Tag Archives: reconstitution

DMTs, Treatment strategy

How immunosuppressed am I?

Do you understand the difference between short-term intermittent and long-term continuous immunosuppression? Here we address another of the key questions to consider before deciding on a specific disease-modifying therapy (DMT).

Key points

  • Immunosuppressive disease-modifying therapies (DMTs) reduce the immune system’s effectiveness.
  • It is important to weigh up the benefits and risks of short-term versus continuous immunosuppression.
  • Non-selective DMTs suppress the adaptive and innate immune systems; selective DMTs do not affect the innate immune system and are thus associated with a low risk of bacterial infections.
  • The implications of immunosuppression need to be considered within the context of other health and lifestyle factors.

Which DMTs cause immunosuppression?

A useful way of thinking about DMTs is based on whether they are immunosuppressive. Broadly speaking, an immunosuppressive is any DMT that reduces the immune system’s activation or effectiveness. 

From a regulatory perspective, for a drug to be classified as immunosuppressive, it should: 

  • cause significant lymphopaenia or leukopenia (reduced white cell counts)
  • be associated with opportunistic infections (infections that don’t occur in people with a normal, healthy immune system)
  • reduce antibody and/or T-cell responses to vaccines 
  • increase the risk of secondary malignancies. 

Based on the above criteria, the interferon-beta preparations and glatiramer acetate are immunomodulatory rather than immunosuppressive. Teriflunomide is also an immunomodulatory therapy with the potential, albeit small, to cause immunosuppression. In real life, however, very few people with MS treated with teriflunomide develop significant lymphopaenia or leukopenia; if they do, we tend to stop the drug. The other licensed DMTs are immunosuppressive to a greater or lesser degree. 

Short-term versus continuous immunosuppression

The duration and intensity of immunosuppression further determine the risks. Short-term or intermittent immunosuppression associated with an immune reconstitution therapy (IRT) front-loads the risks, which decrease substantially once the immune system has reconstituted itself. In comparison, long-term continuous or persistent immunosuppression, which occurs with most maintenance DMTs, accumulates problems over time, particularly opportunistic infections and secondary malignancies.

Live vaccines are, in general, contraindicated in patients on continuous immunosuppressive therapies. However, someone with MS on an IRT who has reconstituted their immune system can tolerate and respond to live vaccines. The benefits of administering live vaccines always need to be balanced against the risks of the vaccine.

How immunosuppressed are you table updated format 180625 SS

The main characteristics of continuous persistent and short-term (intermittent) immunosuppression. Modified from Giovannoni, Curr Opin Neurol.1
AHSCT, autologous haematopoietic stem cell transplantation; PML, progressive multifocal leukoencephalopathy.

Selective versus non-selective immunosuppression

Immunosuppression that accompanies DMTs may be selective or non-selective. Non-selective therapies deplete and/or suppress both the adaptive immune system (T cells and B cells) and the innate immune system (monocytes, neutrophils and natural killer [NK] cells). Alemtuzumab, AHSCT (autologous haematopoietic stem cell transplantation) and mitoxantrone are non-selective and are therefore associated with acute bacterial infections such as listeriosis, nocardiosis and cytomegalovirus reactivation. In comparison, anti-CD20 agents (ocrelizumab and ofatumumab) and cladribine are selective, do not affect the innate immune system and are therefore associated with a low risk of acute bacterial infections. 

How immunosuppressed are you_MET vs IRT_2 Dec 2024

Classification of disease-modifying therapies for relapsing forms of MS. Modified from Giovannoni, Curr Opin Neurol.1
AHSCT, autologous haematopoietic stem cell transplantation.

Other considerations

Please note that the implications of immunosuppression are not black and white but interact with other factors such as:

These factors have been highlighted during the COVID-19 pandemic, particularly in relation to the risk of severe COVID-19 and the variations in vaccine responses among people with MS (including waning of the immune response).

It is important to realise that we can derisk (reduce the risk of) some complications associated with long-term immunosuppression and the use of DMTs. Please see the post entitled How can I reduce my chances of adverse events on specific DMTs?

References

  1. Giovannoni G. Disease-modifying treatments for early and advanced multiple sclerosis: a new treatment paradigm. Curr Opin Neurol 2018;31:233 ̶ 43.
DMTs, Treatment strategy

How do I want my MS to be treated?

What is the difference between a maintenance ̶ escalation DMT and an immune reconstitution therapy (IRT)? Why is it important to understand the distinction?

Key points

  • Maintenance–escalation and immune reconstitution therapy (IRT) are two approaches to MS treatment currently favoured.
  • IRT is a one-off, short course which acts on immune system cells in three stages: reduction, repopulation and reconstitution.
  • Maintenance–escalation is given continuously without interruption. If it does not work well, the treatment is changed to a more effective DMT (known as ‘escalation’).
  • Additional future approaches are likely to include induction ̶ maintenance and/or combination therapy.

If I had MS, how would I want to be treated? This is a difficult question, and one that many of my patients ask me. The answer depends on your life stage, what risks you are prepared to take, personal factors such as family planning considerations and the extent of your understanding of MS and how we approach its treatment.

Currently, there are two main philosophies regarding the treatment of MS with DMTs: maintenance/escalation versus immune reconstitution therapies (IRTs). 

What is an immune reconstitution therapy?

By definition, an IRT is given as a short course, i.e. as a one-off treatment in the case of autologous haematopoietic stem cell transplantation (AHSCT) or intermittently in the case of alemtuzumab, cladribine or mitoxantrone. IRTs are not given continuously, and additional courses of the therapy are given only if there is a recurrence of MS inflammatory activity. IRTs can induce long-term remission and, arguably, in some cases a potential cure.

IRTs have three phases to their mode of action, which I refer to as the ‘three Rs’.

  1. Reduction, or depletion, when we try to kill the autoimmune cells that cause MS.
  2. Repopulation, when the immune system recovers from stem cell transplantation and, hopefully, the autoimmune cells don’t return.
  3. Reconstitution, when the immune system is recovered and fully competent. The recovered immune system following treatment with an IRT is different from what was there before. Some people like to think of an IRT as a reboot of the immune system, but without MS.
Slide1

The three Rs of immune reconstitution therapy: reduction, repopulation and reconstitution. From Giovannoni, Curr Opin Neurol.1 

What is an MS ’cure’?

One attempt at a definition describes an MS cure as no evidence of disease activity (NEDA) 15 years after the administration of an IRT. I justify using 15 years because it is the time-point most accepted for defining ‘benign MS‘ and is also beyond the average time to onset of secondary progressive MS in natural history studies.

What is a maintenance therapy?

A maintenance therapy is given continuously without an interruption in dosing. Although maintenance therapies can induce long-term remission (i.e. NEDA), they cannot result in a cure. The recurrence or continuation of inflammatory disease activity with maintenance therapies is an indication of a suboptimal response to treatment and typically results in a treatment switch. Ideally, this switch should be to a more effective class of DMTs – hence the term ‘escalation’. 

What would I recommend?

I can’t choose for you. The debate is complex and depends on many factors. One important consideration is vaccine readiness: will I be able to mount an adequate immune response to a vaccine? IRTs have the advantage that they allow reconstitution of the immune system; once it recovers, vaccine responses are restored, and even live vaccines can be given.

The table below highlights key differentiators. Further, detailed information about most of the products listed in the Table can be accessed through the DMT comparison tool available at ClinicSpeak or via the Multiple Sclerosis Trust MS Decisions aid.

Similarities and differences between maintenance treatments and immune reconstitution therapies. Registered trade names (UK market) of the generic drugs listed are shown in brackets. *How to define a ‘cure’ in MS is controversial. Modified from Giovannoni, Curr Opin Neurol.1
DMT, disease-modifying therapy; HSCT, haematopoietic stem cell transplant; IRT, immune reconstitution therapy.

The future

I envisage two more treatment strategies emerging.

  • One approach is induction ̶ maintenance therapy, using an IRT followed by an immunomodulatory therapy rather than an immunosuppressive DMT (which is a safer option) the aim is to keep MS in long-term remission. This approach is used in oncology, where the cancer is hit hard with induction chemotherapy and then kept at bay with a well-tolerated maintenance therapy (e.g. antihormonal therapies in breast cancer).
  • Another approach is combination maintenance therapy; the aim would be to combine an anti-inflammatory therapy with, say, neuroprotective therapies to target smouldering MS.

The diagram below illustrates the scheduling of the four approaches discussed in this section. You may like to try out the DMT comparison tool to find out how some of the drugs listed in the comparison Table above align with your personal life choices and priorities.

Slide5

Four approaches discussed in this section. The white panels illustrate the two approaches currently available; the shaded panels illustrate two strategies that may emerge in the future. Modified from Giovannoni, Curr Opin Neurol.1

References

  1. Giovannoni G. Disease-modifying treatments for early and advanced multiple sclerosis: a new treatment paradigm. Curr Opin Neurol 2018;31:233 ̶ 43.