Tag Archives: mitoxantrone

Detail, DMTsDetail, Treatment strategy

What are the attributes of the specific DMTs?

Multiple sclerosis (MS) treatment has evolved rapidly, with 11 classes of disease-modifying therapy (DMT) now available in the UK. I will summarise them briefly and explain how they fit within a treatment paradigm for effective and safe use.

Maintenance therapies versus immune reconstitution: what’s the difference?

There is a divide between the two main treatment philosophies: maintenance ̶ escalation versus immune reconstitution therapies (IRTs).

An IRT is given as a short course – a one-off treatment in the case of autologous haematopoietic stem cell transplantation (AHSCT) or intermittently for alemtuzumab, cladribine or mitoxantrone. IRTs are not given continuously, and additional courses are given only if inflammatory activity recurs. IRTs can induce long-term remission and, in some cases, potentially a cure.

Maintenance therapies, by comparison, are given continuously without an interruption in dosing (‘continuous’ administration may be daily, one or more times weekly, monthly or even once every few months). Although maintenance therapies can induce long-term remission, they cannot, by definition, result in a cure. The recurrence or continuation of inflammatory activity indicates a suboptimal response to treatment and typically requires a treatment switch. Ideally, this switch should be an escalation to a more effective class of DMT.

An article in our list of key questions, entitled How do I want my MS to be treated?, provides a more detailed comparison of maintenance and IRT therapies, including frequency of administration, efficacy, risks, use in pregnancy, vaccine response and potential for a cure.

The DMTs currently licensed in the UK (in August 2024) are listed in the table under the relevant category.

table format updated 180625 SS

Disease-modifying therapies for MS licensed in the UK. *Please note, Bonspri is available in other markets but not the UK.

How effective are the different DMTs?

The measures used to assess the effectiveness of a DMT include its ability to reduce or prevent relapses, focal inflammatory activity (that is, new or enlarging lesions) on magnetic resonance imaging (MRI), and disability progression. Additional factors that can help to assess the relative efficacy of DMTs include the proportion of clinical trial subjects who experience improvement in disability and the impact of the treatment on brain volume loss.

The MS-Selfie InfoCards are an easy-to-use resource to help people with MS compare the key features of each DMT. They contain bite-sized information designed to aid treatment choices and an overview of the key aspects of each DMT.

Efficacy of the licensed DMTs for MS can be visualised as pyramid, with the moderately effective treatments at the bottom and the more effective approaches at the top. What determines the most appropriate DMT efficacy level for an individual depends on several factors, such as baseline prognostic profile, family planning requirements, local or national treatment guidelines, socioeconomic factors, consideration of any co-existing illnesses, cognitive impairment, risk aversion and lifestyle issues.

Pyramid format updated 180625 SS

UK licensed DMTs for MS, in ascending order of efficacy.
HSCT/AHSCT, haematopoietic stem cell transplantation/autologous haematopoietic stem cell transplantation.

What is the goal of treatment? Introducing NEIDA as a target

In the past, we used no evident disease activity (NEDA) as a treatment target. ‘Disease activity’ included progression or disease worsening independent of relapse activity (termed smouldering MS). Although some of the more effective DMTs may modify this stage of the disease, many neurologists feel uncomfortable switching or stopping a DMT based simply on smouldering MS disease activity. 

Relapses and ongoing focal MRI activity are associated with a worse short-term to intermediate-term prognosis. These observations have led to the increasing adoption of ‘no evident inflammatory disease activity’ (NEIDA) as a new treatment target. For more information about treatment targets, please see the article in our key questions, Do I understand the concepts of treat-2-target and NEDA?

Many healthcare professionals (HCPs) remain sceptical of using NEIDA as a treatment target, fearing that this could lead to more people with MS being on ‘riskier’ high-efficacy therapies. However, achieving long-term remission, or NEIDA, is a well-established treatment target in other autoimmune diseases such as rheumatoid arthritis and inflammatory bowel disease. People with MS treated-to-target of NEIDA from the outset do better than those whose treatment is escalated following breakthrough disease (at a clinical or subclinical/MRI level)1. I would, therefore, strongly encourage people with MS and their HCPs to adopt NEIDA as an initial treatment target.

Flipping the pyramid

The effectiveness, or relative effectiveness, of individual DMTs becomes less critical in the context of a treatment target of NEIDA. Choosing a DMT with a lower efficacy rate simply means that a greater proportion of treated people with MS will need to be switched to higher efficacy therapies over time to achieve NEIDA. We refer to the latter of these three approaches – starting with high-efficacy treatment – as flipping the pyramid. In recent trials of alemtuzumab, ocrelizumab, ofatumumab and ublituximab, people with MS randomised to 2 years of lower efficacy DMTs (interferon-beta-1a or teriflunomide) had poorer outcomes than those receiving highly active therapy from the outset. Real-world data from registries also support this; groups of people with MS with delayed access to high-efficacy DMTs did worse than those who received high-efficacy treatments early.1,2

Horizontal versus vertical switching

If we consider the conventional step care paradigm, people with MS who switch horizontally from interferon-beta to glatiramer acetate, or vice-versa (i.e. from one moderate efficacy DMT to another moderate efficacy DMT) do less well than those who switch vertically to fingolimod, a highly effective DMT. Similarly, people with MS escalating to natalizumab, a very high-efficacy DMT, do better than those being escalated to the less effective, but still high-efficacy, DMT fingolimod. 

Continuous and intermittent immunosuppression

Another useful way of classifying DMTs is whether they are immunosuppressive, that is, they reduce the activation, or effectiveness, of the immune system. Drug regulators stipulate that a drug may be classified as immunosuppressive if it (1) causes significant lymphopaenia (low lymphocyte count) or leukopenia (low white blood cell count), (2) is associated with opportunistic infections, (3) reduces the antibody and immune response to vaccines and (4) increases the risk of secondary malignancies.

The duration and intensity of immunosuppression further determine 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 some of the maintenance DMTs, accumulates problems over time, particularly opportunistic infections and secondary malignancies. You can read more detail on this topic in the key question How immunosuppressed am I? The following table summarises the main attributes of intermittent and persistent immunosuppression.

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.2
AHSCT, autologous haematopoietic stem cell transplantation; PML, progressive multifocal leukoencephalopathy.

Adverse effects, monitoring and risk reduction

The complications associated with immunosuppression vary from DMT to DMT. Each individual drug summary in the DMTs section of MS-Selfie contains detailed information about the main adverse events, key monitoring requirements, use (or contraindication) during pregnancy and breastfeeding, and response to vaccines. The MS-Selfie InfoCards provide bite-sized summaries of several practical aspects, including side effects, to enable easy comparison of any treatments you are considering; some of this information is collated below for easy reference.

Short-term versus long-term adverse effects

Each drug has been given scores from 1 to 10 based on published analyses of its short-term and long-term side effects. Short-term refers to side effects that emerge when a treatment is started and decrease in severity or disappear within days or weeks. A well-known example of short-term side effects on starting interferon-beta is flu-like symptoms that typically abate within 4 ̶ 8 weeks.

A long-term side effect persists for months or doesn’t disappear on continuing the DMT. Examples include intermittent but persistent flushing after taking dimethyl fumarate, or low B lymphocyte counts with anti-CD20 therapies that may lead to low antibody or immunoglobulin levels (hypogammaglobulinaemia).

A low score denotes few or rare side effects; a high score denotes many or frequent side effects. The score does not correlate to a percentage. More information can be found in each drug summary and the manufacturer’s Summary of Product Characteristics.

Scores for short-term and long-term side effects assigned to the individual DMTs summarised in the MS-Selfie InfoCards, based on a published network meta-analysis.3
Alem, alemtuzumab; GA, glatiramer acetate; HSCT, haematopoietic stem cell transplantation; IFN-beta; interferon-beta; Nat, natalizumab.

Monitoring and risk reduction

Numerous tests are carried out at the start of treatment, and ongoing monitoring is required for many factors, to reduce the risk from adverse events. The key question, How can I reduce my chances of adverse events on specific DMTs?, explains what needs to be done at the start of DMT administration (baseline) and during subsequent monitoring. The specifics vary from DMT to DMT; please refer to the individual summaries for details such as baseline tests, follow-up, infection prevention, cancer risk, pregnancy, breastfeeding and vaccination. It is important to remember that all licensed MS DMTs have had a thorough risk ̶ benefit assessment, and their benefits are considered to outweigh the potential risks.

Administration and other practical considerations

Routes and frequency of administration

The MS-Selfie InfoCards contain a symbol for each DMT, showing how it is administered. Some DMTs are available in more than one formulation (e.g. tablets and injection). The frequency of administration varies greatly from DMT to DMT; please consult the relevant summary in the DMTs section and discuss your preferences and priorities with your MS HCP.

The route of administration for each drug in the MS-Selfie InfoCards is clearly identified by the relevant symbol. (If a DMT is available in more than one formulation, there is a separate card for each delivery route.)

Number of clinic visits

It may be important for you to consider the frequency of clinic visits. This will depend on factors such as the delivery route of your DMT, the monitoring requirements of the drug regulators and the risk of specific side effects. The table below summarises the assessments from the MS-Selfie InfoCards. This is another factor to consider in discussions with your MS HCPs about the most appropriate DMT for you.

Conclusions

People with MS must understand the objectives of MS treatments and the different treatment strategies currently available to achieve these objectives. Although the MS therapeutic landscape is complex and hence may seem overwhelming, framing the choices using a relatively simple construct should help each individual to make informed decisions about managing their MS. MS-Selfie aims to guide you in the process of deciding on the most appropriate therapeutic strategy and specific DMT for treating your disease.

References

  1. Rotstein D, et al. Association of No Evidence of Disease Activity with no long-term disability progression in multiple sclerosis: a systematic review and meta-analysis. Neurology 2022;99:e209̶ ̶ 20.
  2. Giovannoni G. Disease-modifying treatments for early and advanced multiple sclerosis: a new treatment paradigm. Curr Opin Neurol 2018;31:233 ̶ 43.
  3. Samjoo IA, et al. Efficacy classification of modern therapies in multiple sclerosis. J Comp Eff Res 2021;10:495–507.
DMTsDetail

Mitoxantrone

Summary

Mitoxantrone is licensed to treat MS in a few countries (though not in the UK). It is typically used to treat active secondary progressive, progressive relapsing, or worsening relapsing ̶ remitting MS. It is a repurposed chemotherapy agent and is given as an intravenous infusion. It is either given as a monthly infusion for 6 months, or every 3 months for up to 2 years or as a combination of these two protocols. Mitoxantrone is associated with quite severe toxicity (infections, cardiotoxicity, premature ovarian failure and secondary leukaemia) which is why it is not used often now. In some countries it is used as a true induction therapy and is followed by a maintenance DMT, typically interferon-beta or glatiramer acetate. Because mitoxantrone is toxic to the heart there is a limited cumulative dose that can be given safely over a lifetime. I have kept mitoxantrone on the list of essential DMTs because it is generic and hence is available for treating MS in resource-poor settings.

Trade names

Novantrone.

Mode of action

Mitoxantrone is an immune reconstitution therapy. It works by inhibiting the enzyme topoisomerase II which unwinds DNA. As a result of its actions on this enzyme it disrupts DNA synthesis and DNA repair in cells and causes them to die. White blood cells are particularly sensitive to its actions. Mitoxantrone is derived from a group of chemicals called anthracenediones that are toxic to the heart in high doses.

Efficacy

High to very high.

Class

Non-selective immune reconstitution therapy (IRT), short-term immunosuppression.

Immunosuppression

Yes, short-term.

Infusion protocols

  • Edan protocol: Mitoxantrone 20 mg intravenous infusion (ivi) monthly in combination with 1 g methylprednisolone x 6 months (6 doses).
  • Hartung protocol: Mitoxantrone 12 mg/m2 ivi 3-monthly x 2 years (8 doses).
  • Gonsette protocol: Mitoxantrone 12 mg/m2 ivi monthly x 3 months followed by mitoxantrone 12 mg/m2 ivi 3- monthly up to 2 years (10 doses). Please note the Gonsette protocol includes an algorithm to adjust the next dose depending on the recovery of the peripheral blood cell counts.

Additional courses of mitoxantrone can be given beyond what is stated in these protocols provided the total lifetime dose of mitoxantrone does not exceed 140 mg/m² and that cardiac monitoring (echocardiogram [ECG] and ejection fraction) does not show signs of a cardiomyopathy.

Adverse events and events of special interest

Infection

Mitoxantrone causes a low white cell count that may result in an increased susceptibility to infection. Therefore, it is important that all infections are identified early and treated. The presence of an active infection may delay the next infusion. Chest infections and urinary tract infections are common after mitoxantrone. Maintenance of skin integrity is also important because broken skin or ingrown toenails may become areas harbouring infection. People with MS and their families and/or carers should be educated about how to assess and detect infection so that potential problems are recognised early. Please note that individuals treated with mitoxantrone may develop neutropenia and are hence susceptible to neutropenic sepsis, including infection with Listeria monocytogenes.

Nausea and vomiting

Nausea may occur during treatment and the next day. Antiemetic drugs are usually prescribed to help manage this. The doses of mitoxantrone used to treat MS are much lower than those used in cancer, therefore these side effects are milder than those generally experienced by people with cancer.

Hair loss

Hair may become temporally thinner during mitoxantrone treatment but will return to normal once the treatment is finished. Hair loss is uncommon and happens in fewer than 3% of people with MS who receive mitoxantrone. If it does occur, it usually begins 3 ̶ 4 weeks after the first dose has been administered.

Cardiotoxicity

High doses of mitoxantrone have been associated with cardiotoxicity. So a baseline heart scan must be performed before commencing the first dose of treatment. This scan can either be a MUGA scan or an ECG. These routine tests measure the contractility of the heart. The MUGA scan requires the injection of a very low dose of a radionuclide tracer, which is then detected using a machine similar to an x-ray machine. An ECG is a form of ultrasound done using a probe that is applied to the chest. Neither of these tests is painful. The MUGA scan or ECG should be completed at baseline and then 3-monthly before the administration of the next dose of mitoxantrone. Mitoxantrone treatment may have to be stopped if the tests show a significant decrease in cardiac function, i.e. a decrease in ejection fraction below 50%. These problems generally happen in people who receive a total lifetime dose of more than 140 mg/m².

Extravasation

Mitoxantrone is an irritant that can produce pain and inflammation along the path of a vein through which it is administered. Extravasation occurs when the drug accidentally infiltrates the tissue outside the vein. To avoid extravasation, the cannula must be sited in the non-dominant arm and away from areas of joint flexion. The site should not be obscured and should be checked at regular intervals. An extravasation kit should beavailable at the bedside for medical staff to use in case of emergency.

Therapy-related leukaemia

Secondary acute myelogenous leukaemia (or acute myeloid leukaemia, AML) has been reported in people with MS or with cancer treated with mitoxantrone. Therapy-related leukaemia associated with topoisomerease II inhibitors such as mitoxantrone typically develops within 2 ̶ 4 years after chemotherapy has started. Based on the current data, the risk of leukaemia in subjects with MS treated with mitoxantrone is ~1 in 200–400 subjects.

Infertility

Amenorrhea (lack of periods) may occur during treatment and should be investigated because it may respond to treatment with hormonal replacement therapy. A less common complication is the induction of menopause, which should be fully investigated should it occur. Transient amenorrhea occurs in ~12% of patients and persistent amenorrhea, or premature menopause, in ~10% of patients. The risk of persistent amenorrhoea is higher in women older than 35 years (14%) and lower in women less than 35 years of age (6.5%). If indicated, women should either be offered GnRH agonists as ovarian protection throughout therapy or the option of egg harvesting and storage.

Pharmacovigilance monitoring requirements and de-risking strategies

Baseline

Full blood count, urea and electrolytes, liver function tests, thyroid function tests, serum protein electrophoresis, serum immunoglobulin levels, serology (varicella zoster virus, human immunodeficiency virus 1 and 2, hepatitis B and C, syphilis), tuberculosis enzyme-linked immune absorbent spot (TB ELISpot), up-to-date cervical smear and/or human papillomavirus testing, pregnancy test, ECG and cardiac ejection fraction (echocardiography or MUGA scan).

Follow-up

  • 1- to 3-monthly (predosing): FBC, U&E and LFTs and in women a pregnancy test
  • 3-monthly: ECG and cardiac ejection fraction (echocardiography or MUGA scan)
  • 12-monthly: TFTs
  • Endocrine work-up for women with MS with persistent amenorrhea.

Infection prophylaxis

  • Varicella zoster virus (VZV): if found to be VZV seronegative you will need to receive the VZV vaccine at least 6 weeks before being treated with mitoxantrone to allow sufficient time to develop immunity and protective antibodies against the virus.
  • Urinary tract infections (UTIs): if you have a history of recurrent UTIs you should be taught to self-monitor your urine using home dipstix, given a supply of urine specimen bottles for laboratory testing and possibly an unfilled prescription for a standard first-line antibiotic. Then, if you do develop a UTI and self-diagnose it, you can take your urine specimen for microscopy, culture and antibiotic sensitivity testing (MCS) at your GP surgery or the laboratory and then collect your prescription and start your antibiotics. Once the culture and antibiotic sensitivities come back from the laboratory this may prompt your doctor to change the antibiotics. Please note, however, that not all GPs and family practitioners support self-monitoring and self-management of your MS.
  • Listeriosis: you are at risk of developing listeriosis after mitoxantrone. To decrease this risk, you should receive advice about starting a listeriosis diet and a behavioural programme to reduce your likelihood of exposure to the infection. You may also be offered antibiotic prophylaxis. For example, the Association of British Neurologists gives the following summary advice for people with MS receiving alemtuzumab (also a risk for listeriosis): ‘We recommend several preventative measures, of which the most straightforward is co-trimoxazole 960 mg three times a week for one month after each cycle of alemtuzumab’. Here too is a link to a short online web application on this topic (Alemtuzumab safety advice).

Rebaselining

A rebaseline MRI needs to be done after completing the course of mitoxantrone. Depending on which protocol you have been treated with, this could be performed at 6 or 24 months.

Pregnancy

Pregnancy is contraindicated when using mitoxantrone as it may harm the developing foetus. While taking mitoxantrone, women who might become pregnant should use effective birth control and should be sure, before each dose, that they are not pregnant. If unsure, a pregnancy test should be performed.

Breastfeeding

Mitoxantrone is excreted in human milk, and significant concentrations (18 ng/ml) have been reported for up to 28 days after the last administration. Because of the potential for serious adverse reactions in infants from mitoxantrone, breast-feeding should be discontinued before starting treatment.

Male fertility

Although mitoxantrone causes transient oligospermia, male infertility has not been a problem. In contrast to other chemotherapy agents (e.g., alkylating agents such as cyclophosphamide), after cessation of mitoxantrone therapy there is complete recovery of sperm production without morphological changes in vitro or genotoxic effects on germinal cells in vivo. In view of this, it is not necessary to offer male patients the option of routine sperm banking.

Vaccination

Immunisation may be ineffective when given during mitoxantrone therapy. Immunisation with live virus vaccines is generally not recommended until after the immune system has reconstituted.

Summary of Product Characteristics (SmPC) 

Novantrone (USA)

Switching-2-mitoxantrone

Mitoxantrone repeat course

As mitoxantrone is an Immune Reconstitution Therapy (IRT), breakthrough activity may trigger the need for additional courses to be given, provided the total lifetime dose of mitoxantrone does not exceed 140 mg/m² and that cardiac monitoring (ECG and echo/MUGA) does not show signs of underlying cardiomyopathy.

Other DMTs

Provided the baseline screening tests are acceptable and there are no specific contraindications, it is feasible (from a clinical perspective) to use mitoxantrone after another licensed DMT; please check the licensing regulations in your country.

Interferon-beta and glatiramer acetate

There are no specific cautions.

S1P modulators (fingolimod, siponimod, ozanimod and ponesimod)

The development of mitoxantrone-related cardiomyopathy and/or cardiac arrhythmia is a contraindication for using fingolimod and other S1P modulators (siponimod, ozanimod and ponesimod) after mitoxantrone. It is important to be extra-vigilant when doing the routine baseline cardiac checks post-mitoxantrone. If it has been some time since mitoxantrone’s last dose, I recommend checking a cardiac ejection fraction with echocardiography or a MUGA scan.

Alemtuzumab and HSCT (non-selective cell depleting DMTs)

A persistently low peripheral white cell count post-alemtuzumab, HSCT or other DMT, i.e. a neutrophil count <1000/mm³ or a total lymphocyte count <800/mm³ is a relative contraindication to using mitoxantrone. Another hit on the bone marrow and primary and secondary lymphoid organs may render an individual more immunosuppressed and worsen their leukopaenia. The decision to use mitoxantrone in this situation has to be based on the potential benefits versus the risks of these treatments and the risks of untreated active MS. 

Cladribine (selective cell depleting DMT)

A persistently low peripheral lymphocyte cell count post-cladribine, i.e. a total lymphocyte count <800/mm³ is a relative contraindication to using mitoxantrone. The effect of mitoxantrone on primary and secondary lymphoid organs may worsen the lymphopaenia and is a risk factor for developing grade 3 or grade 4 lymphopaenia, i.e. <500/mm³ or <200/mm³, respectively. However, the decision to use mitoxantrone in this situation has to be based on the potential benefits of the treatment versus the risks of lymphopaenia and the risks of untreated active MS.

Anti-CD20 therapies (selective cell depleting DMTs)

Anti-CD20 therapies (ocrelizumab, ofatumumab and others) are selective B-cell depleting agents, so mitoxantrone is theoretically much safer than the other less selective and non-selective agents post-ocrelizumab.

Natalizumab

As mitoxantrone is an IRT that can’t be rapidly reversed, it is critical to ensure that there is no asymptomatic PML. Carry-over PML from natalizumab to mitoxantrone is potentially fatal. Therefore, a baseline MRI scan and possibly a CSF examination is essential to exclude the possibility of PML before starting mitoxantrone. 

Dimethyl fumarate

DMF reduces the lymphocyte count by approximately 30% and in some people with MS by more than this. Therefore, individuals with lymphopaenia on DMF may be more susceptible to developing clinically significant prolonged lymphopaenia post-mitoxantrone.

Teriflunomide

Because teriflunomide is an antiproliferative agent, it may delay or prevent the recovery of the peripheral white cell count post-mitoxantrone. One option is to do an accelerated teriflunomide washout to prevent this potential problem. Interestingly, rheumatologists who use leflunomide, a prodrug converted to teriflunomide, don’t use an accelerated washout when using antiproliferative agents post-leflunomide. I, therefore, don’t think an accelerated washout is necessary.

Special circumstances

The presence of other specific comorbidities and adverse events may make it difficult to start mitoxantrone after another DMT.

Pregnancy and childbirth, Women's health

Planning for pregnancy

This article discusses the effects of MS on fertility, decisions about starting or stopping a DMT, the use and safety of oral contraceptives and the possible impact of in vitro fertilisation on MS disease course.

Does MS affect my fertility?

No, MS does not affect fertility. Women and men with MS are as fertile as people without MS. However, MS does not protect women and men from other causes of infertility. Fertility treatment may impact MS (see below). Please be aware that mitoxantrone, AHSCT (autologous haemopoietic stem cell treatment) and other chemotherapy treatments, such as cyclophosphamide used off-label to treat MS, may be toxic to ovarian and testicular function and require egg and sperm banking before treatment.

Should I go onto a DMT and get my MS under control before starting a family or first start my family?

In general, I recommend that women with active MS delay pregnancy until their disease is under control, optimise their general health and prepare properly for becoming a parent. There is no point in having active MS, not starting a DMT and having a catastrophic relapse in the period during which you are trying to fall pregnant.

However, a desire to start or extend your family should not change the way you want your MS managed. Early effective treatment, treating to a target of NEIDA, potentially flipping the pyramid, preventing end-organ damage and the holistic management of MS are all compatible with pregnancy. There are no rules for implementing this strategy in pregnancy because all decisions should be personalised. For example, a woman with rapidly evolving severe MS may choose natalizumab and stay on it throughout pregnancy and while breastfeeding because her MS was so active and potentially devastating. Another woman who is young, risk adverse and with a very good prognosis may choose to delay starting a DMT until she has had a child. Yet another woman, diagnosed at 40, may not want to delay falling pregnant and may opt for a DMT that is safe during pregnancy.

It is up to the person with MS, their partner and sometimes their extended family to make the final decisions about how to manage their MS during pregnancy. The healthcare professional (HCP) is there to provide information and guidance in this process.

Are oral contraceptives safe in people with MS?

To my knowledge, contraceptives are safe and effective in women with MS. The same contraindications and relative contraindications to specific contraceptives apply to women with MS as to the general population. Hormonal contraceptives are associated with an increased risk of thrombosis; women with MS who are immobile thus have a higher risk of deep vein thrombosis than those who are mobile.

Which contraceptive would you recommend?

MS should not be the deciding factor around the choice of contraceptive unless the degree of MS-related disability makes managing menstrual hygiene difficult. In this case, contraceptives that suppress menstruation have advantages, for example, continuous hormonal contraceptives or the progestin-tipped intrauterine contraceptive device (Mirena).

Inclusion criteria for participation in specific drug trials sometimes mandate double contraception, for example, a hormonal contraceptive and a barrier method. This is to try and avoid accidental pregnancies while taking an investigational compound without a safety track record in humans.

How long before I fall pregnant must I stop my DMT?

It depends on which DMT you are taking. Only the DMTs that are teratogenic or potentially teratogenic (i.e., may cause foetal malformations) need to be stopped before you fall pregnant. It is essential to allow sufficient time for these agents to be eliminated from the body.

Teriflunomide

Teriflunomide has the potential to cause birth defects; therefore, patients must have effective contraception whilst on this treatment. It has a very long half-life because it is reabsorbed in the intestine and is eliminated slowly from the plasma. Without an accelerated elimination procedure, it takes up to 8 months to reach plasma concentrations of less than 0.02 mg/l, which are considered safe. Remarkably, due to individual variations in teriflunomide clearance, it may take up to 2 years to fall to acceptable levels. An accelerated elimination procedure with cholestyramine or activated charcoal can be used at any time after the discontinuation of teriflunomide.

Teriflunomide accelerated elimination procedure

After stopping treatment with teriflunomide:

• Cholestyramine 8 g is administered three times daily for 11 days, or cholestyramine 4 g three times a day can be used if cholestyramine 8 g three times a day is not well tolerated.

• Alternatively, 50 g of activated powdered charcoal is administered every 12 hours for 11 days.

Following either of the accelerated elimination procedures, it is recommended to verify elimination by checking teriflunomide blood levels and allow a waiting period of 1.5 months between the first occurrence of a plasma concentration below 0.02 mg/l and planned fertilisation.

S1P modulators

S1P modulators are contraindicated during pregnancy, owing to the risk to the foetus. Before starting treatment in women of childbearing potential, we do a urine pregnancy test. Women taking an S1P modulator must use effective contraception during treatment and then continue for:

  • 2 months after stopping treatment with fingolimod (Gilenya)
  • 10 days after stopping treatment with siponimod (Mayzent)
  • 3 months after stopping treatment with ozanimod (Zeposia)
  • 7 days after stopping treatment with ponesimod (Ponvory).

Stopping the S1P modulators brings the potential for rebound disease activity, so most neurologists now prefer to transition women on one of these therapies to another class of DMT that is considered safer in pregnancy.

Safer options

Safer options during pregnancy include an injectable (interferon-beta or glatiramer acetate), a fumarate, an anti-CD20 therapy, natalizumab or an immune reconstitution therapy (cladribine or alemtuzumab). I cover some of the issues related to anti-CD20 therapies in the MS-Selfie case study ‘Wait to fall pregnant or start a DMT now?’.

The good news is that several DMT options are now available to women with MS wanting to fall pregnant.

Can I have IVF, and what will IVF do to my MS?

There is no reason why a person with MS cannot have IVF (in vitro fertilisation). However, there appears to be a slightly increased risk of relapse after IVF and egg harvesting. Whether this is due to stopping DMTs before undergoing IVF or due to the drugs used to stimulate ovulation is unknown. Studies reporting an increase in disease activity after IVF are more likely to be published than studies not showing such an increase so that publication bias may affect the findings. I recommend viewing IVF as a planned pregnancy and giving women with MS the option of receiving a DMT that is relatively safe in pregnancy or treating their MS with immune reconstitution therapy before IVF.

References

Krysko KM et al. Treatment of women with multiple sclerosis planning pregnancy. Curr Treat Options Neurol 2021;23:11.

Other articles in this series on Pregnancy and childbirth:
Managing MS during pregnancy
Preparing to give birth
Breastfeeding if you are on a DMT
Concerns about parenting

DMTsSafety, Monitoring MS

How can I reduce my chances of adverse events on specific DMTs?

The complications associated with immunosuppression vary from DMT to DMT. You will find it helpful to understand what investigations to expect before and during treatment and how these may vary depending on the DMT(s) you are considering.

Key points

  • Numerous tests are carried out at the start of your treatment (baseline); these include blood, urine and tests for a range of infections.
  • Some patients will need tests or procedures specific to their DMT that are inappropriate for everyone with MS – for example, vaccination against some infections; pregnancy and/or genetic counselling; prevention of cardiovascular complications; and management of infusion reactions.
  • Ongoing monitoring is required for many but not all of the above factors.
  • All licensed MS DMTs have had a thorough risk ̶ benefit assessment, and their benefits are considered to outweigh the potential risks.

Standard tests … and why we do them

If you have read the article on immunosuppression, you will know that immunosuppressive DMTs may reduce white blood cell counts and antibody responses to vaccines and increase the likelihood of some infections and cancers. However, we can reduce the risk of many complications associated with long-term immunosuppression (we use the shorthand ‘de-risk’). This article explains what needs to be done at the start of DMT administration (baseline) and during subsequent monitoring. The specifics, however, vary from DMT to DMT.

Baseline tests

Tests at baseline (before starting DMT administration) include full blood count, platelets, liver, kidney and thyroid function tests, and a urine screen. Recording baseline immunoglobulin levels is particularly important if you are about to start an anti-CD20 therapy (ocrelizumab, ofatumumab or rituximab) so that we have a reference level for future comparisons. 

Serum protein electrophoresis is done for patients considering starting interferon-beta; having a so-called monoclonal gammopathy (an abnormal immunoglobulin) is a contraindication to starting an interferon-beta formulation in people with MS. The drug has been associated with a form of capillary leak syndrome, leading in rare cases to death from an adult respiratory distress syndrome.

The table below summarises the routine investigations required at baseline; subsequent sections provide further detail.

Tests routinely carried out at the start of treatment (baseline).
AHSCT, autologous haematopoietic stem cell transplantation; CMV, cytomegalovirus; CSF, cerebrospinal fluid; DMT, disease-modifying therapy; EBV, Epstein ̶ Barr virus; ECG, electrocardiogram; FBC, full blood count; HIV, human immunodeficiency virus; HPV, human papillomavirus; JCV, JC virus; LFTs, liver function tests; MMR, measles/mumps/rubella; MRI, magnetic resonance imaging; PCP, pneumocystis pneumonia; PML, progressive multifocal leukoencephalopathy; TB ELISpot, tuberculosis enzyme-linked immune absorbent spot; TFTs, thyroid function tests; U&E, urea and electrolytes; VZV, varicella zoster virus.

Infection screening

At our centre, we screen for a relatively large number of infectious diseases so that we can treat any subclinical infection before starting a DMT. This is particularly relevant for HIV-1 and 2, hepatitis B and C, syphilis and tuberculosis (TB).  

Screening for the JC virus (JCV), which causes progressive multifocal leukoencephalopathy (PML), is only really needed for people with MS considering starting natalizumab. Even if you are JCV positive, you can be treated with natalizumab for 6 ̶ 12 months and sometimes longer if you are prepared to take on the risk of PML and the extra monitoring required to detect PML early. 

We only check measles/mumps/rubella (MMR) status in patients without documentation of full vaccination as children. We check varicella zoster virus (VZV) status before starting immunosuppression and vaccinate seronegative individuals. Currently, we are still using the live VZV vaccine. This will change, and we will likely be offering all people with MS in the UK the component inactive VZV vaccine (Shingrix, that has had its licence extended) to reduce the chances of zoster reactivation in all adults starting immunosuppression. This new Shingrix indication is similar to the pneumococcal vaccine (Pneumovax). Our centre is only recommending Pneumovax in patients about to start an anti-CD20. However, when Shingrix becomes available on the NHS, it will make sense to bundle this with the Pneumovax and make it routine for all people with MS before starting immunosuppressive therapy. Please check with your healthcare team which products are available locally.

Routine tests and monitoring for Epstein-Barr virus (EBV) and cytomegalovirus (CMV) are only needed for subjects undergoing autologous haematopoietic stem cell transplantation (AHSCT), which causes profound short-term immunosuppression that can result in CMV and EBV reactivation. CMV reactivation also occurs with alemtuzumab, so this needs to be considered when investigating patients who develop complications after receiving alemtuzumab (please see Opportunistic infection in MS). 

For patients starting long-term immunosuppression, it is advisable to screen for active human papillomavirus (HPV) infection (by cervical smear or vaginal swab) and for warts or active infection with molluscum contagiosum. Warts are caused by HPV skin infection; molluscum contagiosum is due to a relatively benign pox virus that typically affects young children but occasionally affects adults. Warts and molluscum contagiosum can spread rapidly in patients receiving alemtuzumab, so I recommend treating these skin infections before starting immunosuppression for MS. 

Vaccinations

We encourage all patients to be vaccinated against COVID-19 and seasonal flu; outside the flu vaccine season, we remind people to get vaccinated during the next vaccine season. 

Hepatitis B, meningococcal and Haemophilus influenzae vaccines are considered only for people with MS who are at high risk of infection and have not had these vaccines as part of a national vaccine programme, i.e. healthcare and laboratory workers for hepatitis B, school and university students and military recruits for meningococcal vaccine and paediatric patients for Haemophilus influenzae. 

The issue around having the HPV vaccine as an adult is more complex. For example, in the UK, the NHS does not cover the cost of the vaccine for people over 25. In addition, most people have only had the quadrivalent vaccine (Gardasil-4), which covers about two-thirds of the strains that cause cancer. Some people with MS may want to upgrade their immunity with the polyvalent vaccine (Gardasil-9) that covers over 95% of the cancer-causing strains of HPV. For more information on HPV vaccination, please see Case study: cervical intraepithelial neoplasia (CIN) and ocrelizumab.

MMR is a live vaccine given in childhood (see MMR vaccine: to vaccinate or not? ). Owing to vaccine hesitancy, however, many people do not receive this vaccine as children. Therefore, if an adult with MS is about to start immunosuppressive therapy and has not been vaccinated against MMR, we advise them to do so. This is particularly important for people about to start natalizumab because these viruses are neurotropic and can infect the brain. Natalizumab blocks immune response within the brain; hence, exposure to a neurotropic virus could cause serious infection, similar to what we see with the JC virus – which causes PML.

Travel vaccines for people who travel as part of their work or plan to travel shortly need to be considered. In particular, the yellow fever vaccine is a live vaccine (made from a weakened yellow fever virus strain) and it should ideally be given before someone starts on immunosuppressive therapy. 

Cardiovascular screening

You may need an ECG (electrocardiogram), to rule out an abnormal heart rhythm or electrical conduction abnormality and to check your left ventricular function (ejection fraction). These abnormalities are a relative contraindication to using the S1P modulators (fingolimod, siponimod, ozanimod, ponesimod), which may affect the conduction of the heart. In patients treated with mitoxantrone, the left ventricular ejection fraction (LVEF) must be done at baseline and regularly monitored because mitoxantrone is toxic to the heart. If the LVEF drops significantly, further dosing of mitoxantrone is contraindicated. 

Pregnancy, family planning and genetic testing

Many chemotherapy agents used in AHSCT for ablating (extracting) the bone marrow are toxic to the ovaries and testes. Therefore, patients receive counselling before treatment and can have eggs (oocytes) or sperm banked for future use. Egg banking is also a consideration for women with MS being treated with mitoxantrone. Men receiving mitoxantrone do not need to bank sperm, however, because mitoxantrone does not cross the testes ̶ blood barrier. 

Genetic testing is only required at present if you wish to receive siponimod. Siponimod is metabolised by a specific liver enzyme (biological catalyst) with two functional variants – slow metabolising and fast metabolising. People who carry two slow-metabolising variants of the enzyme cannot receive siponimod. Intermediate metabolisers (those that carry one slow- and one fast-metabolising version of the enzyme) receive low-dose siponimod, while those with two fast-metabolising enzymes receive high-dose siponimod. 

Protecting against progressive multifocal leukoencephalopathy

I have included magnetic resonance imaging (MRI) and lumbar puncture with cerebrospinal fluid (CSF) testing for JCV among the baseline tests. This is specific to patients at high risk of developing PML who are switching from natalizumab to a depleting immune reconstitution therapy such as alemtuzumab or another therapy that depletes their immune system (e.g. cladribine or an anti-CD20 therapy). These tests are done to exclude asymptomatic PML, which will otherwise be carried over to the new treatment. The effects of these immunosuppressive therapies on your immune system cannot be rapidly reversed, which is a problem because immune reconstitution is needed to clear PML. Most MS centres do not mandate CSF testing in this situation because it does not always reveal the presence of PML. However, I still request this test on my patients to gain as much information as possible on which to base potentially life-changing decisions.

Prophylactic antivirals and antibiotics

Patients in our centre undergoing AHSCT or receiving alemtuzumab will be given antivirals and antibiotics to reduce the likelihood of certain infections. This is particularly relevant for listeriosis, which is a rare infection transmitted via food. We also encourage all our patients to start and maintain a specific diet to reduce the chances of listeriosis. The risk of listeriosis is only present for a short period when both the adaptive and innate immune systems are compromised, that is, for 4 weeks after receiving alemtuzumab, so we recommend antibiotic prophylaxis for 4 weeks. Our online resource provides more information about listeriosis. If you live in the UK, you can order our free listeriosis prevention kit, which contains a booklet (also downloadable) and various practical items to help keep you safe.

Strategies for limiting the risks from immune reconstitution therapies and infusion DMTs.

Infusion reactions

When you use agents that cause cell lysis (breakdown), such as alemtuzumab and intravenous anti-CD20 therapies, the contents of cells cause infusion reactions. To prevent such reactions or reduce their severity, we pretreat patients with corticosteroids, antihistamines and antipyretics. The exact protocols for each DMT differ; for example, ocrelizumab infusion reactions are generally only a problem with the first and second doses; therefore, many centres don’t give steroids with the third and subsequent infusions. The latter was particularly important during the COVID-19 pandemic when it was shown that the recent administration of high-dose steroids increased your chances of severe COVID-19. 

Ongoing monitoring

Once someone has been treated with a DMT, ongoing monitoring is required. What gets monitored and how frequently depends on the individual DMT. For a list of DMTs associated with important adverse events, please see our summary Table in ‘De-risking’ guide: monitoring requirements of individual DMTs.

The regulatory authorities usually put in place specific monitoring requirements, which can differ worldwide. It is important that you also enrol in your national cancer screening programmes. Being on chronic immunosuppression increases your chances of developing secondary malignancies, so please remain vigilant. 

Tests carried out regularly as part of ongoing monitoring.
FBC, full blood count; LFTs, liver function tests; MRI, magnetic resonance imaging; PML, progressive multifocal leukoencephalopathy; TFTs, thyroid function tests; U&E, urea and electrolytes.

I want to reassure you that all licensed MS DMTs have undergone a thorough risk ̶ benefit assessment by the drug regulators, and the benefits of these treatments are considered to outweigh the potential risks. On balance, the level of immunosuppression associated with MS DMTs is typically mild to moderate; hence, the complications are relatively uncommon. MS is a serious disease and, if left to run its natural course, would result in most patients becoming disabled. To learn more about the natural course of MS, please read the section entitled What are the consequences of not treating MS?

DMTsSafety, Monitoring MS

‘De-risking’ guide: monitoring requirements of individual DMTs

Before you start taking a disease-modifying therapy (DMT), your MS team will carry out routine tests and investigations, many of which are repeated during subsequent monitoring or before switching to another DMT. The regulatory authorities that license the drugs specify their monitoring requirements. What gets monitored and how frequently depends on the individual DMT.

All licensed MS DMTs have undergone a thorough risk ̶ benefit assessment by the drug regulators, and the benefits of these treatments are considered to outweigh the potential risks. The table below summarises the main monitoring requirements of individual DMTs or DMT classes. For more detailed information, see the post on reducing your chances of adverse events.

AHSCT, autologous haematopoietic stem cell transplantation; CMV, cytomegalovirus; CSF, cerebrospinal fluid; EBV, Epstein ̶ Barr virus; ECG, electrocardiogram; HPV, human papillomavirus; JCV, JC virus; LVEF, left ventricular ejection fraction; MRI, magnetic resonance imaging; PML, progressive multifocal leukoencephalopathy.

DMTsShort

Mitoxantrone – short summary

Summary

Mitoxantrone is licensed to treat MS in a few countries (though not in the UK). It is typically used to treat active secondary progressive, progressive relapsing, or worsening relapsing remitting MS. It is a repurposed chemotherapy agent and is given as an intravenous infusion. Mitoxantrone is associated with quite severe toxicity (infections, cardiotoxicity, premature ovarian failure and secondary leukaemia) so it is not used often. In some countries, it is used as a true induction therapy followed by a maintenance DMT, typically interferon-beta or glatiramer acetate. Because mitoxantrone is toxic to the heart, a limited cumulative dose can be given safely over a lifetime. I have kept mitoxantrone on the list of essential DMTs because it is generic and hence is available for treating MS in resource-poor settings.

Trade name

Novantrone.

Mode of action

Mitoxantrone is an immune constitution therapy. It works by inhibiting the enzyme topoisomerase II which unwinds DNA. As a result, it disrupts DNA synthesis and DNA repair in cells and causes them to die. White blood cells are particularly sensitive to its actions.

Efficacy

High to very high.

Immunosuppression

Yes.

Infusion protocols

It is either given as a monthly infusion for 6 months, or every 3 months for up to 2 years, or as a combination of these two protocols. The total lifetime dose of mitoxantrone should not exceed 140 mg/m² and cardiac monitoring (ECG and ejection fraction) needs to be performed to detect any signs of cardiomyopathy.

Adverse events and special precautions

Infection: mitoxantrone causes a low white cell count that may result in increased susceptibility to infection. Chest infections and urinary tract infections are common. Broken skin or ingrown toenails may become areas harbouring infection. Neutropenia may develop and hence susceptibility to neutropenic sepsis, including infection with Listeria monocytogenes. Patients who are negative for varicella zoster virus should receive the VZV vaccine.

Nausea and vomiting (mild) may occur during treatment and the next day.

Hair thinning may occur temporarily. Hair loss is uncommon (occurring in fewer than 3% of people with MS who receive mitoxantrone).

Cardiotoxicity: a heart scan (MUGA or ECG) must be completed at baseline (before the first dose) and then 3-monthly before administration of the next dose. Mitoxantrone treatment may have to be stopped if the tests show a significant decrease in cardiac function.

Extravasation: pain and inflammation may occur along the path of a vein through which mitoxantrone is administered if the drug accidentally infiltrates the tissue outside the vein.

Leukaemia related to the drug is a risk in ~1 in 200–400 subjects with MS treated with mitoxantrone.

Infertility: transient lack of periods may occur in ~12% of patients and premature menopause in ~10% of patients.

Pregnancy and breastfeeding are contraindicated when using mitoxantrone.

Further details about mitoxantrone

Switching-2-mitoxantrone

Switching

Switching-2-mitoxantrone

Possible reasons to switch

  • The benefits of mitoxantrone may be greater than the potential risks from chronic immunosuppression or untreated MS in resource-poor environments.
  • Mitoxantrone is safer than other agents that are non-selective or less selective; this is relevant following treatment with ocrelizumab.
  • If mitoxantrone is available in your country, there is no reason why it cannot be used after any of the licensed DMTs, provided the baseline screening tests are within acceptable limits and there are no specific contraindications (please see individual DMTs below).

Reasons for caution

  • The presence of other specific comorbidities and adverse events.
  • The total lifetime dose should not exceed 140 mg/m².
  • Underlying cardiomyopathy (detected with ECG and echo/MUGA monitoring).
  • Low white cell counts post-alemtuzumab, -cladribine or –HSCT.
  • People with MS who have lymphopaenia on dimethyl fumarate may be more susceptible to prolonged lymphopaenia post-mitoxantrone.
  • Carry-over PML from natalizumab could be potentially fatal.
  • Patients with indwelling urinary catheters and/or recurrent urinary tract and other infections are at risk of infections post-mitoxantrone.

Mitoxantrone repeat course

As mitoxantrone is an immune reconstitution therapy (IRT), breakthrough activity may trigger the need for additional courses to be given, provided the total lifetime dose of mitoxantrone does not exceed 140 mg/m² and that cardiac monitoring (ECG and echo/MUGA) does not show signs of underlying cardiomyopathy.

Other DMTs

Mitoxantrone is licensed in the USA and in some European countries (though not the UK). Provided the baseline screening tests are acceptable and there are no specific contraindications, it is feasible (from a clinical perspective) to use mitoxantrone after another licensed DMT; please check the licensing regulations in your country.

Interferon-beta and glatiramer acetate

There are no specific cautions.

S1P modulators (fingolimod, siponimod, ozanimod and ponesimod)

The development of mitoxantrone-related cardiomyopathy and/or cardiac arrhythmia is a contraindication for using fingolimod and other S1P modulators (siponimod, ozanimod and ponesimod) after mitoxantrone. It is important to be extra-vigilant when doing the routine baseline cardiac checks post-mitoxantrone. If it has been some time since mitoxantrone’s last dose, I recommend checking a cardiac ejection fraction with echocardiography or a MUGA scan.

Alemtuzumab and HSCT (non-selective cell depleting DMTs)

A persistently low peripheral white cell count post-alemtuzumab, HSCT or other DMT, i.e. a neutrophil count < 1000/mm³ or a total lymphocyte count <800/mm³ is a relative contraindication to using mitoxantrone. Another hit on the bone marrow and primary and secondary lymphoid organs may render an individual more immunosuppressed and worsen their leukopaenia. The decision to use mitoxantrone in this situation has to be based on the potential benefits versus the risks of these treatments and the risks of untreated active MS. 

Cladribine (selective cell depleting DMT)

A persistently low peripheral lymphocyte cell count post-cladribine, i.e. a total lymphocyte count <800/mm³ is a relative contraindication to using mitoxantrone. The effect of mitoxantrone on primary and secondary lymphoid organs may worsen the lymphopaenia and is a risk factor for developing grade 3 or grade 4 lymphopaenia, i.e. <500/mm³ or <200/mm³, respectively. However, the decision to use mitoxantrone in this situation has to be based on the potential benefits of the treatment versus the risks of lymphopaenia and the risks of untreated active MS.

Anti-CD20 therapies (selective cell depleting DMTs)

Anti-CD20 therapies (ocrelizumab, ofatumumab and others) are selective B-cell depleting agents, so mitoxantrone is theoretically much safer than the other less selective and non-selective agents post-ocrelizumab.

Natalizumab

As mitoxantrone is an IRT that can’t be rapidly reversed, it is critical to ensure that there is no asymptomatic PML. Carry-over PML from natalizumab to mitoxantrone is potentially fatal. Therefore, a baseline MRI scan and possibly a CSF examination is essential to exclude the possibility of PML before starting mitoxantrone. 

Dimethyl fumarate

DMF reduces the lymphocyte count by approximately 30% and in some people with MS by more than this. Therefore, individuals with lymphopaenia on DMF may be more susceptible to developing clinically significant prolonged lymphopaenia post-mitoxantrone.

Teriflunomide

Because teriflunomide is an antiproliferative agent, it may delay or prevent the recovery of the peripheral white cell count post-mitoxantrone. One option is to do an accelerated teriflunomide washout to prevent this potential problem. Interestingly, rheumatologists who use leflunomide, a prodrug converted to teriflunomide, don’t use an accelerated washout when using antiproliferative agents post-leflunomide. I, therefore, don’t think an accelerated washout is necessary.

Special circumstances

The presence of other specific comorbidities and adverse events may make it difficult to start mitoxantrone after another DMT. 

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.