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How immunosuppressed are you?
The duration and intensity of immunosuppression determine risks. Short-term immunosuppression from IRTs is front-loaded and don't accumulate with time, which is what happens with maintenance DMTs.
In this Newsletter, I address another of the questions you need to ask yourself and understand before deciding on and starting a specific DMT. If you are new to MS-Selfie you may want to catch up with the previous Newsletters on this theme.
Am I eligible for treatment with a DMT?
Do I understand the difference between short-term intermittent and long-term continuous immunosuppression?
Do I understand the concept of treat-2-target?
What are the attributes of the specific DMTs?
How can I derisk or reduce my chances of getting certain adverse events on specific DMTs?
A useful way of thinking about disease-modifying therapies (DMTs) is based on whether or not they are immunosuppressive. Broadly speaking an immunosuppressive is any DMT that reduces the activation, or effectiveness, of the immune system.
From a regulatory perspective for a drug to be classified as being immunosuppressive it should:
Cause significant lymphopaenia or leukopenia (reduced white cell counts).
Be associated with opportunistic infections, which are infections that don’t occur in people with a normal immune system.
Reduce antibody and/or T-cell responses to vaccines.
Increase the risk of secondary malignancies.
Based on this definition the interferon-beta preparations and glatiramer acetate are not immunosuppressive. I prefer to call these therapies immunomodulatory DMTs. Teriflunomide (Aubagio) is also an immunomodulatory therapy with the potential, albeit small, of being immunosuppressive. The latter is based on teriflunomide’s mode of action. However, in real-life very few pwMS treated with teriflunomide develop significant lymphopaenia or leukopenia and if they did we tend to stop the drug. Therefore, I usually refer to teriflunomide as not being an immunosuppressive therapy. The remainder of the licensed DMTs are immunosuppressive to a greater or lesser degree.
The duration and intensity of immunosuppression further determine the risks. For example, short-term or intermittent immunosuppression associated with IRTs front-load the risks, which are substantially lower once the immune system has reconstituted itself. In comparison, long-term continuous or persistent immunosuppression, which occurs with most of the maintenance DMTs, accumulates problems over time, in particular opportunistic infections and secondary malignancies.
Immunosuppression that accompanies the DMTs can be selective or non-selective. Non-selective refers to therapies that deplete and/or immunosuppress both the adaptive (T and B cells) and the innate immune system (monocytes, neutrophils and natural killer cells or NK cells). Alemtuzumab, HSCT and mitoxantrone are non-selective and are therefore associated with acute bacterial infections such as Listeriosis, Nocardiosis and cytomegalovirus (CMV) reactivation. In comparison, anti-CD20 (ocrelizumab) and cladribine are selective and don't affect the innate immune system and are therefore associated with a low risk of acute bacterial infections.
The table summarises the main characteristics of intermittent and persistent immunosuppression. Live vaccines are in general contraindicated in patients on continuous immunosuppressive therapies. In comparison, pwMS on IRTs who have reconstituted their immune systems are able to tolerate and respond to live vaccines. The decision to administer live vaccines in this situation needs to be balanced against the risks of the vaccine.
Please note that the consequences of immunosuppression are not black-and-white and interact with other factors such as ageing (immunosenescence), carryover effects from previous DMTs, concomitant medications, comorbidities (smoking, obesity, diabetes, sedentary lifestyle, etc.), disability and social determinants of health such as levels of deprivation and the lived environment. These factors have been particularly highlighted in the COVID-19 pandemic in terms of the risk of getting severe COVID-19 and COVID-19 vaccine responses, including the rate of the waning of the immune response.
I have personal experience with long-term immunosuppression. My father had a renal transplant and was on long-term immunosuppression with a combination of three drugs. He suffered frequently from thrush or oral candidiasis that sometimes would extend down his oesophagus. He developed terrible warts that need to be aggressively managed surgically by his dermatologist and later on he had multiple basal cell carcinomas. He would have a rolling monthly appointment with his dermatologists to manage the skin manifestations of immunosuppression. Saying this the level of immunosuppression associated with MS maintenance DMTs is not as intense as that used in solid organ transplantation, however, it can be a problem. For example, we have had to stop fingolimod in a few patients who have developed warts.
I think it is important to realise that we can de-risk some of the associated complications associated with long-term immunosuppression and the use of DMTs. The following figure is a summary of what needs to be done at baseline, during the administration of DMTs and monitoring. The specifics, however, vary from DMT to DMT.
I predict that after the COVID-19 pandemic that the issues around chronic immunosuppression are going to play a major role in the choice of DMT, in particular, in the older population of pwMS.
I would be interested to know if any of you have had problems in relation to being immunosuppressed and how these problems have been managed.
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The MS-Selfie case study from the 13th of October is about a patient with MS who is anxious that he may have early secondary progressive MS and that rituximab is failing him. He is keen to explore AHSCT. I discuss the complex issues about defining a treatment failure and whether or not AHSCT is appropriate.
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General Disclaimer: Please note that the opinions expressed here are those of Professor Giovannoni and do not necessarily reflect the positions of Barts and The London School of Medicine and Dentistry nor Barts Health NHS Trust. The advice is intended as general advice and should not be interpreted as being personal clinical advice. If you have problems please tell your own healthcare professional who will be able to help you.