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Detail, DMTsDetail, Treatment strategy

What are the attributes of the specific DMTs?

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

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

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

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

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

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

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

table format updated 180625 SS

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

How effective are the different DMTs?

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

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

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

Pyramid format updated 180625 SS

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

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

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

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

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

Flipping the pyramid

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

Horizontal versus vertical switching

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

Continuous and intermittent immunosuppression

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

The duration and intensity of immunosuppression further determine the risks. For example, short-term or intermittent immunosuppression associated with IRTs front-loads the risks, which are substantially lower once the immune system has reconstituted itself. In comparison, long-term continuous or persistent immunosuppression, which occurs with some of the maintenance DMTs, accumulates problems over time, particularly opportunistic infections and secondary malignancies. You can read more detail on this topic in the key question How immunosuppressed am I? The following table summarises the main attributes of intermittent and persistent immunosuppression.

How immunosuppressed are you table updated format 180625 SS

The main characteristics of continuous (persistent) and short-term (intermittent) immunosuppression. Modified from Giovannoni, Curr Opin Neurol.2
AHSCT, autologous haematopoietic stem cell transplantation; PML, progressive multifocal leukoencephalopathy.

Adverse effects, monitoring and risk reduction

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

Short-term versus long-term adverse effects

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

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

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

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

Monitoring and risk reduction

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

Administration and other practical considerations

Routes and frequency of administration

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

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

Number of clinic visits

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

Conclusions

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

References

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

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

DMTsShort

Cladribine – short summary

Summary

Cladribine is an immune reconstitution therapy (IRT) that works by depleting your lymphocytes and allowing them to recover over several months. It is selective, mainly targeting B lymphocytes. After your immune system recovers, hopefully without the cells that cause MS, it can fight infections, respond to vaccines and provide peripheral immune surveillance for tumours. Cladribine is given as two courses of oral tablets, each of 2 treatment weeks, during which a patient receives 10 or 20 mg daily for 4 or 5 days.

Cladribine’s mode of action triggers a process called programmed cell death or apoptosis. This means that lymphocytes don’t release their contents via cell lysis but are gradually taken up by cells of the immune system by phagocytosis. As a result, lymphocyte cell death occurs slowly after cladribine administration, and there is no cell lysis syndrome. Therefore, cladribine-treated patients with MS don’t get infusion-type reactions, nor do they need steroids and antihistamines to prevent such reactions.

Cladribine is a highly effective disease-modifying therapy (DMT) with a high rate of no evident inflammatory disease activity (NEIDA), and it slows down disability worsening. It is very well tolerated, with very few side effects. The most common adverse effects are infections, usually mild. A minority of patients may experience a non-specific headache post-cladribine. No delayed secondary autoimmunity is seen, differentiating cladribine from other IRTs used to treat MS.

Cladribine is unlikely to be associated with an increased risk of secondary malignancies, but it is contraindicated in MS patients with active malignancies. Many patients treated with cladribine go into long-term remission. Whether these individuals are cured or not will require much longer follow-up. Cladribine works similarly to alemtuzumab (Lemtrada) or AHSCT (autologous haemopoietic stem cell transplantation) but is a much safer treatment option.

Trade name

Mavenclad.

Mode of action

As an IRT, cladribine aims to kill the cells that cause MS and then reboot the immune system to reset the regulatory mechanisms that keep autoreactive cells under control. It works similarly to alemtuzumab and AHSCT but does not cause infusion-type reactions.

Efficacy

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

Class

Selective immune reconstitution therapy (IRT).

Immunosuppression

Yes, short-term, whilst the immune system is depleted.

Dosing

Two courses of oral tablets over 2 years, with a recommended cumulative dose of 1.75 mg/kg per year.

  • Year 1: month 1, week 1, days 1 ̶ 5; month 2, week 1, days 1 ̶ 5. Each treatment week consists of 4 or 5 days on which a patient receives 10 or 20 mg daily.
  • Year 2: as in year 1 but starting the first dosing week any time up to month 6.

No further cladribine treatment is required in subsequent years unless there is a recurrence of disease activity. No anti-inflammatory pretreatments or prophylactic antivirals and/or antibiotics are required to prevent infusion reactions or infections with cladribine. For fuller details, please refer to Dosing section of cladribine full details summary.

Main adverse events

  • Herpes zoster due to reactivation of the varicella-zoster virus (VZV).
  • Increased likelihood of infections.

Pharmacovigilance monitoring requirements

  • Full range of tests and infection screening at baseline, plus negative urine pregnancy test.
  • Cladribine is contraindicated in MS patients with active malignancies.
  • Full blood count and liver function tests 2 and 6 months after the start of treatment in each treatment year.
  • Be vigilant for unexplained bleeding, bruising, nausea, vomiting, abdominal pain, fatigue, loss of appetite, jaundice and/or dark urine and any symptoms of an infection.
  • A rebaseline MRI is recommended 18 ̶ 24 months after starting treatment, including Gd-enhancement. A monitoring MRI annually thereafter.

Further details about cladribine

Switching-2-cladribine

DMTsShort

Alemtuzumab – short summary

Summary

Alemtuzumab is a monoclonal antibody that targets the surface molecule CD52 on white blood cells or leukocytes. It is given as two courses of intravenous infusions. The first course is five infusions, usually given over five consecutive days in year 1. The second course is three infusions over three consecutive days in year 2. Alemtuzumab works by depleting your white cells and then allowing them to recover over several months. It is an immune reconstitution therapy (IRT); hence, after your immune system returns to normal, hopefully without the cells that cause MS, it can fight infections, respond to vaccines and provide peripheral immune surveillance for tumours. Alemtuzumab is the most effective licensed MS DMT in network analyses comparing it to other DMTs. It promotes a high rate of ‘no evident disease activity’ and prevents or slows down disability worsening; many patients treated with alemtuzumab also notice a sustained improvement in disability. In addition, alemtuzumab effectively ‘normalises’ the accelerated brain volume loss that occurs in people with MS. Its effect on brain volume loss can be explained partially by the fact that alemtuzumab was used early and in relatively young patients with MS in the clinical trials.

The most common adverse effects are infusion reactions, infections and delayed secondary autoimmunity. The adverse event profile changes when alemtuzumab is used in older patients, particularly those with comorbidities. A minority of patients treated with alemtuzumab go into long-term remission with no evident inflammatory disease activity (NEIDA) and no evidence of ongoing end-organ damage. Whether these individuals are cured will require much longer follow-up. Alemtuzumab works similarly to AHSCT (autologous haemopoietic stem cell transplantation) but is a much safer treatment option. 

Trade name

Lemtrada.

Mode of action

An immune reconstitution therapy (IRT) that works by rebooting the immune system. 

Efficacy

Very high.

Class

IRT.

Immunosuppression

Yes, short-term, whilst the immune system is depleted.

Dosing

Two annual courses with up to two additional treatment courses later if needed.

  • Year 1: five 12 mg doses given as five daily intravenous infusions (60 mg total).
  • Year 2: three 12 mg doses given as three daily intravenous infusions (36 mg total). 

Alemtuzumab can be administered successfully by the subcutaneous route in patients who cannot take steroids.

Pre-treatment and prophylaxis treatment

Our centre has a protocol of drugs we administer before alemtuzumab infusions to prevent inflammatory reactions, pain, infection and other common side effects. Guidance about listeriosis prevention is also important.

Main adverse events

  • Infusion reactions: most infusion reactions are mild to moderate; severe infusion reactions are uncommon in patients pretreated with steroids.
  • Infections, notably during the first 4 weeks after starting treatment. Common community-acquired infections (usually mild) can occur later; more serious, opportunistic infections occur in only 2 ̶ 3% of treated patients.
  • Delayed secondary autoimmunity. The most common autoimmune diseases are Grave’s disease, immune thrombocytopenic purpura and Goodpasture’s syndrome. These autoimmune diseases are treatable, generally monophasic (occur just once) and reversible. 
  • Additional adverse events (e.g. cardiovascular and respiratory) have been seen in older people with more advanced MS and multiple comorbidities or risk factors.

Pharmacovigilance monitoring requirements 

  • Standard blood tests and comprehensive screening for infection, pregnancy and blood pressure are done at baseline.
  • A full blood count and urine assessments are done monthly after starting alemtuzumab and up to 4 years after the last course.
  • Unexplained clinical signs and/or symptoms must be detected early and treated promptly. Delayed secondary autoimmunity complications can be avoided with vigilance and monthly blood monitoring.
  • A rebaseline MRI scan should be done 18 ̶ 24 months after starting treatment, including Gd-enhancement. A monitoring MRI is performed annually after that. 
  • Women of childbearing age require a negative urine pregnancy test before starting alemtuzumab. Breastfeeding is not advised. 

Further details about alemtuzumab

Switching-2-alemtuzumab

DMTsShort

Fumarates – short summary

Summary

Fumarates (dimethyl fumarate and diroximel fumarate) are moderate- to high-efficacy platform therapies for treating active MS; they reduce the relapse rate by ~45 ̶ 50% and slow the acquisition of disability. They reduce magnetic resonance imaging (MRI) activity by over 80% but have little effect on brain volume loss in the first 2 years of treatment.

The fumarates are licensed as first-line therapies in the UK but are not recommended for second-line use unless they are being prescribed because another DMT is not tolerated. After the first 7 days, they are taken twice daily; this dosing regimen can lead to poor adherence in some people with MS. Fumarates have a complex and interesting dual mode of action. Firstly, they activate antioxidant and cell survival pathways; secondly, they are anti-inflammatory medications targeting a critical pathway in the inflammatory cascade inside cells. They reduce the circulating lymphocyte count by about 30%, which is not a problem for most people with MS. However, about 5% or 15% of people with MS, respectively, develop grade 3 (<500/mm3) or grade 2 (<800/mm3) lymphopaenia; if prolonged (>6 months) this can increase their risk of opportunistic infections. Progressive multifocal leukoencephalopathy (PML) and other opportunistic infections are rare on fumarates. However, extra vigilance is recommended in patients who are lymphopaenic.

The most common side effects of fumarates are flushing and gastrointestinal events, i.e. diarrhoea, nausea and abdominal pain, all of which tend to begin early (primarily during the first month) and may continue intermittently, particularly the flushing. About one in 10 people with MS discontinues a fumarate due to side effects. Diroximel fumarate is better tolerated than dimethyl fumarate regarding gastrointestinal side effects and flushing.

Blood and urine monitoring is done 3­-monthly for the first 12 months; if there are no problems, we switch to 6-monthly monitoring. Fumarates have no known potential to cause foetal abnormalities when women fall pregnant on the drug or during pregnancy; however, they are not recommended in women of childbearing potential not using appropriate contraception. The decision to stop the drug to fall pregnant or to continue during pregnancy is based on a personal benefit ̶ risk assessment. 

Trade names

Tecfidera (dimethyl fumarate), Vumerity (diroximel fumarate).

Mode of action

Dimethyl and diroximel fumarate are both broken down in the body into monomethyl fumarate. They activate antioxidant and cell survival pathways and have anti-inflammatory effects; their exact mode of action in MS is not known.

Efficacy

Moderate to high; intended as first-line therapy only (in the UK).

Class

Maintenance, immunosuppressive.

Immunosuppression

Yes, but only high-risk if there is persistent lymphopaenia.

Dosing

Dimethyl fumarate dosing

Starting dose: 120 mg twice a day for 7 days; if tolerated, increase to 240 mg twice daily.

Diroximel fumarate dosing

Starting dose: 231 mg twice a day; after 7 days, increase to 462 mg twice daily.

Dose reduction and missed doses

If you miss a dose, do not take a double dose. You may take the missed dose only if it leaves 4 hours between doses. Otherwise, wait until the next scheduled dose. A temporary reduction to the starting dose may reduce flushing and gastrointestinal symptoms. This guidance applies to both fumarates.

Main adverse events

  • Gastrointestinal side effects (cramps, abdominal pain and occasional diarrhoea).
  • Transient flushing, or redness of the face and upper body.
  • Increased risk of PML in older people with MS with prolonged lymphopaenia who are JC virus seropositive.

Pharmacovigilance monitoring requirements

  • Tests for liver function, urine protein and pregnancy.
  • A rebaselining MRI 6 months after starting treatment and including Gd-enhancement.
  • Not recommended for use during pregnancy unless the potential treatment benefit justifies the potential undefined risk to the foetus.
  • Avoid live attenuated vaccines unless the risk of not being vaccinated could outweigh the potential risk of infection.

Further details about fumarates

Switching-2-fumarates

DMTsShort

HSCT (haematopoietic stem cell transplant) – short summary

Summary

HSCT (haematopoietic stem cell transplant) is not a drug, it is a procedure that involves harvesting of stem cells that first need to be mobilised from the bone marrow using a ‘conditioning’ regimen of low-dose chemotherapy and growth factors. The stem cells are harvested from the blood and frozen down or stored. People with MS undergoing HSCT then have their immune system depleted with chemotherapy to a greater (myeloablative HSCT) or lesser extent (non-myeloablative HSCT). The stem cells are re-infused to allow more rapid recovery of bone marrow and immune function. HSCT is not a ‘licensed therapy’ for MS, but it is offered as a treatment for more active disease in many countries – typically for MS that has not responded to standard DMTs. HSCT is on the list of essential off-label DMTs because it is a generic procedure available in many countries. In other words, it can also be used for treating MS where access to high-cost licensed DMTs is limited. 

Types of HSCT

  • So-called myeloablative therapy aims to wipe out your immune system completely and replace it with a new immune system.
  • Non-myeloablative therapy is less intense: it partially depletes your immune system and allows it to be rebooted (partially). Non-myeloablative therapy is less toxic and less risky than myeloablative therapy but also less effective.

Mode of action

HSCT is an immune reconstitution therapy (IRT). It works by depleting your immune system and allowing it to reconstitute. The hope is that when the immune system has reconstituted, the autoimmune cells that cause MS are absent.

Efficacy

Very high.

Class

Non-selective IRT, short-term immunosuppression.

Immunosuppression

Yes, short-term, whilst the immune system is depleted. Once it reconstitutes itself, the immune system is competent.

Protocols

HSCT protocols of different intensities are used to treat MS. Those used in non-myeloablative therapy are less toxic and less risky than in myeloablative therapy but also less effective:

  • low intensity (non-myeloablative)
  • intermediate intensity (non-myeloablative)
  • high intensity (myeloablative).

Adverse events and events of particular interest

High doses of chemotherapy used as part of HSCT can cause serious adverse events. Some of the complications can be life-threatening.

Infection: during the first 6 weeks after HSCT, the risk of getting a serious bacterial or viral infection is high. You will be told what precautions to follow. It takes 3 ̶ 12 months after transplant for the immune system of most patients to recuperate.

Nausea and vomiting are common and are treated with antiemetics.

Mouth and throat pain is a short-term side effect of high-intensity chemotherapy.

Hair loss typically begins within 2 ̶ 3 weeks of treatment. Hair growth will return to normal once the treatment is finished.

Bleeding and bruising are a risk in the early weeks after HSCT; you may be susceptible to nosebleeds and bleeding gums. A platelet transfusion or red blood cell transfusion may be required.

Cardiotoxicity may result from chemotherapy, particularly in older people with MS and people who have received prior cardiotoxic drugs, for example, mitoxantrone.

Neurotoxicity is most likely in people with advanced MS and significant disability treated with high-intensity chemotherapy regimens.

Other complications may include lung problems, hepatic veno-occlusive disease, infertility, secondary autoimmune diseases, graft-versus-host disease, graft failure and secondary cancers.

Pharmacovigilance monitoring and derisking

  • During HSCT, blood tests are frequently done to monitor for bone marrow recovery. If relevant, peripheral blood may be checked for possible reactivation of Epstein-Barr virus or cytomegalovirus.
  • People with MS without antibodies to varicella zoster virus (VZV) should receive the VZV vaccine at least 6 weeks before HSCT to allow time to develop immunity.
  • You should receive advice about minimising your risk of exposure to listeriosis.
  • You may be offered antibiotics to reduce your chances of developing bacterial, fungal and parasitic infections.
  • Pregnancy is contraindicated, and breastfeeding should be discontinued before starting HSCT.
  • A rebaseline MRI is typically done at around 6 months after HSCT.
  • Some units recommend a routine revaccination programme approximately 2 years after HSCT, particularly for individuals who have received an intensive chemotherapy regimen.

Further details about HSCT

Switching-2-HSCT

DMTsShort

Teriflunomide – short summary

Summary

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

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

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

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

Trade name

Aubagio.

Mode of action

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

Efficacy

Moderate.

Class

Maintenance, immunomodulatory.

Immunosuppression

No.

Dosing

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

Main adverse events and monitoring requirements 

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

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

Rebaseline MRI scan, ideally after 6 months of treatment.

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

Further details about teriflunomide

Switching-2-teriflunomide

DMTsShort

Natalizumab – short summary

Summary

Natalizumab is a first-in-class selective adhesion molecule blocker that reduces the trafficking of lymphocytes into the central nervous system (CNS). It is a very high-efficacy DMT capable of achieving long-term NEIDA (no evident inflammatory disease activity) and limiting end-organ damage (brain volume loss) in most people with MS who receive it. Following rebaselining, average annual brain volume loss for patients treated with natalizumab is within the expected range for age-matched people without MS. Natalizumab has a rapid onset of action; when it is used early in the disease course, many people with MS report a reduction in symptoms of disability and fatigue.

One result of reduced lymphocyte trafficking in the brain is reduced immune surveillance. This puts patients receiving natalizumab at high risk of progressive multifocal leukoencephalopathy (PML) if infected with the JC virus that causes it. The risk of PML is variable and can be reduced by using extended interval dosing (EID), whereby natalizumab is given as a 6-weekly infusion and is very well tolerated. (Normally natalizumab is given every 4 weeks.) A small number of people with MS (<5%) may develop infusion reactions, which can be serious. Infusion reactions typically come on with the second, third or fourth natalizumab infusion and are associated with developing so-called neutralising antibodies (NAbs). 

Trade name

Tysabri.

Mode of action

Natalizumab is an immunosuppressive, and it is associated with opportunistic infections and possibly secondary malignancies of the central nervous system (CNS). Natalizumab blocks one of the surface molecules on lymphocytes so that they cannot cross the blood ̶ brain barrier.

Efficacy

Very high, particularly in people with rapidly evolving severe MS.

Class

Maintenance, immunosuppressive.

Immunosuppression

Yes, but limited to the CNS.

Dosing

  • Natalizumab 300 mg is administered by intravenous infusion or subcutaneous injection once every 4 weeks.
  • Extended interval dosing (EID), decreasing the frequency of infusions to every 6 weeks, reduces the risk of PML.

Main adverse events of special interest

  • Infusion reactions; hypersensitivity reactions with repeated infusion of the drug.
  • JC virus (JCV), the commonest opportunistic infection, causes progressive multifocal leukoencephalopathy (PML) and granule cell neuronopathy. Management of PML is described separately.
  • Other opportunistic infections include cryptosporidium diarrhoea, cryptococcal meningitis, life-threatening encephalitis and meningitis.
  • CNS lymphoma is a risk because of reduced immune surveillance.

Pharmacovigilance monitoring requirements

  • Tests for liver function, neutralising antibodies, JCV.
  • Rebaseline magnetic resonance imaging (MRI) 3 ̶ 6 months after starting treatment and increased MRI monitoring where PML risk is high.
  • Self-monitoring for opportunistic infections; monthly breast checks.
  • Live vaccines can infect the CNS and are contraindicated.

Further details about natalizumab

Further details about natalizumab PML

Switching-2-natalizumab

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

DMTsShort

Interferon-beta – short summary

Summary

Interferon-beta (IFN-beta) preparations have been the workhorse of MS treatment for decades. They are moderately effective; only a minority of people with MS receiving IFN-beta achieve long-term NEIDA (no evident inflammatory disease activity). Their impact on preventing end-organ damage (brain volume loss) and reducing neurofilament levels (an indicator of damaged nerve fibres) is modest. In general, IFN-beta formulations are poorly tolerated in the short term owing to injection site reactions and flu-like side effects, but both these side effects can be effectively managed in most people with MS. Monitoring requirements are not too onerous. Adherence has been a problem long-term owing to injection fatigue. IFN-beta is a biological so it can induce neutralising antibodies (NAbs), the rate of which varies according to the different formulations.

IFN-beta belongs to the class of cytokines and is produced by the body to help fight infections, particularly viral infections and possibly cancers. IFN-beta also plays a role in foetal bone development. I have long had concerns about the potential of anti-IFN-beta NAbs to neutralise one’s own IFN-beta and to cross the placenta and affect the role of IFN-beta in foetal development. Therefore, I have favoured the formulations with the lowest NAb levels. Given that more effective DMTs are now available, with more favourable attributes, most people with MS tend to choose other, non-injectable treatments. Despite this, there is still a role for IFN-beta preparations in the treatment of MS, particularly as they have now been shown to be safe in pregnancy.

Trade names

Avonex (IFN-beta-1a), Betaferon (IFN-beta-1b), Betaseron (IFN-beta-1b), Extavia (IFN-beta-1b), Plegridy (Peg-IFN-beta-1a), Rebif (IFN-beta-1a).

Mode of action

Immunomodulatory, with many different effects on the immune system. In general, IFN-beta is not immunosuppressive.

Efficacy

Moderate.

Class

Maintenance, immunomodulatory.

Immunosuppression

No.

Dosing 

  • Betaseron, Betaferon, Extavia; 250 micrograms (µg) subcutaneous (SC) alternate days.
  • Avonex; 30 µg IM weekly.
  • Rebif; 22/44 µg SC three times a week.
  • Plegridy; 125 µg SC or IM 2-weekly.

Main adverse events and monitoring requirements

  • Injection site reactions, flu-like symptoms, abnormal liver function tests (LFTs), low lymphocyte counts (lymphopaenia), low white cell counts (leukopaenia).
  • Increased risk of spontaneous abortion. Initiation of treatment is not recommended during pregnancy, but termination of pregnancy is not necessary in case of unplanned pregnancy; established IFN-beta treatment can generally be continued throughout pregnancy.

Rare adverse events of special interest

  • Thrombotic microangiopathy, which manifests as so-called thrombotic thrombocytopenic purpura or haemolytic ̶ uraemic syndrome, i.e. low platelet levels, blood clots, brusing and renal failure.
  • Liver failure or autoimmune hepatitis.
  • Pulmonary oedema, or capillary leak syndrome, in patients with a monoclonal gammopathy.
  • Severe bone marrow suppression.

Further details about IFN-beta

Switching-2-interferon-beta