Tag Archives: ofatumumab

DMTsShort

Anti-CD20 therapies – short summary

Summary

Anti-CD20 therapies are a class of monoclonal antibodies that bind to CD20 on the surface of B cells. They work by depleting peripheral B-cells. Four anti-CD20 antibodies are available for treating MS and are administered by intravenous or subcutaneous injection. The three licensed agents for treating relapsing forms of MS are ocrelizumab (Ocrevus), ofatumumab (Kesimpta) and ublituximab (Briumvi). In addition, ocrelizumab is the only anti-CD20 therapy with a license to treat primary progressive MS. In many countries, rituximab (MabThera) is used off-label. Rituximab will be increasingly used as it has recently been included on the WHO’s essential medicines list as a treatment for MS.  

Most B-cell killing due to anti-CD20 is done through immunological processes that burst or lyse the cells, releasing their contents. This can cause a cell lysis syndrome or infusion reaction, which in the case of anti-CD20 therapies tends to be mild to moderate. The infusion reactions are typically managed by predosing with steroids, antihistamines and/or antipyretics (paracetamol/acetaminophen or a non-steroid anti-inflammatory such as ibuprofen). The doses and dosing schedules of the anti-CD20 therapies differ.

Ocrelizumab (600 mg), ublituximab (450 mg) and rituximab (1000 mg) are given as 6-monthly intravenous infusions and ofatumumab (20 mg) as monthly subcutaneous injections.

The anti-CD20 therapies are highly effective DMTs with a high rate of no evident inflammatory disease activity (NEIDA), slowing down disability worsening and brain volume loss. A recent real-world study suggests that ocrelizumab is more effective than rituximab. However, as these agents have yet to be compared head-to-head in a clinical trial, it is difficult to claim one is more or less effective than the others. 

Rituximab and ublituximab are the least humanised of the anti-CD20s and are associated with a higher rate of antidrug antibodies (ADAs), which are usually neutralising antibodies (NAbs). It is reported that 6.4% of ublituximab-treated subjects and even more rituximab-treated patients develop ADAs. In comparison, 1 ̶ 2% of ocrelizumab-treated patients and fewer than 0.5% of ofatumumab-treated patients develop ADAs as these therapeutic antibodies are more humanised than the others and less likely to induce an antidrug immune response. The ADAs are important considerations when choosing between these products. 

The most common adverse effects of anti-CD20 therapies are mild infusion-like reactions (generally not seen with subcutaneous ofatumumab), infections, low antibody levels in the blood (hypogammaglobulinaemia), blunted vaccine responses and (rarely) delayed neutropenia. In the ocrelizumab trials, the number of malignancies (including breast cancers) was increased. The incidence was, however, within the background rate expected for an MS population, and post-marketing studies have not shown an increased rate of malignancies. 

Anti-CD20 therapies are generally available first line to treat DMT-naive patients. As a class, anti-CD20 therapies have transformed the management of MS by allowing the adoption of a treatment strategy of using high-efficacy DMTs as the first treatment, which I refer to as ‘flipping the pyramid’. Importantly, ocrelizumab has also ushered in the era in which we can treat some patients with primary progressive MS. 

Trade names

Ocrevus, Kesimpta, Bonspri, Briumvi, MabThera.

Mode of action

Via peripheral B-cell depletion. It is hypothesised that anti-CD20 therapies work via several mechanisms involving the B cell and possibly through a small population of CD20-expressing T cells.

Efficacy

High, with a positive impact on annual relapse rate, 3-month disability progression, no evident disease activity (NEDA) rates and slowing of accelerated brain volume loss. 

Class

Maintenance therapy – continuous B-cell depletion.

Immunosuppression

Yes, long-term.

Dosing

Ocrevus (ocrelizumab) dosing

600 mg administered as two infusions of 300 mg (with a 2-week gap). Subsequent doses of 600 mg ocrelizumab every 6 months.

Kesimpta/Bonspri (ofatumumab) dosing

20 mg administered by subcutaneous injection at weeks 0, 1 and 2, then monthly dosing from week 4.

Briumvi (ublituximab) dosing

150 mg intravenous infusion (first infusion); 450 mg intravenous infusion 2 weeks later. All subsequent doses are administered as a single 450 mg intravenous infusion every 24 weeks. 

MabThera (rituximab) dosing

Generally, 1000 mg intravenously on days 1 and 15 then 1000 mg intravenously every 6 months. Rituximab is off patent and dosing regimens vary.

Pre-treatment and prophylaxis treatment

100 mg of corticosteroid is administered intravenously before infusion to help manage infusion reactions; this may not be needed with later infusions. Premedication is not necessary with subcutaneous ofatumumab. Prophylactic antivirals or antibiotics are not required. 

Main adverse events

  • Infections, usually minor, are the most common adverse event. Herpes infections are reported more frequently than with other DMTs. 
  • Infusion-related reactions are relatively common with the first and second infusions. The risk of anaphylaxis is very low.
  • Laboratory abnormalities such as decreased antibody levels, lymphopaenia or neutropaenia are associated with a higher risk of infection.
  • Standard breast cancer screening measures are mandated for women aged 50 ̶ 70 years.

Pharmacovigilance monitoring requirements 

  • Standard blood tests and comprehensive screening for infection, pregnancy and blood pressure are done at baseline.
  • Vaccine review is recommended, followed by vaccination where indicated.
  • Follow-up blood tests are not mandated, but our centre performs them every 6 ̶ 12 months.
  • A rebaseline MRI scan should be done ~6 months after starting an anti-CD20 therapy, ideally including Gd-enhancement. A monitoring MRI is performed annually after that.
  • In the event of pregnancy, the next infusion should be delayed until after delivery.
  • In general, the anti-CD20 therapies are safe when breastfeeding, except during weeks 2 ̶ 3 post-partum when colostrum is produced.

Further details about anti-CD20 therapies

Switching-2-anti-CD20s

DMTsDetail

Anti-CD20 therapies  

Summary

Anti-CD20 therapies are a class of monoclonal antibodies that bind to CD20 on the surface of B cells. They work by depleting peripheral B-cells. Four anti-CD20 antibodies are available for treating MS and are administered by intravenous or subcutaneous injection. The three licensed agents for treating relapsing forms of MS are ocrelizumab (Ocrevus), ofatumumab (Kesimpta) and ublituximab (Briumvi). In addition, ocrelizumab is the only anti-CD20 therapy with a license to treat primary progressive MS. In many countries, rituximab (MabThera) is used off-label. Rituximab will be increasingly used as it has recently been included on the WHO’s essential medicines list as a treatment for MS.  

Most B-cell killing due to anti-CD20 is done through immunological processes that burst or lyse the cells, releasing their contents. This can cause a cell lysis syndrome or infusion reaction, which in the case of anti-CD20 therapies tends to be mild to moderate. The infusion reactions are typically managed by predosing with steroids, antihistamines and/or antipyretics (paracetamol/acetaminophen or a non-steroid anti-inflammatory such as ibuprofen). The doses and dosing schedules of the anti-CD20 therapies differ.

Ocrelizumab (600 mg), ublituximab (450 mg) and rituximab (1000 mg) are given as 6-monthly intravenous infusions and ofatumumab (20 mg) as monthly subcutaneous injections.

The anti-CD20 therapies are highly effective DMTs with a high rate of no evident inflammatory disease activity (NEIDA), slowing down disability worsening and brain volume loss. A recent real-world study suggests that ocrelizumab is more effective than rituximab. However, as these agents have yet to be compared head-to-head in a clinical trial, it is difficult to claim one is more or less effective than the others. 

Rituximab and ublituximab are the least humanised of the anti-CD20s and are associated with a higher rate of antidrug antibodies (ADAs), which are usually neutralising antibodies (NAbs). It is reported that 6.4% of ublituximab-treated subjects and even more rituximab-treated patients develop ADAs. In comparison, 1 ̶ 2% of ocrelizumab-treated patients and fewer than 0.5% of ofatumumab-treated patients develop ADAs as these therapeutic antibodies are more humanised than the others and less likely to induce an antidrug immune response. The ADAs are important considerations when choosing between these products. 

The most common adverse effects of anti-CD20 therapies are mild infusion-like reactions (generally not seen with subcutaneous ofatumumab), infections, low antibody levels in the blood (hypogammaglobulinaemia), blunted vaccine responses and (rarely) delayed neutropenia. In the ocrelizumab trials, the number of malignancies (including breast cancers) was increased. The incidence was, however, within the background rate expected for an MS population, and post-marketing studies have not shown an increased rate of malignancies. 

Anti-CD20 therapies are generally available first line to treat DMT-naive patients. As a class, anti-CD20 therapies have transformed the management of MS by allowing the adoption of a treatment strategy of using high-efficacy DMTs as the first treatment, which I refer to as ‘flipping the pyramid’. Importantly, ocrelizumab has also ushered in the era in which we can treat some patients with primary progressive MS. 

Trade names

Ocrevus (ocrelizumab), Kesimpta/Bonspri (ofatumumab), Briumvi (ublituximab), MabThera (rituximab). Please note rituximab is off patent and many biosimilars are available globally; hence the treatment you receive may have a different tradename.

Mode of action

Anti-CD20 therapies work via peripheral B-cell depletion. It is unknown how B-cell depletion works as a treatment for MS. However, it is hypothesised that anti-CD20 therapies work via several mechanisms involving the B cell and possibly through a small population of CD20-expressing T cells:

  • preventing autoantigen presentation via the B cell
  • reducing B-cell-derived proinflammatory cytokines
  • reducing B-cell production of autoantibodies
  • depleting pro-inflammatory effector CD20-expressing T cells
  • as an anti-EBV agent: EBV (Epstein-Barr virus) resides in memory B cells, and depleting these cells decreases EBV viral loads. However, it is currently unknown what role EBV plays in the pathogenesis of MS. 

Efficacy

High. Compared with active comparators (interferon-beta and teriflunomide), anti-CD20 therapies reduce the annual relapse rate by ~50% and 3-month disability progression by one-third. The no evident disease activity (NEDA) rates across 2 years of the pivotal trials are ~50%, and these drugs slow down accelerated brain volume loss to ~0.3 ̶ 0.4% per annum. This rate of brain volume loss, however, is still considered to be above what is expected when compared to the rate of <0.2% per annum in age-matched healthy subjects.

Class

Maintenance therapy – continuous B-cell depletion.

Immunosuppression

Yes, long-term.

Dosing and availability

Ocrevus (ocrelizumab) dosing

The initial 600 mg dose is administered as two separate intravenous infusions, first as a 300 mg infusion, followed 2 weeks later by a second 300 mg infusion. These initial infusions are given over 2.5 hours. Subsequent doses of ocrelizumab are administered as a single 600 mg intravenous infusion every 6 months. The infusion rate will vary from 2.0 to 3.5 hours, depending on how well it is tolerated. It is recommended that a minimum interval of 5 months should be maintained between each dose of ocrelizumab.

Kesimpta/Bonspri (ofatumumab) dosing

The recommended dose is 20 mg ofatumumab administered by subcutaneous injection with initial dosing at weeks 0, 1 and 2, followed by monthly dosing, starting at week 4.

Kesimpta is sold in an autoinjector, and Bonspri is sold as a vial for self-administration. Bonspri is only available in some middle-income and low-middle-income countries, where it is sold at a discount to Kesimpta.

Briumvi (ublituximab) dosing

The first dose is administered as a 150 mg intravenous infusion over 4 hours (first infusion), followed 2 weeks later by a 450 mg intravenous infusion over one hour (second infusion). All subsequent doses are administered as a single 450 mg intravenous infusion every 24 weeks over one hour. 

Ublituximab is the latest anti-CD20 therapy to be shown to be effective in MS and it may not yet be available in your country. 

MabThera (rituximab) dosing

Please note rituximab is off patent, and many biosimilars are now available across the world. The most common dose is 1000 mg of intravenous rituximab on days 1 and 15 and then 1000 mg intravenously every 6 months. There are variations to this dosing scheme, with many neurologists reducing the dose or extending the interval between doses to try and reduce the risk of long-term adverse effects. 

Pre-treatment and prophylaxis treatment

For the anti-CD20 therapies, 100 mg of methylprednisolone (or an equivalent corticosteroid) is administered intravenously approximately 30 minutes before each infusion to reduce the frequency and severity of infusion reactions. This can be combined with chlorpheniramine 10 mg. Paracetamol 1g and/or ibuprofen 400 mg is given on an ‘as-required’ basis for pyrexia, myalgias or pain, which can rarely occur as part of the infusion reaction. As the infusion reactions are only a problem with the first and second courses, many centres now omit methylprednisolone and antihistamines once patients are B-cell depleted and established on the treatment. The infusion reactions are due to a cell lysis syndrome. Once B-cell depletion is established, there are too few circulating B cells to cause a cell lysis syndrome. Prophylactic antivirals or antibiotics are not required with the anti-CD20 therapies. 

Please note premedication is not necessary with subcutaneous ofatumumab.

Off-label rituximab

Rituximab is off patent and is relatively cheap, which explains why it is one of the drugs on the MS-Selfie off-label essential DMT list for treating MS in resource-poor environments. It is also worth noting that rituximab is one of three DMTs added to the WHO List of Essential Medicines to treat MS. 

Main adverse events

Infusion-related reactions

Infusion-related reactions (IRRs) are relatively common and are experienced by about one in three subjects with the first and second infusions. Typical IRRs include pruritus, rash, urticaria, erythema, flushing, low blood pressure, pyrexia, fatigue, headache, dizziness, throat irritation, oropharyngeal pain, nausea, tachycardia, shortness of breath and throat or laryngeal swelling. The risk of anaphylaxis is very low.

Infection

Infections, particularly of the respiratory tract, are the most common adverse event with anti-CD20 therapies. Infections tend to be minor, but occasional severe infections occur. Herpes infections, including herpes zoster and oral or genital herpes simplex virus infection, are reported more frequently in patients treated with anti-CD20 therapies than in those receiving other DMTs. 

Laboratory abnormalities

Anti-CD20 treatment decreases total immunoglobulins (antibodies), mainly driven by reduced IgM (immunoglobulin M) and IgA levels. Decreased levels of IgG tend to occur later and are associated with a higher risk of infection and severe infections. Not all patients treated with anti-CD20s develop hypogammaglobulinaemia.

A minority of people with MS treated with anti-CD20 therapies develop mild lymphopaenia; a small number (<1%) develop grade 3 lymphopaenia (<500 cells/mm3). An increased rate of serious infections has been seen during episodes of lymphopaenia.

A small number of patients treated with anti-CD20s develop neutropaenia, generally mild and transient; fewer than 1% developed grade 3 (500 ̶ 1000 cells/mm3) or grade 4 neutropaenia (<500 cells/mm3) in the trials. Please note that neutropaenia can occur several months after starting anti-CD20 therapy and has been associated with infections. 

To minimise infectious complications, we recommend all patients have a vaccine review and ensure they are up to date with their seasonal flu and COVID-19 vaccines. In addition, we recommend all patients have the pneumococcal vaccine (Pneumovax) and the varicella zoster virus (VZV) vaccine (Shingrex) before starting anti-CD20 therapy (please see our derisking guide and article on reducing side effect risk). Some people with MS may want to consider additional vaccines before starting an anti-CD20 therapy. 

As anti-CD20 therapies are immunosuppressive, they increase the likelihood of infections. To derisk infections, we recommend routine baseline screening for human immunodeficiency virus (HIV), syphilis, hepatitis B and C and tuberculosis. In addition, we screen for exposure to VZV and if seronegative we strongly recommend VZV vaccination before starting therapy. 

Malignancy

An increased number of malignancies (including breast cancer) were seen in ocrelizumab-treated subjects in clinical trials. However, the incidence appears to be within the background rate expected for an MS population. Patients must follow standard breast cancer screening guidelines, i.e. monthly self-examination, and women between 50 and 70 years of age should have a mammogram every 3 years. Other potential cancers linked to anti-CD20 therapies include basal cell carcinoma.

Pharmacovigilance monitoring requirements 

Baseline

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

Follow-up

No routine follow-up blood tests are mandated. However, we now monitor the full blood count and serum immunoglobulin levels every 6 ̶ 12 months when patients come for their infusions or annual follow-up appointments. The latter is particularly relevant for patients on subcutaneous ofatumumab. 

Rebaselining

A rebaseline MRI scan needs to be done after starting an anti-CD20 therapy. I recommend that an MRI is done at ~6 months after starting treatment and that Gd-enhancement is ideally included as part of the rebaselining MRI. A monitoring MRI is then done annually after that (resources permitting). 

Women of childbearing potential and pregnancy

The SmPCs recommend that women of childbearing age should use contraception while receiving anti-CD20 treatment and, in the case of ocrelizumab, for up to 12 months after the last infusion. However, I tend to give women who want to start or extend their families the option of starting an anti-CD20 and falling pregnant in their own time. There are several reasons for this. Most women don’t fall pregnant immediately; it takes, on average, four ovulation cycles and often much longer. Anti-CD20 therapies do not affect fertility and are not teratogenic (i.e. it does not affect the developing baby). In addition, the placenta does not mature until towards the end of the second trimester, when it allows antibodies (anti-CD20 is an antibody) to cross from the maternal circulation into the developing baby’s circulation. So once a woman falls pregnant, we delay the next infusion until after the baby’s delivery. Even if small amounts of anti-CD20 cross over into the baby’s circulation, it tends to cause a transient B-cell depletion in the baby.

Breastfeeding

In general, monoclonal antibodies, including the anti-CD20 therapies, are safe during breastfeeding because little drug gets into the breast milk; the small amounts that reach the breast milk will be metabolised in the baby’s gastrointestinal tract. The exception is in the first 2 ̶ 3 weeks post-partum when a woman’s breasts produce colostrum, and the newborn’s intestinal tract is immature and can transfer antibodies across the intestinal surface.

Colostrum, or first milk, is produced immediately after the newborn’s delivery and for about 2 ̶ 3 weeks after delivery. Colostrum is exceptionally high in antibodies and other factors to protect the newborn against disease and infection. As the newborn’s gastrointestinal tract is immature, many of the proteins in colostrum are absorbed and will have systemic immune effects. 

Most of the antibodies in colostrum are IgA and IgM produced by plasma cells in the breast. Therefore, I suspect that circulating IgG, including the anti-CD20, is transferred into breast milk in small amounts. However, the breast epithelial cells express the so-called neonatal Fc-receptor, the molecular shuttle for transporting antibodies into milk. In addition, this neonatal Fc receptor shuttle is also expressed in the newborn intestine. So, the molecular mechanisms are in place potentially to increase your developing baby’s exposure to anti-CD20. 

Neonatal Fc Receptor - for MS-Selfie gg1-RB

Neonatal Fc-receptors expressed on breast epithelial cells transport small amounts of antibodies into breast milk.

If you plan to breastfeed, which I recommend, you will want to avoid ocrelizumab while your breasts produce colostrum. There are no black-and-white answers to any problem in MS. Delaying recommencing ocrelizumab treatment for a few weeks post-partum outweighs the chances of rebound disease activity. 

Fertility

Animal studies and experience in humans reveal no issues concerning fertility in women receiving anti-CD20 treatment. 

Vaccination

It is recommended that anti-CD20-treated patients are immune to the VZV before starting treatment. Patients should also be offered the pneumococcal (Pneumovax) and VZV (Shingrex) component vaccines to boost immunity before treatment. Antibody response, but not T-cell responses, to neoantigens (new vaccines) is blunted in patients on anti-CD20 therapies. Therefore, patients on such therapies can receive inactivated vaccines and mount a partial response to them. Live attenuated vaccines are not recommended for these patients. 

Travel

People with MS need to be aware that being on an anti-CD20 may affect travel; for example, some countries require you to be vaccinated against yellow fever, a live attenuated vaccine. Therefore, the yellow fever vaccine must be given before starting anti-CD20 treatment.

High-dose versus low-dose anti-CD20

To move our treatment target in MS beyond NEIDA, the new focus must be on preventing end‑organ damage and the processes driving smouldering MS; that target therefore includes:

  • stopping disability progression
  • normalising brain volume loss
  • flattening the area under the neurofilament level curve
  • stopping slowly expanding lesions from getting bigger
  • clearing the cerebrospinal fluid of oligoclonal IgG bands
  • if possible, promoting repair and recovery of the nervous system. 

What good is it to be free of relapses and focal MRI activity if your MS gets worse? This is why the concept of using low-dose anti-CD20 therapy seems flawed. Trial participants exposed to lower doses of ocrelizumab in the phase 3 trials, owing to greater body size, do as well as those exposed to higher doses in relation to relapses and MRI activity, but not in relation to worsening disability or smouldering disease. 

The phase 3 ocrelizumab trials in both relapsing and primary progressive MS used a fixed dose of 600 mg of ocrelizumab intravenously every 6 months.1,2 Therefore, smaller people with MS got a larger dose of ocrelizumab than larger people. For example, someone weighing 60 kg got 10 mg/kg of ocrelizumab 6-monthly compared to 5 mg/kg for someone with MS weighing 120 kg. By measuring drug concentrations, trial subjects could be divided into four groups or quartiles representing four dosing levels. Although the treatment effect of ocrelizumab on relapses and MRI activity showed no difference between the four groups in these pivotal studies, post-hoc analyses showed that subjects who received higher doses and had more significant B-cell depletion were less likely to exhibit disease progression than those on low doses. This higher-dose treatment effect on smouldering MS, i.e. beyond NEIDA, was seen in both the relapsing and primary progressive populations.3

It is clear from these post-hoc analyses that higher, not lower, doses of anti-CD20 therapy may be needed to tackle smouldering MS. Currently, these observations apply only to the initial 2 years of treatment. Hence, we don’t know if people with MS will only need higher doses as an induction strategy to purge the various B-cell compartments of pathogenic (disease-causing) cells. 

Once you have purged these B-cell compartments after 2 years of high-dose anti-CD20 treatment, you may not need to maintain people with MS on such high doses, which would continue suppressing normal B-cell biology and immune responses – with long-term complications. 

Two large phase 3 trials are ongoing, testing high-dose ocrelizumab (1200 and 1800 mg every 6 months) compared with standard-dose ocrelizumab (600 mg every 6 months) in both relapsing and primary progressive MS. The results of these trials should answer some of the lingering questions about dosing of anti-CD20 therapies.

Please note that lower dose anti-CD20 therapies are a moving target. Anti-CD20 dosing should not be based on B-cell counts in the peripheral blood, which are a poor surrogate for what is happening in the deep tissues and central nervous system. We need better and more accessible biomarkers to study these B-cell compartments. Receiving ocrelizumab less frequently than the licensed 6-monthly dose and rituximab, ofatumumab or ublituximab could potentially be considered as low-dose anti-CD20 therapy. 

Summaries of Product Characteristics (SmPC)

Ocrevus (ocrelizumab), Kesimpta (ofatumumab), Briumvi (ublituximab), MabThera (rituximab).

Switching-2-anti-CD20 therapy

Interferon and glatiramer acetate

An anti-CD20 therapy can be started immediately after discontinuing interferon-beta or glatiramer acetate. All the recommended baseline screening tests and vaccination reviews must be done before starting one of the anti-CD20s.

Natalizumab

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

S1P modulators (fingolimod, siponimod, ozanimod and ponesimod)

Because fingolimod has quite a long half-life, some neurologists recommend a short washout period, i.e. 4 ̶ 6 weeks, before switching to another DMT; this may be appropriate, depending on the reason for switching. I recommend waiting for the total peripheral lymphocyte counts to exceed 800/mm3 to exclude the uncommon occurrence of lymphopaenia following S1P modulator administration. All the recommended baseline screening tests and vaccination reviews must be done before starting an anti-CD20. If you are switching because of abnormal liver function tests on an S1P modulator, you would ideally want the liver enzymes to normalise or at least drop to below three times the upper limit of normal before starting an anti-CD20.

Fumarates

All the recommended baseline screening tests and vaccination reviews must be done before starting an anti-CD20. If lymphopaenia is the main reason for switching from fumarate, I recommend waiting for the total peripheral lymphocyte counts to exceed 800/mm3 before starting an anti-CD20. 

Teriflunomide

All the recommended baseline screening tests and vaccination reviews must be done before starting an anti-CD20. I recommend the total peripheral lymphocyte counts are above 800/mm3 before starting an anti-CD20. We don’t routinely do an accelerated washout of teriflunomide before starting an anti-CD20. 

Anti-CD20 therapies (selective cell depleting DMTs)

If patients switch between formulations of anti-CD20 therapies out of choice (patient preference), it can be done without safety concerns or needing to wait for B-cell counts to recover. If patients are switching for loss of efficacy, I suggest checking for antidrug antibodies and reviewing the diagnosis of MS to try and understand why the individual has not responded to the specific anti-CD20 and/or its formulation. 

Mitoxantrone/alemtuzumab/cladribine/AHSCT

Before starting an anti-CD20 therapy, I recommend waiting for the neutrophil and total peripheral lymphocyte counts to go above 1000/mm3 and 800/mm3, respectively. An exception to this would be the cases of severe rebound that are rarely seen after alemtuzumab. In these circumstances, the anti-CD20 therapy is given to treat very active, often pseudotumoral or tumefactive, MS. All the recommended baseline screening tests must be done before starting an anti-CD20 therapy.

References

  1. Hauser SL, et al. Ocrelizumab versus interferon beta-1a in relapsing multiple sclerosis. N Engl J Med 2017; 376: 221 ̶ 34. doi: 10.1056/NEJMoa1601277.
  2. Montalban X, et al. Ocrelizumab versus placebo in primary progressive multiple sclerosis. N Engl J Med 2017; 376: 209 ̶ 20. doi: 10.1056/NEJMoa1606468.
  3. Hauser SL, et al. Association of higher ocrelizumab exposure with reduced disability progression in multiple sclerosis. Neurol Neuroimmunol Neuroinflamm 2023; 10:e200094. doi:10.1212/NXI.0000000000200094.
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.

Disease-modifying treatmentGuidance
AlemtuzumabNot recommended during breastfeeding; consider breastfeeding for 4 ̶ 6 weeks before restarting alemtuzumab treatment
CladribineCrosses over into the breast milk and may affect the baby. Do not breastfeed whilst taking cladribine and for 10 days after the last pill; consider breastfeeding for 4 ̶ 6 weeks before restarting cladribine treatment
Fumarates (dimethyl fumarate, diroximel fumarate)The manufacturer’s licence recommends caution; however, monomethyl fumarate, a naturally occurring metabolite of the fumarates, is compounded with other medications that are considered safe in pregnancy
Monoclonal antibodies (natalizumab, ocrelizumab, ofatumumab, rituximab)Cross over into breast milk in small amounts, but at low levels that do not generally affect the newborn
S1P modulators (fingolimod, siponimod, ozanimod, ponesimod)Cross over into the breast milk and may affect the baby
TeriflunomideCrosses over into the breast milk and may affect the baby

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

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?

DMTs, Treatment strategy

How immunosuppressed am I?

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

Key points

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

Which DMTs cause immunosuppression?

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

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

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

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

Short-term versus continuous immunosuppression

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

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

How immunosuppressed are you table

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

Selective versus non-selective immunosuppression

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

How immunosuppressed are you_MET vs IRT_6 Sept 2022

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

Other considerations

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

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

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

References

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

Am I eligible for an MS disease-modifying therapy?

Key points

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

  • Disease-modifying treatments (DMTs) change the long-term trajectory of MS and protect the central nervous system.
  • 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 recent years, ocrelizumab and siponimod have been approved for the treatment of active primary progressive MS (PPMS) and active secondary progressive MS (SPMS), respectively, in some countries.
  • 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-effective 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).