Tag Archives: siponimod

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

S1P modulators

Summary

‘S1P modulators’ is the ‘short-hand’ we use to describe a group of drugs called sphingosine 1-phosphate receptor modulators (see Mode of action below). Fingolimod was the first of the S1P modulators to be licensed in MS (in 2010) and the first oral tablet approved for use in MS. Since then, three more S1P modulators have been licensed: siponimod, ozanimod and ponesimod. These are highly effective drugs, decreasing the relapse rate by over 50%, reducing worsening disability and the development of new lesions on magnetic resonance imaging (MRI), and slowing the loss of brain volume. S1P modulators work by trapping lymphocytes in lymph nodes and causing a low lymphocyte count in virtually all people with MS on the drugs. These drugs are maintenance therapies taken continuously and hence cause systemic immunosuppression. As a result, S1P modulators are associated with rare opportunistic infections and secondary malignancies, for example, lymphomas and skin cancers. They are anti-trafficking drugs, i.e. they block lymphocytes migrating into the CNS of people with MS, so when they are stopped, they are associated with rebound disease activity. Rebound typically occurs at around 6 ̶ 8 weeks after stopping fingolimod and siponimod and may also occur with ozanimod and ponesimod. S1P modulators have off-target side effects; for example, they slow the heart rate down and may need to be started in a hospital or under observation.

Trade names

Gilenya (fingolimod), Mayzent (siponimod), Zeposia (ozanimod), Ponvory (ponesimod).

Mode of action

Fingolimod is a sphingosine 1-phosphate (S1P) receptor modulator. Fingolimod is converted to an active drug, fingolimod phosphate, in the body. Fingolimod phosphate binds to its receptor (the S1P receptor) subtype 1 located on lymphocytes, which causes the receptors to be internalised and removed from the surface of the cells. By preventing S1P receptors from recirculating onto the surface of lymphocytes, fingolimod blocks the capacity of lymphocytes to leave lymph nodes, causing their redistribution rather than depletion. Siponimod, ozanimod and ponesimod are active drugs and do not need to be phosphorylated, but they work in the same way as fingolimod.

Efficacy

High; fingolimod is licensed in the UK and Europe as a second-line therapy for people with highly active MS. In other countries, fingolimod can be used first-line. Siponimod is licensed for people with MS with active secondary progressive MS. Ozanimod and ponesimod are licensed as first-line treatments for people with active MS.

Class

Maintenance, immunosuppressive.

Immunosuppression

Yes, systemic.

Dosing

Fingolimod dosing

In adults, the recommended dose of fingolimod is one 0.5 mg capsule taken orally once daily. In children with MS (10 years of age and above), the recommended dose is dependent on body weight:

  • body weight ≤40 kg: one 0.25 mg capsule taken orally once daily
  • body weight >40 kg: one 0.5 mg capsule taken orally once daily.

When people with MS start on 0.25 mg capsules and reach a stable body weight above 40 kg, they should be switched to 0.5 mg capsules. Fingolimod can be taken with or without food. Fingolimod capsules should always be swallowed intact without opening them.

Although the Gilenya SmPC states that when switching from a 0.25 mg to a 0.5 mg daily dose it is recommended to repeat the same first dose monitoring as for treatment initiation, we have not done this. The following text is from the Gilenya SmPC:

The same first dose monitoring as for treatment initiation is recommended when treatment is interrupted for:

  • 1 day or more during the first 2 weeks of treatment
  • more than 7 days during weeks 3 and 4 of treatment
  • more than 2 weeks after one month of treatment.

If the treatment interruption is of a shorter duration than the above, the treatment should be continued with the next dose as planned.

Siponimod dosing

The dose of siponimod depends on how rapidly you can metabolise the drug. Before starting treatment, people with MS must be genotyped to determine their metaboliser status. In people with MS who metabolise the drug slowly and have the so-called 3-3 genotype, siponimod should not be used. In intermediate metabolisers (genotype 2-3 or 1-3), the recommended maintenance dose is 1 mg taken once daily (four tablets of 0.25 mg). In people with all other genotypes who are rapid metabolisers, the dose of siponimod is 2 mg per day.

To reduce off-target side effects, siponimod treatment is started with a titration pack that lasts for 5 days, as follows:

  • days 1 and 2: 0.25 mg once daily
  • day 3: 0.5 mg once daily
  • day 4: 0.75 mg once daily
  • day 5: 1.25 mg once daily
  • day 6: increase to the patient’s prescribed maintenance dose of siponimod.

During the first 6 days of treatment initiation, the recommended once-daily dose should be taken in the morning with or without food (see SmPC for more details).

Ozanimod dosing

The recommended dose is 0.92 mg of ozanimod once daily. To reduce off-target side effects, an initial dose titration is required over the first 7 days (see SmPC for more details):

  • days 1 ̶ 4: 0.23 mg once daily
  • days 5 ̶ 7: 0.46 mg once daily
  • day 8 onwards: 0.92 mg once daily.

Ponesimod dosing

The recommended dose is 20 mg of ponesimod once daily. To reduce off-target side effects, an initial dose titration is required over the first 14 days. The dose starts at 2 mg per day and builds up over 14 days to the maintenance dose of 20 mg per day (see SmPC for specific details).

Dose reduction

The European Medicines Agency recommends that if someone with MS has a persistent lymphopaenia of below 200/mm3 (grade 4), then S1P modulators should be stopped until the lymphocyte counts recover. It is our practice to put these patients on alternate-day dosing or to reduce the daily dose and to rechallenge them with the full dose once the counts have recovered to above 200/mm3. Now that fingolimod has been licensed for treating children with MS, with a dose based on weight, a 0.25 mg tablet is available. So instead of taking 0.5 mg on alternate days, there is also the possibility of taking 0.25 mg daily.

As the response to fingolimod or other S1P modulators and the risk of opportunistic infections are unrelated to the lymphocyte counts, the US Food and Drug Administration has not recommended routine monitoring of lymphocyte counts. Because of this, I am not unduly concerned about lymphocyte counts in patients on fingolimod and other S1P modulators and tend only to respond to counts of less than 100/mm3.

Main adverse events of special interest

Cardiac

The main adverse event of S1P modulators is a transient slowing of the heart rate that can, rarely, be associated with a heart block. This is why fingolimod is started in hospital with cardiac monitoring. With the newer generation S1P modulators, this is managed by a dose titration. Cardiac conduction abnormalities are usually transient and asymptomatic. Owing to the cardiac side effects, concurrent therapy with beta-blockers, heart-rate-lowering calcium channel blockers (such as verapamil or diltiazem), or other substances which may decrease heart rate (e.g. ivabradine, digoxin, anticholinesterase inhibitors or pilocarpine) is not recommended. The effects on heart rate and cardiac conduction may recur on the reintroduction of S1P modulator treatment, depending on the duration of the interruption and the time since the start of treatment. S1P modulators may prolong the so-called QT interval on your ECG, so they are best avoided in individuals with relevant risk factors, for example, low potassium or congenital QT prolongation.

Immunosuppressive effects

S1P modulators predispose people with MS to an infection risk, including opportunistic infections, and increase the risk of developing lymphomas and other malignancies, particularly those of the skin. Potential opportunistic infections include fungal infections, for example, cryptococcal meningitis and progressive multifocal leukoencephalopathy (PML). Before initiating treatment with S1P modulators, it is important to do a baseline infection screen and to check the full blood count. You must have antibodies or immunity to varicella (chickenpox) prior to starting treatment. If you are varicella negative, it is recommended that you receive a full course of one of the varicella vaccines. Similarly, you must have a full vaccine review before starting this class of treatment. Human papillomavirus (HPV) infection, including papilloma, dysplasia, warts and HPV-related cancers, has been reported in people with MS on S1P modulators, which is why we recommend cervical smears or HPV testing at baseline before starting treatment.

Macular oedema

Swelling of the macula, the central part of the retina, occurs in ~ 1 in 200 people with MS treated with fingolimod or another S1P modulator. This can cause symptoms and can be detected using the so-called Amsler grid (see below). You must be assessed at an eye clinic 3 ̶ 4 months after initiating an S1P modulator to screen for this complication. Some clinicians do baseline testing of the eye before initiating S1P modulators; in fact, this is in the SmPC for ponesimod. Please note that if you have a history of uveitis (inflammation in the eye) or have diabetes mellitus, you are at increased risk of developing macular oedema. I tend to avoid prescribing S1P modulators to patients with diabetes.

The Amsler grid (left) is a simple square containing a grid pattern and a dot in the middle. If there are problem spots in your field of vision, areas of the grid may appear blank or distorted (right, example).

Liver

Increased liver enzymes have been reported in people with MS on S1P modulators such as fingolimod. This is why your LFTs (liver function tests) are monitored after starting fingolimod and other S1P modulators, and if they exceed five times the upper limit of normal fingolimod needs to be stopped. LFTs are recommended at 1, 3, 6, 9 and 12 months after therapy and then 6 monthly after that. Please be aware that if you develop any symptoms suggestive of liver problems, such as unexplained nausea, vomiting, abdominal pain, fatigue, loss of appetite, or jaundice and/or dark urine, you should have liver enzymes checked. If you have pre-existing liver disease, most neurologists will avoid using this class of therapy.

High blood pressure

S1P modulators increase your blood pressure by a small amount. If you develop hypertension, you may need to start antihypertensive medications; hypertension occurs in ~ 1 in 20 people with MS treated with fingolimod and is less common with the newer generation S1P modulators.

Respiratory effects

S1P modulators cause a minor reduction in lung function, so neurologists tend to avoid using fingolimod and other S1P modulators in people with MS with pre-existing lung disease.

Vascular effects

Rare cases of posterior reversible encephalopathy syndrome (PRES) have been reported on S1P modulators. Symptoms can include sudden onset of severe headache, nausea, vomiting, altered mental status, visual disturbances and seizures. If you suspect you have PRES, you should contact your doctor urgently.

Cutaneous neoplasms

Basal cell carcinoma (BCC) and other cutaneous neoplasms, including malignant melanoma, squamous cell carcinoma, Kaposi’s sarcoma and Merkel cell carcinoma, have all been reported in people with MS on fingolimod, and there is the potential for these conditions to occur with the other S1P modulators. Please be vigilant for any new skin lesions and bring them to the attention of your doctor, who may need to refer you to a dermatologist. In our centre, we encourage our patients to take pictures of lesions with their smartphone camera and email them to us. We often get back a dermatology opinion very quickly this way. In people with MS at high risk, i.e. those with a dysplastic naevus syndrome, severe sun damage and/or prior history of skin cancer, we refer to dermatology for regular (annual) skin cancer screening. At present, annual skin screening is not justified in low-risk patients. Owing to the potential risk of malignant skin lesions, you need to be careful with excessive sunlight exposure or phototherapy with UV-B-radiation or PUVA-photochemotherapy.

Rebound disease activity

Severe exacerbation of disease has been observed in people with MS stopping fingolimod and siponimod treatment and may also occur with ozanimod and ponesimod. The possibility of recurrence of exceptionally high disease activity needs to be carefully considered when deciding on the sequence of treatments. Rebound typically occurs 6 ̶ 8 weeks after stopping fingolimod, siponimod and ozanimod. If it occurs with ponesimod, it will likely happen much earlier because ponesimod washes out more rapidly than the other S1P modulators.

Neutralising antibodies (NAbs)

NAbs are not a problem with S1P modulators because these DMTs are all small molecules 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, syphilis), tuberculosis enzyme-linked immune absorbent spot (TB ELISpot), up-to-date cervical smear and/or human papillomavirus testing, pregnancy test, blood pressure and electrocardiogram. Lung function tests are recommended for anyone with a history of asthma or lung disease.

Follow-up

FBC, LFTs and blood pressure should be monitored at months 1, 3, 6, 9 and 12 on therapy and 6-monthly thereafter.

Visual function

Macular oedema screening should be done 3 ̶ 4 months after treatment start in an eye clinic. The SmPC for ponesimod recommends a baseline eye scan, but this may not be necessary in people with low-risk MS.

Self-monitoring

All people with MS should be warned about opportunistic infections and informed to look out for symptoms suggestive of infections, suspicious skin lesions and symptoms of liver dysfunction. Women should be reminded to self-examine their breasts monthly and should have cervical smears and/or HPV testing done every 3 years. People with MS need to be aware of visual symptoms and can self-assess their macular function with an Amsler grid. There are several Amsler grid apps available for smartphones. Routine blood pressures also need to be taken.

Rebaselining

A rebaseline MRI scan needs to be done after the S1P modulator has had sufficient time to work. As S1P modulators work quite rapidly, I would recommend that an MRI is done 3 ̶ 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 S1P modulator treatment, I would recommend a negative pregnancy test result. S1P modulators are potentially teratogenic, i.e. they can cause birth defects, therefore, you must have effective contraception whilst on treatment. It takes approximately 2 months to eliminate fingolimod from the body and 3 months to eliminate ozanimod; for ponesimod and siponimod, the elimination times are 1 week and 10 days, respectively. Therefore, on stopping treatment the potential risk to the foetus may persist and contraception should be continued during the drug elimination period. If you do fall pregnant whilst on an S1P modulator, 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 S1P modulators in the uterus have been born without any overt problems.

Breastfeeding

S1P modulators are excreted in the breast milk of lactating women and have the potential for serious adverse reactions in nursing infants, so women on these drugs should not breastfeed.

Fertility

I am not aware of any data to suggest that S1P modulators are associated with reduced female fertility.

Male fertility

S1P modulators have not been shown to affect sperm counts or sperm motility. There is no need for men with MS to stop fingolimod if they want to father a child.

Vaccination

It is safe to receive component or inactivated vaccines, but the antibody responses may be blunted. Live vaccines are contraindicated in people with MS on S1P modulators. Live viruses, particularly ones that can infect the central nervous system, are potentially dangerous.

Travel

People with MS need to be aware that being on an S1P modulator may affect travel; for example, some countries require you to be vaccinated against yellow fever, which involves a live attenuated vaccine and is hence contraindicated. If you travel to places associated with exotic infections, for example, dengue fever, you may be at risk of complications from these infections because S1P modulators are immunosuppressive.

Summaries of Product Characteristics (SmPC)

Gilenya, Mayzent, Zeposia, Ponvory.

Switching to an S1P modulator

Interferon and glatiramer acetate

In general, S1P modulators 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 S1P modulators.

SIP modulator to S1P modulator switch

In general, switching from one S1P modulator to another is possible. I would recommend rechecking baseline investigations before making the switch and ensuring a 4-week washout with fingolimod, siponimod and ozanimod prior to starting the new agent. With ponesimod, I limit the washout to 7 days. Overlapping the washout of one S1P modulator with the titration phase of the newer agent should prevent rebound activity and limit off-target effects, particularly cardiac events.

Natalizumab

Most often the reason for switching from natalizumab to an S1P modulator is to reduce the risk of carry-over PML from natalizumab. In our centre, we do an MRI and lumbar puncture for cerebrospinal fluid analysis to exclude JC virus DNA on PCR (polymerase chain reaction test). Provided these two tests are clear, we typically initiate S1P modulators within 4 weeks of the last natalizumab infusion. A prolonged wash-out period (8 weeks or longer) is associated with rebound disease activity on stopping natalizumab and is therefore not recommended. It is important that all the recommended baseline screening tests and vaccination reviews are done before starting an S1P modulator.

Teriflunomide

Because teriflunomide has such a long half-life, some neurologists would recommend an accelerated washout using cholestyramine or activated charcoal. Rheumatologists rarely do this when switching patients with rheumatoid arthritis from leflunomide (teriflunomide prodrug) to other DMTs, so I am not sure this accelerated washout is necessary. It is important that all the recommended baseline screening tests and vaccination reviews are done before starting an S1P modulator.

If the main reason for switching from teriflunomide is leukopaenia or lymphopaenia I would recommend waiting for the neutrophil and lymphocyte counts to go above 1,000/mm3 and 800/mm3 respectively. Similarly, if the switch is for abnormal LFTs on teriflunomide you would ideally want the liver enzymes to normalise or at least drop to below 3x the upper limit of normal.

Fumarates

It is important that all the recommended baseline screening tests and vaccination reviews are done before starting an S1P modulator. If the main reason for switching from a fumarate is lymphopaenia, I would recommend first waiting for the peripheral blood neutrophil and lymphocyte counts to go above 1,000/mm3 and 800/mm3, respectively.

Alemtuzumab

It is important that all the recommended baseline screening tests and vaccination reviews are done before starting an S1P modulator. I would recommend first waiting for the total peripheral blood neutrophil and lymphocyte counts to go above 1,000/mm3 and 800/mm3, respectively.

Anti-CD20 therapies (selective cell depleting DMTs)

It is important that all the recommended baseline screening tests and vaccination reviews are done before starting an S1P modulator.

Cladribine (selective cell depleting DMT)

It is important that all the recommended baseline screening tests and vaccination reviews are done before starting an S1P modulator. I would recommend first waiting for the total peripheral blood neutrophil and lymphocyte counts to go above 1,000/mm3 and 800/mm3, respectively.

Mitoxantrone

It is important that all the recommended baseline screening tests and vaccination reviews are done before starting an S1P modulator. I would recommend first waiting for the total peripheral blood neutrophil and lymphocyte counts to go above 1,000/mm3 and 800/mm3 respectively.

HSCT

It is important that all the recommended baseline screening tests and vaccination reviews are done before starting an S1P modulator. I would recommend first waiting for the peripheral blood neutrophil and lymphocyte counts to go above 1,000/mm3 and 800/mm3 respectively.

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

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

DMTsShort

S1P modulators – short summary

Summary

‘S1P modulators’ is the ‘short-hand’ we use to describe a group of drugs called sphingosine 1-phosphate receptor modulators (see Mode of action below). Fingolimod was the first of the S1P modulators to be licensed in MS (in 2010) and the first oral tablet approved for use in MS. Since then, three more S1P modulators have been licensed: siponimod, ozanimod and ponesimod. These are highly effective drugs, decreasing the relapse rate by over 50%, reducing worsening disability and the development of new lesions on magnetic resonance imaging (MRI), and slowing the loss of brain volume. S1P modulators work by trapping lymphocytes in lymph nodes and causing a low lymphocyte count in virtually all people with MS on the drugs. These drugs are maintenance therapies taken continuously and hence cause systemic immunosuppression. As a result, S1P modulators are associated with rare opportunistic infections and secondary malignancies, for example, lymphomas and skin cancers. They are anti-trafficking drugs, i.e. they block lymphocytes migrating into the CNS of people with MS, so when they are stopped, they are associated with rebound disease activity. Rebound typically occurs at around 6 ̶ 8 weeks after stopping fingolimod and siponimod and may also occur with ozanimod and ponesimod. S1P modulators have off-target side effects; for example, they slow the heart rate down and may need to be started in a hospital or under observation.

Trade names

Gilenya (fingolimod), Mayzent (siponimod), Zeposia (ozanimod), Ponvory (ponesimod).

Mode of action

Sphingosine 1-phosphate (S1P) receptor modulators block the capacity of lymphocytes to egress from lymph nodes, causing their redistribution, rather than depletion.

Efficacy

High.

Class

Maintenance, immunosuppressive.

Immunosuppression

Yes, systemic.

Dosing

Fingolimod dosing

  • Adults: one 0.5 mg capsule orally once daily.
  • Children (10 years and above): one 0.25 mg or 0.5 mg capsule orally once daily, dependent on body weight.

Siponimod dosing

Treatment is titrated upwards for days 1 ̶ 6 to reduce off-target side effects. Genotyping is carried out before starting treatment to determine dose, based on your speed of metabolising siponimod.

  • Slow metabolisers: should not take siponimod
  • Intermediate metabolisers: 1 mg per day
  • Rapid metabolisers: 2 mg per day.

Ozanimod dosing

0.92 mg once daily; treatment is titrated upwards for days 1 ̶ 7, to reduce off-target side effects.

Ponesimod dosing

20 mg once daily; treatment is titrated upwards for days 1 ̶ 14, to reduce off-target side effects. 

Dose reduction

In cases of persistent lymphopaenia, the European Medicines Agency recommends stopping S1P modulator administration until lymphocyte counts recover. 

Main adverse events and monitoring requirements

  • Transient slowing of the heart rate; raised liver enzymes.
  • Infection risk (opportunistic infections, lymphomas, fungal infections); skin cancer; progressive multifocal leukoencephalopathy.
  • Macular oedema; regular self-monitoring advised; routine clinic monitoring in at-risk patients.
  • Rebound disease activity: repeat MRI scan recommended 3 ̶ 6 months after treatment start.

Rare adverse events of special interest

  • Rare potential for heart block (associated with slowed heart rate) necessitates initial dose titration for all S1P modulators and cardiac monitoring with fingolimod.
  • Rare cases of posterior reversible encephalopathy syndrome; requires urgent medical attention.

Further details about S1P modulators

Switching-2-S1P modulators

Switching

Switching-2-S1P modulators

Possible reasons to switch

  • S1P modulators are highly effective DMTs and they have been shown to:
    • decrease relapse rates
    • reduce the development of new lesions visible on magnetic resonance imaging
    • reduce disability worsening
    • slow down brain volume loss.
  • For people with MS currently on natalizumab and concerned about progressive multifocal leukoencephalopathy (PML), switching to an S1P modulator may reduce the risk of carry-over PML.

Reasons for caution

  • S1P modulators cause a transient slowing of the heart rate; they are not recommended if you are already taking medicine(s) that slow your heart rate.
  • They cause systemic immunosuppression, which increases the risk of opportunistic infections, for example PML and cryptococcal fungal infections, and secondary malignancies.
  • Rebound MS disease activity often occurs when S1P modulators are stopped.
  • Visual disturbances can develop owing to swelling of the macula (the central part of the retina). The risk of macular oedema is increased if you have a history of inflammation in the eye or diabetes mellitus.
  • Most neurologists will avoid using S1P modulators in patients with pre-existing liver or lung disease.
  • Testing for human papillomavirus infection is recommended prior to starting treatment.
  • People with MS at high risk of skin lesions (e.g. from previous severe sun damage and/or skin cancer) should be referred for regular skin cancer screening.
  • Women of child-bearing potential should avoid pregnancy and breast feeding.

Interferon and glatiramer acetate

In general, S1P modulators 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 S1P modulators.

S1P modulator to S1P modulator switch

In general, switching from one S1P modulator to another is possible. I would recommend rechecking baseline investigations before making the switch and ensuring a 4-week washout with fingolimod, siponimod and ozanimod prior to starting the new agent. With ponesimod, I limit the washout to 7 days. Overlapping the washout of one S1P modulator with the titration phase of the newer agent should prevent rebound activity and limit off-target effects, particularly cardiac events.

Natalizumab

Most often the reason for switching from natalizumab to an S1P modulator is to reduce the risk of carry-over PML from natalizumab. In our centre, we do an MRI and lumbar puncture for cerebrospinal fluid analysis to exclude JC virus DNA on PCR (polymerase chain reaction test). Provided these two tests are clear, we typically initiate S1P modulators within 4 weeks of the last natalizumab infusion. A prolonged wash-out period (8 weeks or longer) is associated with rebound disease activity on stopping natalizumab and is therefore not recommended. It is important that all the recommended baseline screening tests and vaccination reviews are done before starting an S1P modulator.

Teriflunomide

Because teriflunomide has such a long half-life, some neurologists would recommend an accelerated washout using cholestyramine or activated charcoal. Rheumatologists rarely do this when switching patients with rheumatoid arthritis from leflunomide (teriflunomide prodrug) to other DMTs, so I am not sure this accelerated washout is necessary. It is important that all the recommended baseline screening tests and vaccination reviews are done before starting an S1P modulator.

If the main reason for switching from teriflunomide is leukopaenia or lymphopaenia I would recommend waiting for the neutrophil and lymphocyte counts to go above 1,000/mm3 and 800/mm3 respectively. Similarly, if the switch is for abnormal LFTs on teriflunomide you would ideally want the liver enzymes to normalise or at least drop to below 3x the upper limit of normal.

Fumarates

It is important that all the recommended baseline screening tests and vaccination reviews are done before starting an S1P modulator. If the main reason for switching from a fumarate is lymphopaenia, I would recommend first waiting for the peripheral blood neutrophil and lymphocyte counts to go above 1,000/mm3 and 800/mm3, respectively.

Alemtuzumab

It is important that all the recommended baseline screening tests and vaccination reviews are done before starting an S1P modulator. I would recommend first waiting for the total peripheral blood neutrophil and lymphocyte counts to go above 1,000/mm3 and 800/mm3, respectively.

Anti-CD20 therapies (selective cell depleting DMTs)

It is important that all the recommended baseline screening tests and vaccination reviews are done before starting an S1P modulator.

Cladribine (selective cell depleting DMT)

It is important that all the recommended baseline screening tests and vaccination reviews are done before starting an S1P modulator. I would recommend first waiting for the total peripheral blood neutrophil and lymphocyte counts to go above 1,000/mm3 and 800/mm3, respectively.

Mitoxantrone

It is important that all the recommended baseline screening tests and vaccination reviews are done before starting an S1P modulator. I would recommend first waiting for the total peripheral blood neutrophil and lymphocyte counts to go above 1,000/mm3 and 800/mm3 respectively.

HSCT

It is important that all the recommended baseline screening tests and vaccination reviews are done before starting an S1P modulator. I would recommend first waiting for the peripheral blood neutrophil and lymphocyte counts to go above 1,000/mm3 and 800/mm3 respectively.

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?

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).
Brain health and holistic management of MS, Treatment strategy

What are the consequences of not treating MS?

Are there valid reasons not to treat MS with a disease-modifying therapy? What are the consequences of not treating MS? Is watchful waiting justified?

Key points

  • Untreated MS will, given time, result in physical disability, impaired quality of life and ‘hidden’ problems such as cognitive impairment, anxiety and depression.
  • Brain atrophy, or shrinkage, occurs at a faster rate in people with MS than in healthy individuals.
  • Optic neuritis, inflammation or destruction of nerve fibres in the brain and spinal cord, and extensive damage to the cerebral cortex (grey matter) are some consequences of MS lesion development.
  • Quality of life impacts may include reduced mobility, relationship difficulties, increased likelihood of unemployment and memory impairment.
  • Without treatment, the life expectancy of people with MS is reduced by about 6 ̶ 8 years.
  • There are, however, several valid reasons why some people with MS prefer not to receive disease-modifying treatments.

Risks from no disease-modifying treatment

Many patients ask me what will happen to their MS if they don’t take a disease-modifying treatment (DMT) and how effective DMTs are at preventing negative outcomes. Here I try and address questions you need to ask yourself before starting a DMT.

If you are an individual with MS, predicting your disease course is difficult. However, many studies monitoring groups of people with MS show patterns in relation to the progression of the disease and its outcome, with various data sets being consistent.

Given sufficient time, most people with MS who are not treated will become disabled. Most people focus on physical disability, but MS causes many hidden problems, such as cognitive impairment, anxiety and depression.

How untreated MS can progress – headline results

The slides below summarise some of the outcomes of untreated MS; these include brain changes (atrophy), further MS lesion development, reduced health-related quality of life, long-term impact on physical and mental health and shorter life expectancy. (To enlarge an individual slide, click on the arrow at the top right.)

Brain changes
MS lesion development
Quality of life impact
Long-term outlook

DMTs have changed the landscape

It is important to note that these outcomes are from the pre-DMT era and don’t apply to populations of people with MS treated with DMTs. New real-life data indicate that DMTs, particularly high-efficacy DMTs, are preventing many of these problems. By not being on a DMT, if you have active MS, you are at risk of acquiring damage from focal inflammatory lesions. Early in the disease course, you may not be aware of this damage because of the remarkable capacity of the nervous system to compensate for damage (neurological reserve). However, once the compensatory mechanisms have been exhausted, further damage results in overt disability. It is important to regard DMTs as preventive treatments, i.e. their aim is to delay, and hopefully prevent, future disability.

Possible reasons for not receiving a DMT

Many people with MS will not be on a DMT, for a variety of reasons. The list below is probably not extensive; if you know of other reasons why someone who qualifies is not taking a DMT, please let me know.

Inactive MS

Someone with inactive MS will not be eligible for a DMT. There is no standard definition of active MS. To me, active MS is recent evidence of focal inflammatory disease activity, defined as:

  • clinical relapse(s) in the last 2 years
  • OR magnetic resonance imaging (MRI) activity in the last 12 ̶ 36 months (new or enlarging T2 lesions or T1 Gd-enhancing lesions)
  • OR a raised cerebrospinal fluid (CSF) neurofilament light chain level in the last 12 months.

Worsening disability in MS without focal inflammatory disease activity is not active disease. It can be due to damage caused by past inflammation, smouldering MS or the effects of premature ageing; anti-inflammatory DMTs can’t address this problem. We need different types of DMTs to address these mechanisms – for example, neuroprotective and/or remyelination therapies and anti-ageing therapies.

Watchful waiting

In many situations, some neurologists think someone with MS will end up having benign disease, so they are not prepared to start treatment until the patient develops some overt disability. I abhor this practice and it is one of the reasons I spend so much of my time disseminating knowledge and getting involved with health politics. Watchful waiting, in terms of treating MS, is not supported by data. The earlier and more effectively you treat MS, the better the outcome. The only situation I could condone watchful waiting in someone with active MS is when the diagnosis of MS is in question. Sometimes in neurology, time is the best diagnostician. If the person has MS, it will declare itself with further disease activity, and this would be the trigger to start a DMT.

Family planning

Trying to fall pregnant, pregnancy or breastfeeding are common reasons to interrupt or stop DMTs. Please note that most neurologists now have options to treat MS during pregnancy and while breastfeeding, so this is becoming a less common reason for not taking a DMT.

Risk aversion

Some people with MS are not prepared to take the potential risks associated with DMTs.

Personal reasons

Some people with MS don’t believe in having their MS treated, preferring to try alternative medicines and turn down traditional DMTs. If you are one of these people, I would recommend you continue to interact with your MS team and have regular monitoring of your MS (clinical, MRI, patient-related outcome measures [PROMS] and possibly CSF analyses). Then, if these alternative strategies don’t work, you will keep open the option of treatment with a ‘traditional DMT‘. Most alternative treatment strategies for MS are compatible with DMTs and hence should be viewed as complementary. Understanding the difference between complementary and alternative treatments is important. Complementary treatment strategies are part of the holistic management of MS.

Financial constraints

In some parts of the world, MS treatment is not covered by a national health service or medical insurance scheme and some people with MS simply can’t afford DMTs. Even in rich countries, people with MS who are disenfranchised don’t have access to treatment; these may include illegal immigrants, refugees and asylum seekers waiting for their applications to be processed.

Progressive or more advanced MS

In most countries, neurologists don’t initiate treatment in patients with more advanced MS. This approach is based on a lack of evidence of the effectiveness of DMTs in this population. However, we are increasingly offering ocrelizumab (for active primary progressive MS), siponimod (for active secondary progressive MS) or off-label therapies on a compassionate basis to people with more advanced MS. In addition, there is also the potential to participate in clinical trials of new treatments for more advanced MS.

Ageism

Some healthcare systems and some neurologists are reluctant to start DMTs in people with MS who are over a certain age. This is based on a lack of evidence of the effectiveness of DMTs in this population, and it is why we need to do clinical trials in older people with MS.

Comorbidities

Many people have other medical problems for which the treatment takes priority over the treatment of MS. For example, a patient of mine was diagnosed with stage four bowel cancer. After her surgery, she started an intensive period of chemotherapy during which we stopped her DMT.

References

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  2. Barkhof F, et al. Imaging outcomes for neuroprotection and repair in multiple sclerosis trials. Nat Rev Neurol 2009;5:256–66.
  3. Simon JH. Brain atrophy in multiple sclerosis: what we know and would like to know. Mult Scler 2006;12:679–87.
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  5. Hickman SJ, et al. Detection of optic nerve atrophy following a single episode of unilateral optic neuritis by MRI using a fat-saturated short-echo fast FLAIR sequence. Neuroradiology 2001;43:123–8.
  6. Trapp BD, et al. Axonal transection in the lesions of multiple sclerosis. N Engl J Med 1998;338:278–85.
  7. Peterson JW, et al. Transected neurites, apoptotic neurons, and reduced inflammation in cortical multiple sclerosis lesions. Ann Neurol 2001;50:389–400.
  8. Orme M, et al. The effect of disease, functional status, and relapses on the utility of people with multiple sclerosis in the UK. Value Health 2007;10:54–60.
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  11. Feuillet L, et al. Early cognitive impairment in patients with clinically isolated syndrome suggestive of multiple sclerosis. Mult Scler 2007;13:124–7. 
  12. Confavreux C and Compston A. Chapter 4. The natural history of multiple sclerosis. In: McAlpine’s Multiple Sclerosis, Fourth Edition, 2006; 183 ̶ 272. Churchill Livingstone.
  13. Weinshenker BG et al. The natural history of multiple sclerosis: a geographically based study. I. Clinical course and disability. Brain 1989;112:133 ̶ 46.
  14. Torkildsen GN, et al. Survival and cause of death in multiple sclerosis: results from a 50-year follow-up in Western Norway. Mult Scler 2008;14:1191–8.
  15. Kingwell E, et al. Relative mortality and survival in multiple sclerosis: findings from British Columbia, Canada. J Neurol Neurosurg Psychiatry 2012;83:61–6.
  16. Sadovnick AD, et al. Cause of death in patients attending multiple sclerosis clinics. Neurology 1991;41:1193–6.
  17. Brenner P, et al. Multiple sclerosis and risk of attempted and completed suicide – a cohort study. Eur J Neurol 2016;23:1329–36.