CD20 therapies are relatively safe based on their profiles defined in phase 3 trials and we should continue to use them in patients that need them.
Another issue is neutralizing anti-drug antibodies. If you interrupt dosing of ocrelizumab, say after the first course, you may prevent high-zone tolerance from kicking in, i.e. the immunological mechanism that results in the immune system tolerizing itself to foreign proteins. This means that not continuing ocrelizumab therapy may increase the chance of a particular patient developing NABs and being a poor responder to the drug when it is recommenced.
Clearly any decision to start a DMT during the COVID-19 epidemic will need to be taken carefully and will depend on the state of the COVID-19 epidemic, not only in the particular country concerned, but in the specific area, the patient lives and is being treated in. For example, aggressive public health steps to contain the spread of the virus locally may make it relatively safe for a patient to start an immunosuppressive therapy. My concern is that the COVID-19 epidemic may trigger a large number of neurologists and patients to reconsider their treatment strategy and choice of initial DMT and to opt for less effective immunomodulatory DMTs. A change in treatment strategy driven by COVID-19 needs to be carefully considered. The COVID-19 epidemic in all likelihood will be short-lived and it would be unfair to patients treated during the epidemic to be disadvantaged in the long term regarding the management of their MS. We have spent an extraordinary amount of time and effort to activate the MS community; to get across the principle that ‘time is brain’, to treat MS proactively to a target of no evident disease activity (NEDA) and more recently to flip the pyramid and use higher efficacy treatments first line. These treatment principles are evidence-based and should not be thrown out in the context of a potential but yet undefined risk to our patients that in my opinion is being overemphasised; please remember we have no data on COVID-19 infection in patients with MS on DMTs.
Is there anything we learn from renal transplant physicians? Yes, with the possible exceptions of alemtuzumab, HSCT and mitoxantrone, which cause quite potent short-term immunosuppression, I think it should be business, or decision-making, as usual taking into account the caveats above with a major emphasis on reducing the risk of our patients acquiring the infection in the first place.
Groupthink and knee jerk responses are not necessarily in the best interests of our patients. So after discussing the evidence with many of my patients yesterday, we are cautiously going to continue ocrelizumab and cladribine dosing. In other words, personalised decision-making and a pragmatic approach are required. What is decided for one patient may not necessarily be right for another patient; do you agree with me?
Disclaimer: Please note this post, as with all of my blog posts, represents my personal opinions and not the views of my colleagues at Barts-MS.