Tag Archives: teriflunomide

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.
DMTsShort

Teriflunomide – short summary

Summary

Teriflunomide is a moderately effective platform therapy for treating active MS; it reduces the relapse rate by ~30% and slows the acquisition of disability to a similar degree. It reduces magnetic resonance imaging (MRI) activity by ~70% and slows down brain volume loss, but not to the same degree as highly effective DMTs. Teriflunomide is licensed as a first-line therapy in the UK. It is taken as a daily 14 mg tablet. Although teriflunomide inhibits cell proliferation, it is not an immunosuppressive agent and is classified as an ‘immunomodulatory therapy’.

Teriflunomide has not been associated with opportunistic infections, secondary malignancies, a blunted antibody response to vaccines or lymphopaenia (low lymphocyte counts). Low lymphocyte counts occur in only a small minority of people with MS. In general, teriflunomide is well tolerated, with only a small number of people with MS (< 5%) developing abnormal liver function tests or gastrointestinal symptoms (mainly diarrhoea) that result in them having to stop the therapy. Teriflunomide can cause mild hair thinning that is transient; please note this is not alopecia or baldness and, in my experience, is not a problem for people with MS taking the drug.

Teriflunomide is considered to be potentially teratogenic, i.e. it has the potential to cause foetal abnormalities when women fall pregnant on the drug, which makes it unsuitable for women of childbearing age who are planning to start, or extend, their families. Teriflunomide has a long half-life and hence stays in the body for months. There is a rapid elimination procedure that can remove teriflunomide from the body within days. When teriflunomide is started, the European Medicines Agency (EMA) requires blood monitoring every 4 weeks for 6 months and 2 monthly thereafter. I think these requirements are excessive; many neurologists use the American guidelines, which stipulate monthly tests for 6 months and regularly after that.

It has been difficult to use teriflunomide in the UK, on the NHS, because of its monitoring requirements and associated costs. In clinical practice, teriflunomide seems to be much more effective than suggested by the clinical trial results, which may explain its popularity in other countries. Interestingly, people who start teriflunomide as a second-line or third-line DMT do better than those using it first-line. I have no idea why teriflunomide is more effective after people with MS have failed other DMTs; it may have something to do with its alternative modes of action, for example, its antiviral effects.

Trade name

Aubagio.

Mode of action

Mainly by inhibiting the enzyme dihydroorotate dehydrogenase (DHODH) which affects pyrimidine metabolism in cells.

Efficacy

Moderate.

Class

Maintenance, immunomodulatory.

Immunosuppression

No.

Dosing

14 mg once daily. USA only: 7 mg/day tablet is also licensed (elsewhere, you can take 14 mg tablet on alternate days).

Main adverse events and monitoring requirements 

Raised liver enzymes, particularly in people with pre-existing liver disease; possible high blood pressure; rarely, severe hypersensitivity skin reactions.

Liver enzyme assessments every two weeks for 6 months and every 8 weeks thereafter.

Rebaseline MRI scan, ideally after 6 months of treatment.

Pregnancy and breastfeeding: effective contraception is essential while on treatment and during drug elimination before conception. Breastfeeding is contraindicated.

Further details about teriflunomide

Switching-2-teriflunomide

DMTsDetail

Teriflunomide

Summary

Teriflunomide is a moderately effective platform therapy for treating active MS; it reduces the relapse rate by ~30% and slows the acquisition of disability to a similar degree. It reduces magnetic resonance imaging (MRI) activity by ~70% and slows down brain volume loss, but not to the same degree as highly effective DMTs. Teriflunomide is licensed as a first-line therapy in the UK. It is taken as a daily 14 mg tablet. Although teriflunomide inhibits cell proliferation, it is not an immunosuppressive agent and is classified as an ‘immunomodulatory therapy’.

Teriflunomide has not been associated with opportunistic infections, secondary malignancies, a blunted antibody response to vaccines or lymphopaenia (low lymphocyte counts). Low lymphocyte counts occur in only a small minority of people with MS. In general, teriflunomide is well tolerated, with only a small number of people with MS (< 5%) developing abnormal liver function tests or gastrointestinal symptoms (mainly diarrhoea) that result in them having to stop the therapy. Teriflunomide can cause mild hair thinning that is transient; please note this is not alopecia or baldness and, in my experience, is not a problem for people with MS taking the drug.

Teriflunomide is considered to be potentially teratogenic, i.e. it has the potential to cause foetal abnormalities when women fall pregnant on the drug, which makes it unsuitable for women of childbearing age who are planning to start, or extend, their families. Teriflunomide has a long half-life and hence stays in the body for months. There is a rapid elimination procedure that can remove teriflunomide from the body within days. When teriflunomide is started, the European Medicines Agency (EMA) requires blood monitoring every 4 weeks for 6 months and 2 monthly thereafter. I think these requirements are excessive; many neurologists use the American guidelines, which stipulate monthly tests for 6 months and regularly after that.

It has been difficult to use teriflunomide in the UK, on the NHS, because of its monitoring requirements and associated costs. In clinical practice, teriflunomide seems to be much more effective than suggested by the clinical trial results, which may explain its popularity in other countries. Interestingly, people who start teriflunomide as a second-line or third-line DMT do better than those using it first-line. I have no idea why teriflunomide is more effective after people with MS have failed other DMTs; it may have something to do with its alternative modes of action, for example, its antiviral effects.

Trade name

Aubagio.

Mode of action

Teriflunomide probably has several modes of action but mainly works by inhibiting an enzyme called dihydroorotate dehydrogenase (DHODH) which affects pyrimidine metabolism in cells. This inhibits cell division, so it is called an antiproliferative agent. It is thought to work in a similar way in MS, by reducing the proliferation of activated lymphocytes. Teriflunomide also has broad-spectrum activity against many viruses.

Efficacy

Moderate. It is licensed in the UK as a platform or first-line therapy for people with active MS.

Class

Maintenance, immunomodulatory.

Immunosuppression

No.

Dosing

The recommended dose of teriflunomide is 14 mg once daily, but 7 mg/day has also been shown to be effective. In the USA, both the 7 mg and the 14 mg doses of teriflunomide are licensed. Outside the USA, only the 14 mg dose is licensed.

The 14 mg dose was superior to the 7 mg dose on several outcomes in the phase 3 trials. In general, 7 mg is prescribed to people with MS who can’t tolerate the higher 14 mg dose because of gastrointestinal symptoms or other blood abnormalities. Outside the USA, where the 7 mg tablet is unavailable, you can take the 14 mg tablet on alternate days. Splitting the tablet is not easy because it is not scored, and doing so breaks the enteric coating.

The half-life of teriflunomide is very long, so alternate-day dosing is fine. Teriflunomide can be taken with or without food.

Main adverse events

Liver

Elevations of liver enzymes have been observed on teriflunomide. These are seen within the first 6 months of treatment. People with MS with pre-existing liver disease or those who consume excessive quantities of alcohol may be at increased risk of developing elevated liver enzymes on teriflunomide.

Blood pressure

High blood pressure may occur during treatment with teriflunomide.

Infections

No increase in serious infections has been observed with teriflunomide. The safety of teriflunomide in people with MS with latent tuberculosis (TB) is unknown, which is why I recommend screening for TB infection before starting teriflunomide.

Lung

Interstitial lung disease has been rarely reported in people with MS on teriflunomide. Therefore, any new onset or worsening breathing or chest problems, such as persistent cough and shortness of breath, need to be investigated.

Blood

Teriflunomide causes a small (~15% ) drop in the number of circulating white blood cells, but not sufficient to cause any problems. In a few people with MS (<5%) the drop may be more profound and require them to stop taking the medication.

Skin

A few cases of severe hypersensitivity skin reactions have been reported on teriflunomide, including Stevens-Johnson syndrome, toxic epidermal necrolysis and a condition called DRESS (drug reaction with eosinophilia and systemic symptoms). Please look out for any skin rash.

Neuropathy

Rare cases of peripheral neuropathy have been reported in people with MS on teriflunomide. Please watch out for tingling sensations and/or loss of feeling in the toes and fingers; these adverse events tend to be symmetrical, which helps differentiate them from MS symptoms.

Neutralizing antibodies (NAbs)

NAbs are not a problem on teriflunomide because it is a small molecule and not a biological (protein) therapy.

Pharmacovigilance monitoring requirements 

Baseline

Full blood count, urea and electrolytes, liver function tests, thyroid function tests, serum immunoglobulin levels, serology (varicella zoster virus, human immunodeficiency virus 1 and 2, hepatitis B and C, TB ELISpot, up-to-date cervical smear and/or human papillomavirus testing, a pregnancy test and baseline blood pressure are done.

Follow-up

Liver enzymes should be assessed every 4 weeks during the first 6 months of treatment and regularly thereafter or as indicated by clinical signs and symptoms such as unexplained nausea, vomiting, abdominal pain, fatigue, loss of appetite, or jaundice and/or dark urine. Full blood cell counts need only be performed every 6 months or if you develop an infection on treatment.

Rebaselining

A rebaseline MRI scan needs to be done after teriflunomide has had sufficient time to work. I recommend that an MRI is done 6 months after starting treatment and that Gd-enhancement is included as part of the rebaselining MRI.

Women of childbearing potential and pregnancy

If you are a woman of childbearing age, before starting teriflunomide treatment I would recommend a negative pregnancy test result. Teriflunomide is potentially teratogenic, i.e. it can cause birth defects; therefore, you must have effective contraception whilst on treatment. It takes many months to eliminate teriflunomide from the body. Therefore, on stopping treatment the potential risk to the foetus may persist, and contraception should be continued during the drug elimination period, or you should undergo the rapid elimination procedure. If there is any delay in the onset of your period (menses) or any other reason for suspecting pregnancy, you must notify your nurse or doctor immediately and undergo pregnancy testing. If pregnant, it is possible to rapidly lower the blood level of teriflunomide by instituting the accelerated elimination procedure. If you do fall pregnant whilst on teriflunomide, we would not automatically recommend termination of pregnancy but, rather, refer you to a high-risk antenatal clinic for counselling and foetal screening. Many babies exposed to teriflunomide in the womb have been born without overt problems.

Breastfeeding

Teriflunomide is excreted into the breast milk of lactating women and has the potential for adverse reactions in nursing infants, so women on teriflunomide should not breastfeed.

Fertility

There is no evidence that teriflunomide affects either male or female fertility.

Male fertility

The risk of toxicity to the embryo through teriflunomide affecting the sperm is low. Animal studies have shown no evidence that teriflunomide adversely affects male fertility or damages sperm. Despite this, some regulatory authorities have recommended that men wishing to father a child discontinue teriflunomide treatment and undergo the accelerated elimination procedure. However, the EMA does not recommend this. Based on the data, I don’t recommend that men with MS wanting to start or extend a family stop teriflunomide or take any specific precautions.

Vaccination

Two clinical studies have shown that vaccination with component or inactivated vaccines was safe and effective whilst on teriflunomide. However, the use of live attenuated vaccines may carry a risk of infections and – based on the current recommendation – should be avoided.

Travel

People with MS need to be aware that being on teriflunomide may affect travel; for example, some countries require you to be vaccinated against yellow fever, which is a live attenuated vaccine and hence contraindicated.

Summary of Product Characteristics (SmPC)

Aubagio.

Accelerated elimination

An accelerated elimination procedure may be needed to eliminate teriflunomide from the body very quickly. This is typically done for women of childbearing age who want to fall pregnant or have fallen pregnant. It may also be done when switching treatments.

After stopping treatment with teriflunomide:

  1. Cholestyramine 8 g is administered three times daily for 11 days; alternatively, cholestyramine 4 g three times daily can be used but only if cholestyramine 8 g three times a day is not well tolerated.
  2. Alternatively, 50 g of activated powdered charcoal is administered every 12 hours for 11 days.

For women wanting to fall pregnant, the effectiveness of the accelerated elimination procedure can be verified by two tests at least 14 days apart to determine the plasma concentration of teriflunomide. Once this falls below 0.02 mg/l, a waiting period of one-and-a-half months is required before fertilisation can be advised.

Please note that cholestyramine and activated powdered charcoal may influence the absorption of oestrogens and progestogens. Since the oral contraceptive pill cannot be guaranteed reliable during the accelerated elimination procedure, an alternative contraceptive method is recommended.

Switching-2-teriflunomide

Interferon and glatiramer acetate

In general, teriflunomide can be started immediately after discontinuation of interferon or glatiramer acetate. It is important that all the recommended baseline screening tests and vaccination reviews are done before starting teriflunomide.

Natalizumab

Owing to the risk of rebound activity on stopping natalizumab, a prolonged wash-out period is not recommended before starting teriflunomide. Most often the reason for switching from natalizumab to teriflunomide, or another DMT, is to reduce the risk of carry-over PML (progressive multifocal leukoencephalopathy) from natalizumab. In our centre, we do an MRI and a lumbar puncture for cerebrospinal fluid analysis to exclude JC virus-DNA on polymerase chain reaction testing. Provided these two tests are clear, we would typically initiate teriflunomide as soon as possible after the last natalizumab infusion. We tend, however, not to use teriflunomide post-natalizumab because the data demonstrating that teriflunomide can prevent rebound activity is not as strong as for fingolimod and anti-CD20 therapies. All the recommended baseline screening tests and vaccination reviews must be done before starting teriflunomide.

S1P modulators (fingolimod, siponimod, ozanimod and ponesimod)

Because fingolimod has quite a long half-life, some neurologists recommend a short washout period, i.e. 4 ̶ 6 weeks; this may be appropriate, depending on the reason for switching. I recommend waiting for the total peripheral lymphocyte counts to go above 800/mm3 to exclude the uncommon occurrence of persistent lymphopaenia following S1P modulator administration. It is important that all the recommended baseline screening tests and vaccination reviews are done before starting teriflunomide. If you are switching because of abnormal liver function tests on a S1P modulator, you would ideally want the liver enzymes to normalise or at least drop to below three times the upper limit of normal before starting teriflunomide.

Fumarates

It is important that all the recommended baseline screening tests and vaccination reviews are done before starting teriflunomide. If lymphopaenia is the main reason for switching from a fumarate, I recommend waiting for the total peripheral lymphocyte counts to go above 800/mm3.

Alemtuzumab

It is important that all the recommended baseline screening tests and vaccination reviews are done before starting teriflunomide. I recommend waiting for the total peripheral lymphocyte counts to go above 800/mm3 before starting teriflunomide.

Anti-CD20 therapies (selective cell depleting DMTs)

It is important that all the recommended baseline screening tests and vaccination reviews are done before starting teriflunomide.

Cladribine (selective cell depleting DMT)

It is important that all the recommended baseline screening tests and vaccination reviews are done before starting teriflunomide. I recommend waiting for the total peripheral lymphocyte counts to exceed 800/mm3.

Mitoxantrone

I recommend waiting for the neutrophil and total peripheral lymphocyte counts to go above 1,000/mm3 and 800/mm3, respectively. All the recommended baseline screening tests and vaccination reviews must be done before starting teriflunomide.

HSCT

I recommend waiting for the neutrophil and total peripheral lymphocyte counts to go above 1,000/mm3 and 800/mm3, respectively. All the recommended baseline screening tests must be done before starting teriflunomide.

Switching

Switching-2-teriflunomide

Possible reasons to switch

  • Teriflunomide reduces the relapse rate and acquisition of disability by ~30%.
  • It reduces MRI activity by ~70% and slows down brain volume loss.
  • It is not immunosuppressive; no increase in serious infections has been observed with teriflunomide.
  • Teriflunomide is not associated with a blunted antibody response to vaccines or low lymphocyte counts.
  • People who start teriflunomide as a second-line or third-line DMT do better than those using it first-line; the reason for this is unclear.

Reasons for caution

  • The European Medicines Agency (EMA) requires blood monitoring to be done every 4 weeks for 6 months and regularly after that when teriflunomide is started.
  • People with pre-existing liver disease or those who consume excessive quantities of alcohol may be at increased risk of developing elevated liver enzymes on teriflunomide.
  • It is unsuitable for women of childbearing age who are planning to start, or extend, their families. Women on teriflunomide should not breastfeed.
  • It takes many months to eliminate teriflunomide from the body on stopping treatment; therefore, contraception must be continued during the drug elimination period.
  • Severe hypersensitivity skin reactions have been reported on teriflunomide; please look out for any skin rash.

Interferon and glatiramer acetate

In general, teriflunomide can be started immediately after discontinuation of interferon or glatiramer acetate. It is important that all the recommended baseline screening tests and vaccination reviews are done before starting teriflunomide.

Natalizumab

Owing to the risk of rebound activity on stopping natalizumab, a prolonged wash-out period is not recommended before starting teriflunomide. Most often the reason for switching from natalizumab to teriflunomide, or another DMT, is to reduce the risk of carry-over PML (progressive multifocal leukoencephalopathy) from natalizumab. In our centre, we do an MRI and a lumbar puncture for cerebrospinal fluid analysis to exclude JC virus-DNA on polymerase chain reaction testing. Provided these two tests are clear, we would typically initiate teriflunomide as soon as possible after the last natalizumab infusion. We tend, however, not to use teriflunomide post-natalizumab because the data demonstrating that teriflunomide can prevent rebound activity is not as strong as for fingolimod and anti-CD20 therapies. All the recommended baseline screening tests and vaccination reviews must be done before starting teriflunomide.

S1P modulators (fingolimod, siponimod, ozanimod and ponesimod)

Because fingolimod has quite a long half-life, some neurologists recommend a short washout period, i.e. 4 ̶ 6 weeks; this may be appropriate, depending on the reason for switching. I recommend waiting for the total peripheral lymphocyte counts to go above 800/mm3 to exclude the uncommon occurrence of persistent lymphopaenia following S1P modulator administration. It is important that all the recommended baseline screening tests and vaccination reviews are done before starting teriflunomide. If you are switching because of abnormal liver function tests on a S1P modulator, you would ideally want the liver enzymes to normalise or at least drop to below three times the upper limit of normal before starting teriflunomide.

Fumarates

It is important that all the recommended baseline screening tests and vaccination reviews are done before starting teriflunomide. If lymphopaenia is the main reason for switching from a fumarate, I recommend waiting for the total peripheral lymphocyte counts to go above 800/mm3.

Alemtuzumab

It is important that all the recommended baseline screening tests and vaccination reviews are done before starting teriflunomide. I recommend waiting for the total peripheral lymphocyte counts to go above 800/mm3 before starting teriflunomide.

Anti-CD20 therapies (selective cell depleting DMTs)

It is important that all the recommended baseline screening tests and vaccination reviews are done before starting teriflunomide.

Cladribine (selective cell depleting DMT)

It is important that all the recommended baseline screening tests and vaccination reviews are done before starting teriflunomide. I recommend waiting for the total peripheral lymphocyte counts to exceed 800/mm3.

Mitoxantrone

I recommend waiting for the neutrophil and total peripheral lymphocyte counts to go above 1,000/mm3 and 800/mm3, respectively. All the recommended baseline screening tests and vaccination reviews must be done before starting teriflunomide.

HSCT

I recommend waiting for the neutrophil and total peripheral lymphocyte counts to go above 1,000/mm3 and 800/mm3, respectively. All the recommended baseline screening tests must be done before starting teriflunomide.

Pregnancy and childbirth, Women's health

Breastfeeding if you are on a DMT

This section explains how relapse is managed during breastfeeding and provides detailed guidance on which DMTs are safe (or not safe) to use while breastfeeding.

Will I be able to breastfeed after delivery?

Yes, I see no reason why you can’t breastfeed if you have MS. However, certain DMTs cross over into the breast milk and may affect the baby; these include teriflunomide, cladribine and S1P modulators (fingolimod, siponimod, ozanimod and ponesimod). Although monoclonal antibodies (natalizumab, ocrelizumab, ofatumumab, rituximab) cross over in small amounts, the levels are generally too low to affect the newborn. In addition, the level of the antibodies will likely be further reduced by their digestion as proteins in the baby’s intestinal tract.

Please be aware that most DMTs are licensed with no breastfeeding safety data. Hence, the information in the manufacturer’s Summary of Product Characteristics (SmPC) is not the same as that given to you by neurologists and other HCPs. For example, SmPC information for the fumarates (dimethyl fumarate and diroximel fumarate) states:

“It is unknown whether dimethyl fumarate or its metabolites are excreted in human milk. A risk to the newborns/infants cannot be excluded. A decision must be made whether to discontinue breastfeeding or to discontinue Tecfidera therapy. The benefit of breastfeeding for the child and the benefit of therapy for the woman should be taken into account.”

This is very unhelpful as their active compound, monomethyl fumarate, is a naturally occurring metabolite compounded with many other medications considered safe in pregnancy, e.g. ferrous fumarate, an iron supplement. This is why I tell my female patients on fumarates they can breastfeed without concern for their baby.

We normally don’t recommend alemtuzumab treatment during breastfeeding simply because it carries the risk of listeriosis and infusion reactions, and the medications used to prevent these adverse events cross over into breast milk. In addition, the acute immunosuppression associated with alemtuzumab may increase the risk of breast infections. In general, I advise my female patients to breastfeed for 4 ̶ 6 weeks to give the baby the health benefits of breastfeeding and then to start or be retreated with alemtuzumab after this period.

For cladribine, it is important not to breastfeed whilst being dosed with the drug and for 10 days after the last pill. The recommended 10-day requirement is probably a bit long as cladribine is undetectable in the body after 48 ̶ 72 hours. In my experience, the requirement of a 14- or 15-day gap (4 or 5 days of dosing plus an additional 10 days) in breastfeeding is hard; therefore, most women who want to be treated with cladribine either delay treatment until they have completed breastfeeding or breastfeed for 4 ̶ 6 weeks before stopping and being treated with cladribine.

Breastfeeding

Guidance for women who are considering whether it is safe to breastfeed while taking a specific DMT.

I am aware that many women feel pressured into breastfeeding. However, if you are anxious about having MS rebound post-partum, deciding not to breastfeed and starting or resuming your DMT as soon as possible is not unreasonable. The decision is a personal choice.

How is a relapse managed during breastfeeding?

In the event of a relapse during breastfeeding, a short course of high-dose corticosteroids can be considered. Methylprednisolone – the steroid often used to manage MS relapses – is transferred into breast milk. However, the amount an infant is exposed via breast milk is low (equivalent to less than 1% of the adult dose). Some clinicians recommend women breastfeed before a steroid infusion, express breast milk 1 ̶ 2 hours after the infusion and discard it, to limit the baby’s exposure to methylprednisolone. I don’t think this is necessary.

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
Planning for pregnancy
Managing MS during pregnancy
Preparing to give birth
Concerns about parenting

Pregnancy and childbirth, Women's health

Managing MS during pregnancy

Opinion on how MS impacts pregnancy is based largely on data that predate the current era of active treatment and the newer generation of disease-modifying therapies (DMTs). In this section I have therefore addressed many of the important issues that women who are considering pregnancy need to understand, including:

  • the effect of pregnancy on the course of MS
  • how to manage relapse during pregnancy
  • the role of naturally occurring interferon-beta and its possible implications for women with MS taking therapeutic interferon-beta
  • management of MS symptoms and morning sickness during pregnancy
  • the crucial issue of DMT safety and possible teratogenic effects on the developing foetus.

Will pregnancy affect the course of my MS?

Yes, pregnancy effects on MS have been observed at a group level, though it is difficult to notice changes in individuals. It is well known that MS attack rates drop during the second and third trimesters of pregnancy and relapses rebound again in the first 6 months after delivery. However, only a minority of women with MS have post-partum relapses. Breastfeeding may blunt the post-partum rebound, but this is not absolute. Therefore, most neurologists now recommend starting or restarting DMTs soon after delivery to try and prevent post-partum relapses.

At a population level, the more children you have, the better your overall prognosis. This effect is small and is based on studies done in the pre-DMT era. It may be due to the immunological effects of pregnancy that work like a DMT in MS. Immunologists have tried to understand this phenomenon in the hope of developing treatments for MS that mimic the pregnancy state.

How is a relapse managed during pregnancy?

In the event of having a relapse during pregnancy, a short course of high-dose corticosteroids can be considered. However, I limit using steroids to disabling and/or severe relapses, especially early in the first trimester, as there is a small risk of orofacial abnormalities (cleft lip and palate) and reduced birth weight from exposure of the developing foetus to high-dose steroids. There is also a risk of precipitating gestational diabetes in women receiving high doses of steroids during pregnancy. In the rare situation of a severe relapse unresponsive to high-dose steroids, plasma exchange may need to be considered.

Could neutralising antibodies to therapeutic interferon-beta affect my baby?

Naturally occurring interferon-beta is a cytokine (cell-signalling agent) produced by the body to help fight infections. As there is only one human interferon-beta, antibodies to therapeutic interferon-beta (IFN-beta) will neutralise the body’s own natural interferon-beta. If you are taking IFN-beta for your MS, there is thus a theoretical risk that neutralising antibodies (NABs) to the DMT might cross the placenta and affect the role of human interferon-beta in foetal development.

Interferon-beta is important for innate immunity and neutralising your own interferon-beta may put you at risk of getting viral infections. Interferon-beta also plays a role in foetal bone development, but the placenta does not mature in relation to immunoglobulin transfer until near the end of the second trimester of pregnancy, so it is unlikely that sufficient NABs cross the blood ̶ placental barrier to affect foetal bone development. However, in the third trimester, NABs will cross over the placenta into the foetal circulation and may impact the baby’s innate immunity. Despite these theoretical concerns, there is no indication from published data to support these potential adverse effects of NABs on IFN-beta.

If I fall pregnant while on a DMT, will this affect the baby?

This depends on which DMT you are taking and what you mean by ‘affecting the baby’. We worry most about teratogenic effects, which describe congenital malformations. Teriflunomide, S1P modulators and cladribine are generally classified as drugs that may be teratogenic, and hence precautions need to be taken so as not to fall pregnant on these agents. Foetal malformations usually occur very early in foetal development, often before the woman knows she is pregnant; therefore, it is difficult to do anything about it once foetal exposure occurs. Despite this, even for women who are on these agents and fall pregnant, we don’t automatically recommend termination of pregnancy. We refer them to the high-risk pregnancy clinic to discuss the options with an obstetrician. Many women continue their pregnancies with an uneventful outcome and a normal baby. On the other hand, some women choose the option of terminating their pregnancy.

A large amount of data from MS pregnancy registries and post-marketing surveillance indicates no increased risk of major congenital anomalies or spontaneous abortions (miscarriages) after exposure to interferon-beta or glatiramer acetate. Most neurologists are, therefore, comfortable with their female patients falling pregnant on these agents, continuing the treatment through pregnancy and then breastfeeding their babies.

Fumarates (dimethyl fumarate [Tecfidera], diroximel fumarate [Vumerity]) are not teratogenic and are unlikely to have a negative impact on pregnancy outcomes. We need more data from registries and post-marketing surveillance before we can be confident that the fumarates are safe during pregnancy. However, these agents are prodrugs and converted to monomethyl fumarate, which is part of our metabolism, so it is very unlikely that the fumarates will cause problems. I don’t have an issue with women falling pregnant on the fumarates and continuing them through pregnancy, but there is conflicting advice about this.

Should I continue taking drugs for my MS symptoms during pregnancy?

Yes and no. It depends on what the medications are for and whether they are safe during pregnancy. Ideally, you should wean off any symptomatic therapies or at least change to alternative medications that are safe to take during pregnancy. It is important to try and plan your pregnancy and if necessary be referred to a special medical pregnancy clinic so that these issues can be addressed. Many women with MS find that their MS-related symptoms improve during pregnancy, and they can do without symptomatic therapies. However, unless you are prepared to wean yourself off symptomatic therapies you won’t know.

Physical therapies should be continued during pregnancy. One could argue that everyone with MS should be physically active and do pelvic floor exercises. Pregnancy and childbirth may impact bladder and bowel function, so it is important to see a pelvic floor therapist to start pelvic floor exercises. The latter are taught to women in antenatal classes.

How do you treat morning sickness or hyperemesis gravidarum during pregnancy?

Treating morning sickness or hyperemesis gravidarum is no different in women with MS than in the general population. It involves hydration, vitamin supplements (in particular, thiamine) and the judicious use of antiemetics (for example, cyclizine, prochlorperazine, promethazine, chlorpromazine, metoclopramide and domperidone). If the vomiting extends into the second trimester, ondansetron can be used. In very severe cases of morning sickness, steroids may be required; for example, hydrocortisone 100 mg twice daily can be converted to prednisolone 40 ̶ 50 mg daily by mouth, which can then be tapered to the lowest level that still controls symptoms. For patients taking a fumarate, try and take your medication later in the morning when you are less likely to vomit.

What dose of vitamin D do you advise during pregnancy?

During pregnancy vitamin D requirements are increased and I recommend doubling the dose for supplementation from 4,000 IU of vitamin D3 to 8,000 IU per day. At the same time, women who are pregnant should be on iron and folate supplements that should ideally be started before falling pregnant.

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
Planning for pregnancy
Preparing to give birth
Breastfeeding if you are on a DMT
Concerns about parenting

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

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

Am I eligible for an MS disease-modifying therapy?

Key points

Do you know the eligibility criteria for MS disease-modifying therapies? And who decides what drugs can be prescribed for your MS?

  • Disease-modifying treatments (DMTs) change the long-term trajectory of MS and protect the central nervous system from further damage.
  • Regulators such as the European Medicines Agency (EMA) and the Federal Drug Administration (FDA) decide in which group(s) of patients a particular drug can be used, based on the results of clinical trials.
  • Once a drug has been licensed in your region, local payers decide whether to make it available within your country, based on cost-effective assessments.
  • If you have active MS, your level of disease activity, its severity and speed of development will determine which DMTs you can be offered.
  • In some countries, ocrelizumab has been approved for the treatment of active primary progressive MS (PPMS) and siponimod has been approved for the treatment of active secondary progressive MS.
  • Protecting upper limb function has been a neglected area; studies are now ongoing, however, with a view to finding DMTs that limit the progression of upper limb disability.

What do disease-modifying drugs do?

Disease-modifying therapies (DMTs) are treatments that change the natural history – that is, the long-term trajectory – of the disease. They reduce the rate of disability worsening and so protect the end-organ (in the case of MS, this is the central nervous system). To simplify, let’s say that a person with MS on no treatment may manage for an average of 18-20 years before needing to use a walking stick (corresponding to Expanded Disability Status Scale [EDSS] 6.0), while someone on treatment might manage without aid for 24 years, i.e. a 4-6-year delay, then the treatment can be called disease-modifying. (Please note, the treatment effect or 4-6-year delay in reaching EDSS 6.0 is an average and some people with MS will do better than others. Conversely, some will do worse than average.) 

Is interferon a DMT?

In the early days of interferon therapy, there was debate about whether simply reducing the relapse rate by 30% relative to placebo treatment, without slowing down the worsening of the disease over 2 years, was disease-modification. However, subsequent trials and follow-up of people with MS treated with interferon-beta showed a slowing down of disease worsening, delays in developing secondary progressive MS and a favourable impact on survival.1 

Do symptomatic treatments modify the disease?

Symptomatic treatments improve the symptoms associated with MS without affecting the natural history. Treatments are classified as symptomatic in relation to their mode of action; but some classes of treatment may yet prove to be disease-modifying. For example, we often use sodium channel blocking agents, such as phenytoin, carbamazepine, oxcarbazepine and lamotrigine, for MS-related neuralgia and other pain syndromes. However, there is evidence that this class of therapy may be neuroprotective and hence disease-modifying. 

Who decides on eligibility for a licensed DMT?

Regulators decide in which group of people with MS the DMT can be used, and they grant a licence for its use. Regulators include the EMA, the FDA and the Medicines and Healthcare products Regulatory Agency (MHRA in the UK).

Payers hold the purse strings and decide which licensed drugs to make available. They makecost-effectiveness assessments to try and optimise the use of the drug in clinical practice. Payers include medical insurance companies and the NHS in the UK. 

Guidelines are formulated to help healthcare professionals use DMTs in the most appropriate way within a particular healthcare system. Guidelines often go much further than the regulators and payers, in that they try to address potential ambiguities in the prescribing of DMTs. National, regional or local guidelines that provide expert clinical guidance include the UK NICE (National Institute for Health and Care Excellence) MS management guidelines and the Association of British Neurologists guidelines. 

In the NHS in England, we must abide by NHS England’s algorithm that is predominantly based on NICE technology appraisals, NICE standards of care and the Association of British Neurologists guidelines. To navigate the specifics of the eligibility criteria is quite complex. However, a simpler way of looking at this is to start by defining how active your MS is. 

How does disease activity affect my treatment options?

To be eligible for DMTs, you must have active MS. A summary of the four categories of disease activity is given below. Further details can be found in the section entitled Do I have active MS?

  1. Inactive MS – you are not currently eligible for DMTs.
  2. Active MS – you should be eligible for a so-called platform therapy (interferon-beta, glatiramer acetate, teriflunomide, dimethyl fumarate or ponesimod) and ocrelizumab or ofatumumab.
  3. Highly active MS – you are eligible for all therapies except natalizumab. Please note in England fingolimod can only be used as a second-line therapy (after another DMT has failed).
  4. Rapidly evolving severe MS – you should be eligible for all DMTs.

Advanced or progressive MS

Ocrelizumab and siponimod are now approved in several countries for the treatment of active PPMS and active SPMS, respectively. A classification of active PPMS requires recent MRI evidence of disease activity, that is, the formation of new T2 lesions and/or the presence of gadolinium-enhancing lesions in the last 3 years. Active SPMS is confirmed by the occurrence of superimposed relapses and/or the presence of new T2 lesions and/or gadolinium-enhancing lesions in the last 2 years. Based on these very narrow definitions, most patients with PPMS and SPMS will not be eligible for ocrelizumab or siponimod, respectively. The differences between the MRI criteria for active PPMS and active SPMS reflect the reality that people with PPMS are less likely to be having regular monitoring MRI scans.

Stages of MS currently not eligible for treatment

In the UK, people with MS who are wheelchair users are not eligible for DMTs. The reason for this is that patients with more advanced MS have generally been excluded from phase 3 clinical trials; hence there are no data to show whether licensed DMTs are effective in this group.

There is a long-held view that inflammation is reduced or absent in advanced MS. However, clinical, imaging and pathological data show that inflammation still plays a large, and possibly a major, role in advanced MS. Therefore, not targeting more advanced MS with an anti-inflammatory is counterintuitive.

The importance of upper limb function

In 2016, the #ThinkHand campaign was launched to raise awareness of the importance of hand and arm function in people with MS and the need for clinical trials in this population. Studies currently ongoing that focus on limiting upper limb disability progression include ChariotMS (oral cladribine)2 in people with advanced MS (UK only) and the global, multicentre O’HAND trial  (ocrelizumab)3 in participants with PPMS. 

Once someone with MS becomes a wheelchair user, they still have neuronal systems that are potentially modifiable – for example, upper limb, bulbar (speech and swallowing), cognition and visual function. There is an extensive evidence base showing that several licensed DMTs can slow the worsening of upper limb function despite subjects having advanced MS. Now that ocrelizumab and siponimod have been licensed for active primary and secondary progressive MS, respectively, these DMTs may form the platform for future add-on trials. 

References

  1. Goodin DS, et al. Survival in MS: a randomized cohort study 21 years after the start of the pivotal IFNβ-1b trial. Neurology 2012;78:1315 ̶ 22.
  2. National Institute for Health and Care Research (NIHR). MS clinical trial to focus on people who can’t walk. November 2020. Available at https://www.nihr.ac.uk/news/ms-clinical-trial-to-focus-on-people-who-cant-walk/26227 (accessed June 2022).
  3. US National Library of Medicine. A Study to Evaluate the Efficacy and Safety of Ocrelizumab in Adults With Primary Progressive Multiple Sclerosis (O’HAND). First posted July 2019. Available at https://clinicaltrials.gov/ct2/show/NCT04035005 (accessed June 2022).