The difference between CONTINUOUS and Intermittent immunosuppression

Continuous vs. intermittent immunosuppression

A useful way of thinking about 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:

1. cause significant lymphopaenia;
2. be associated with opportunistic infections;
3. reduce the antibody response to vaccines; and
4. 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, but has the potential to be immunosuppressive based on its mode of action. The remainder of the licensed DMTs are immunosuppressive to a greater or lesser degree.

The duration and intensity of immunosuppression further determines the risks. For example, short-term or intermittent immunosuppression associated with IRTs front-loads 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 not associated with a risk of acute bacterial infections.

The table in the embedded slide presentation summarises the main characteristics of intermittent and persistent immunosuppression. Live vaccines are in general contraindicated in patients on continuous immunosuppressive therapies. In comparison, patient 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.