Tag Archives: ozanimod

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 egress from 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 period of ozanimod 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 period of ponesimod 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 macular, 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)

These are not a problem with S1P modulators as they 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, siponimod and ozanimod from the body, and about 7 days for ponesimod; 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 a 4-week wash-out 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 and 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.

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 macular (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 a 4-week wash-out 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 and 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 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 an issue 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 bad 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?