Disease-modifying therapies for multiple sclerosisBMJ 2018; 363 doi: https://doi.org/10.1136/bmj.k4674 (Published 27 November 2018) Cite this as: BMJ 2018;363:k4674
- Floriana De Angelis, clinical research associate1,
- Nevin A John, clinical research associate1,
- Wallace J Brownlee, clinical research fellow and locum consultant neurologist1 2
- 1Queen Square MS Centre, Department of Neuroinflammation, UCL Queen Square Institute of Neurology, London, UK
- 2National Hospital for Neurology and Neurosurgery, Queen Square, London, UK
- Correspondence to: F De Angelis
- This is one of a series of occasional articles on therapeutics for common or serious conditions, covering new drugs and old drugs with important new indications or concerns. The series advisers are Robin Ferner, honorary professor of clinical pharmacology, University of Birmingham and Birmingham City Hospital, and Patricia McGettigan, clinical senior lecturer in clinical pharmacology, Queen Mary's University, London. To suggest a topic, please email us at .
What you need to know
Disease-modifying therapies (DMTs) early in the course of active relapsing multiple sclerosis can prevent relapses, new brain and spinal cord lesions, and worsening neurological disability
Some DMTs are associated with potentially serious adverse reactions, and careful monitoring is required, usually through a specialist multiple sclerosis clinic
Newer DMTs have better short term outcomes than older DMTs, but there are insufficient data about their long term effectiveness and harms
A 32 year old woman with multiple sclerosis presented to her general practitioner with a five day history of numbness and weakness in the right leg. She felt well in herself and did not describe any symptoms to suggest an intercurrent infection. She had been taking weekly intramuscular injections of interferon beta-1a for the previous 18 months and reported flu-like symptoms that could last for up to 24 hours after each dose. She asked if there was a need to change her treatment and what alternatives were available.
Multiple sclerosis is a chronic, immune-mediated, demyelinating disorder of the central nervous system affecting over two million people worldwide.1 It is a major cause of physical disability in young adults and can have profound implications for cognition, emotional wellbeing, and employment. Patients commonly present with unilateral visual loss (due to optic neuritis), double vision, sensory symptoms, limb weakness, or imbalance.2 The diagnosis is based on clinical features and findings on magnetic resonance imaging (MRI), sometimes supported by lumbar puncture and other investigations.23
Nearly 80-85% of people with multiple sclerosis experience a relapsing course: episodes (attacks or relapses) of new or worsening neurological symptoms lasting at least 24 hours, followed by full or partial recovery, in the absence of fever or infection (fig 1).3 If left untreated, most people with relapsing multiple sclerosis develop disability over time. This can be caused by incomplete recovery from relapses or due to development of progressive multiple sclerosis, with a steady increase in disability. In 10-15% of people with multiple sclerosis the disease is progressive from the onset (primary progressive multiple sclerosis).
What treatments are available for multiple sclerosis?
Several oral and monoclonal antibody therapies for multiple sclerosis have become available in the past decade (fig 2).
Relapsing multiple sclerosis—Currently, 15 disease-modifying therapies (DMTs) are licensed for relapsing multiple sclerosis, including five preparations of interferon beta and three preparations of glatiramer acetate.24
Progressive multiple sclerosis—Ocrelizumab,6 the first treatment for primary progressive multiple sclerosis, has recently been licensed.
Inactive multiple sclerosis—No treatment is advised for patients with inactive multiple sclerosis.7
Clinically isolated syndrome—The ECTRIMS/EAN and AAN guidelines recommend interferon beta or glatiramer acetate in patients with a clinically isolated syndrome. This is the first episode of neurological symptoms suggestive of multiple sclerosis with brain MRI abnormalities (indicating a high risk of multiple sclerosis). The aim of treatment is to delay a second attack.89
The indications differ based on licensing by regulatory agencies (see appendix on bmj.com). International guidelines recommend offering DMTs to patients with active relapsing multiple sclerosis (table 1).789
Mechanisms of action
The DMTs have varying mechanisms of action (box 1) with immunosuppressive and immunomodulatory effects that target:
Mechanisms of action of the licenced disease-modifying therapies for multiple sclerosis
Alemtuzumab—Monoclonal antibody that binds to CD52 surface protein on T and B lymphocytes, resulting in their depletion with subsequent re-population. Exact mechanism of action in relapsing multiple sclerosis not fully elucidated
Cladribine—Anti-metabolite that results in rapid depletion of T and B cells, which interrupts the immune processes involved in the pathophysiology of multiple sclerosis
Dimethyl fumarate—Mechanism of action not fully understood. Nrf2 pathway activation and NFkB inhibition postulated to cause alteration in immune cell activation and inflammatory cytokine balance
Fingolimod—Sphingosine-1-receptor modulator that results in lymphocyte sequestration thus decreasing infiltration of pro-inflammatory T cells into the central nervous system
Glatiramer acetate—Random amino acid copolymer. Mechanism of action in MS not fully elucidated but postulated to exert effects through T cell immunomodulation
Interferon beta—Immunomodulation mediated by enhancement of suppressor T cell activity, reduction of pro-inflammatory cytokine production, down-regulation of antigen presentation, and inhibition of lymphocyte trafficking into the central nervous system
Mitoxantrone—Anthracenedione, antineoplastic agent that has been shown in vitro to inhibit B cell, T cell, and macrophage proliferation. Shown to impair antigen presentation as well as the secretion of several pro-inflammatory cytokines. Its effect in MS is thought to be a result of immunosuppression.
Natalizumab—Monoclonal antibody (α4-integrin receptor antagonist) that decreases activated T cell migration across the blood-brain barrier. Also decreases leucocyte migration with subsequent reduction in inflammation of central nervous system
Ocrelizumab—Recombinant humanised monoclonal antibody directed against CD20 antigen expressed by B cells, resulting in their rapid depletion. Mechanism of action in MS not fully understood
Teriflunomide—Pyrimidine synthesis inhibitor. Decreases proliferation of dividing cells that require de novo synthesis of pyrimidine to expand (such as lymphocytes). Immunomodulatory effect in MS poorly understood but thought to be mediated by reduced number of lymphocytes
MS= multiple sclerosis. Nrf2 = nuclear factor erythroid 2-related factor. NF-κB = nuclear factor kappa-light-chain-enhancer of activated B cells.
Lymphocyte number (alemtuzumab, ocrelizumab, cladribine)
Lymphocyte proliferation (teriflunomide, mitoxantrone)
Lymphocyte trafficking (fingolimod, natalizumab)
Cytokine production (interferon beta, glatiramer acetate).
The mechanisms of action of DMTs are not fully understood because of our incomplete understanding of the disease pathophysiology. Nevertheless, by acting on the immune system that is dysregulated in multiple sclerosis, DMTs limit central nervous system inflammation, preventing the occurrence of relapses and new inflammatory lesions.
How well do they work?
With the exception of ocrelizumab, which is the only drug licensed for primary progressive multiple sclerosis, DMTs have been found to be effective only in the relapsing forms of the disease. There is moderate to high quality evidence from phase III randomised controlled trials and systematic reviews of DMTs.1011 These studies show that DMTs reduce relapses, accumulation of new brain MRI lesions, and disability progression over two to three years in active relapsing multiple sclerosis compared with placebo or an active comparator (interferon beta).4 Table 2 describes findings of phase III randomised placebo-controlled or active comparator trials of DMTS. Based on their impact on relapses compared with placebo (or interferon beta), the DMTs can be categorised as moderately effective (interferon beta, glatiramer acetate, teriflunomide, dimethyl fumarate, fingolimod) or highly effective drugs (natalizumab, ocrelizumab, alemtuzumab, cladribine, and mitoxantrone).7 The highly effective DMTs are associated with more serious safety concerns and require greater safety monitoring.
DMTs generally do not improve established symptoms of multiple sclerosis, though preliminary evidence suggests some improvement in disability with alemtuzumab and natalizumab.2930 Observational studies report conflicting evidence on the impact of interferon beta in reducing long term disability and development of secondary progressive multiple sclerosis.3132
Few studies have directly compared different DMTs. A systematic review (five randomised controlled trials, 2858 participants) comparing interferon beta preparations and glatiramer acetate found a similar effect on relapses and disability progression, although secondary MRI endpoints favoured interferon beta.33 In separate phase III randomised controlled trials, interferon beta had similar efficacy to teriflunomide, and was less effective than fingolimod, alemtuzumab, and ocrelizumab.18192021222326
A Cochrane network meta-analysis in 2015 (39 randomised controlled trials, 25 113 participants) looked at the efficacy of 15 DMTs (including three different preparations of interferon beta). It found moderate to high quality evidence that, over a 24 month period, three treatments were more effective than placebo for preventing relapses—alemtuzumab (risk ratio 0.46 (95% confidence interval 0.38 to 0.55)), natalizumab (0.56 (0.47 to 0.66)), and fingolimod (0.72 (0.64 to 0.81))—and there was moderate quality evidence that natalizumab was more effective than placebo for preventing disability worsening (0.64 (0.49 to 0.85)).10 Most of the studies were sponsored by pharmaceutical companies and had a short follow-up (median 24 months). Long term benefits of DMTs are uncertain as most trials are of two to three years’ duration.
In 2017 a network meta-analysis (33 studies, 21 768 participants with relapsing multiple sclerosis) evaluated 16 DMTs including five formulations of interferon beta and three of glatiramer acetate and the newly approved ocrelizumab (not reported in the Cochrane review).11 Alemtuzumab, natalizumab, and ocrelizumab had the greatest reduction in the annualised relapse rates (approximately 70% reduction compared with placebo); fingolimod and dimethyl fumarate were the next most effective (47-54% reduction); and the interferons, glatiramer acetate, and teriflunomide were less effective (17-37% reduction). This analysis is limited by short duration of trials and the lack of head-to-head trials. Furthermore, the evolving diagnostic criteria for multiple sclerosis may have caused important variations among the studied patient populations across trials.
What are the harms?
Flu-like symptoms (interferon beta); headache (interferon beta, fingolimod); gastrointestinal upset (dimethyl fumarate, teriflunomide); and injection site reactions (interferon beta, glatiramer acetate) are common (≥1% to <10% of patients taking the drug) or very common (≥10% of patients), as reported in the relevant summaries of product characteristics. These reactions are generally mild but can be bad enough that patients stop taking the drug and sometimes require a change of treatment. Infusion reactions are common with alemtuzumab and ocrelizumab. The Cochrane review noted poor reporting of serious adverse events and lack of long-term safety data in most trials, leading to uncertainty about the risk profile of the treatments, particularly in the long-term.10
Oral and monoclonal antibody treatments can have serious adverse reactions (see box 2). Their long term safety profile is unknown. Daclizumab, an anti-CD25 monoclonal antibody, has recently been withdrawn after cases of severe liver injury and immune-mediated encephalitis not observed in phase III clinical trials. Post-authorisation safety studies and pharmacovigilance are essential for all newly approved DMTs, and can lead to marketing authorisation changes by the regulatory agencies. Natalizumab and alemtuzumab are subject to a Risk Evaluation and Mitigation Strategy by the Food and Drug Administration (FDA), requiring training and support for healthcare providers to monitor patients during treatment to reduce the occurrence or severity of serious risks.
Serious adverse reactions with disease-modifying therapies for multiple sclerosis and precautions437
Progressive multifocal leukoencephalopathy (PML)
• This is an opportunistic brain infection, due to reactivation of the John Cunningham virus (JCV), that can complicate treatment with natalizumab and is associated with high rates of death or disability
• JCV serostatus and antibody index should be checked before starting natalizumab (and periodically during treatment) to stratify PML risk
• PML has rarely been reported in patients taking fingolimod (estimated risk <1:10 000) and dimethyl fumarate who have not been treated with natalizumab
• MRI monitoring is mandatory in patients treated with natalizumab, fingolimod, dimethyl fumarate, on at least an annual basis, and every 3-6 months in natalizumab-treated patients at high risk of PML38
• Fingolimod causes first-dose bradycardia (~1-2%) and rarely transient heart block (<0.5%)
• An electrocardiogram should be obtained before starting treatment, and the first dose administered with heart rate monitoring for 6 hours after the first dose
• Cases of ventricular tachycardia and sudden cardiac death have also been reported
• Fingolimod should be avoided in patients with a history of ischaemic heart disease or cardiac arrhythmias
• Deranged liver function tests commonly occur with several DMTs (particularly interferon beta, dimethyl fumarate, and fingolimod)
• Individual cases of fatal liver injury have been reported with leflunomide (the pro-drug of teriflunomide). Teriflunomide should be avoided in people with a history of liver disease
• Autoimmune thyroid disease, immune thrombocytopenic purpura, and glomerulonephritis may occur in people treated with alemtuzumab, most often in the second or third year after starting treatment (risk of secondary autoimmunity ~50% at 5 years)
• DMTs should not be prescribed in patients with an active malignancy, and their safety in patients with a history of cancer is uncertain
• Fingolimod is associated with an increased risk of skin cancers, particularly basal cell carcinoma
• Mitoxantrone is associated with an increased risk of acute myeloid leukaemia (0.5-1%) and possibly solid-organ cancers
• The long term risk of cancer with other DMTs is unknown
How are they given and monitored?
DMTs are prescribed and monitored in secondary care, often through specialist multiple sclerosis clinics with neurologists, nurse specialists, and pharmacists. The route (subcutaneous or intramuscular injection, oral, intravenous) and frequency of administration differ by the drug. A discussion of the risks and benefits of treatment is important. Box 3 lists important considerations when selecting DMTs. Blood monitoring is required for all DMTs (except glatiramer acetate), particularly full blood count (to detect lymphopenia) and liver function tests. The frequency and type of blood test and other monitoring, such as brain MRI or urine test, are mandated by regulatory authorities (table 2).
Factors influencing choices of DMT for multiple sclerosis
Desire for pregnancy
Burden of monitoring
Healthcare system factors
Resources (such as infusion facilities)
Most DMTs require ongoing treatment, with return of disease activity if the drug is interrupted or stopped. Some DMTs (alemtuzumab, cladribine) have immune-reconstitution properties with sustained effects in the absence of ongoing treatment. Adherence to treatment is important, and DMTs may be changed in patients with side effects. There is no guidance on stopping treatment; this is usually decided by the treating neurologist in discussion with the patient based on the response and side effects (box 3).
Periodic clinical reviews to check for relapses or disability progression and for MRI are used to monitor response to treatment. Evidence of disease activity on MRI is associated with an increased risk of disability progression even in patients who are clinically stable.3940 Some neurologists use the target of “no evidence of disease activity” when treating relapsing multiple sclerosis, recommending a change of treatment if there are ongoing relapses, new MRI activity, or disability progression.41 The benefits of this approach are uncertain.4243
How cost effective are they?
DMTs account for over half of direct medical costs in people with multiple sclerosis.44 There is wide variation in the cost of DMTs between countries. The cost of DMTs has increased dramatically in the US over the past 10 years with 10-15% increase annually: the annual cost of most DMTs now exceeds $70 000/year.44 Several studies have found that DMTs are not cost effective at accepted economic thresholds.44 A recent analysis noted that, of the currently available DMTs, alemtuzumab may be most cost effective because of higher efficacy and unique dosing strategy (two cycles of treatment over two years with further treatment given only if needed).11 Lower drug pricing (as in the UK45), the availability of generic drugs,46 off-label prescribing (such as rituximab47), and the increasing use of DMTs that do not require ongoing maintenance treatment may improve cost effectiveness.
Tips for safer prescribing
DMTs are contraindicated in patients with active infections or malignancy, and in patients taking other immunosuppressants37
Fingolimod has interactions with CYP3A4 enzyme inhibitors (azole antifungals, macrolides antibiotics, protease inhibitors) and inducers (rifampicin, carbamazepine, St John’s wort), and pharmacodynamic interactions with β blockers and calcium channel blockers. Co-administration of fingolimod with these drugs should be approached with caution and concomitant administration with St John’s wort is not recommended.
Follow regulatory authority guidance on blood, urine, and MRI monitoring requirements.
Pregnancy and breastfeeding
Women taking DMTs should be counselled to use effective contraception
DMTs are usually stopped before conception, although interferon beta and glatiramer acetate may be safe during conception and pregnancy.48 The EMA recently updated the label of branded glatiramer acetate to remove pregnancy as a contraindication
Teriflunomide is teratogenic, and an accelerated elimination procedure may be required before conception because of its long half-life
Preconception planning to make decisions regarding DMTs and obstetric care should be considered in women with multiple sclerosis49
Live or live attenuated vaccines should be avoided in patients taking most DMTs. Patients who are IgG negative for varicella-zoster virus should be immunised, particularly before treatment with fingolimod or cladribine37
Tips for patients
Several disease-modifying therapies (DMTs) are available for relapsing multiple sclerosis to decrease the risk of developing relapses or new MRI lesions. Discuss the options with a specialist multiple sclerosis team to select the treatment that fits best with your preferences
DMTs do have potential side effects, some of which are serious
Almost all DMTs have monitoring requirements such as routine blood tests, but some treatments need more monitoring than others, such as special blood tests, urine tests, and brain MRI. Your multiple sclerosis team will explain to you what kind of monitoring you require
New symptoms might mean a change of DMT is required. Know how to contact your multiple sclerosis nurse specialist or neurologist if you have new or worsening symptoms between clinic visits
MRI scans are an important part of deciding how well DMTs are working. When was your last MRI?
Some DMTs are unsafe for women who are pregnant or breastfeeding. If you are considering becoming pregnant, then discuss this with your multiple sclerosis team
Education into practice
How might non-specialists be involved in discussions about treatments for multiple sclerosis?
If you provide care for women who take DMTs have you or another clinician discussed contraceptive options?
Would placing an alert on the electronic patient record for people receiving DMTs aid recognition of complications of treatment in patients presenting acutely in primary or secondary care?
How patients were involved in the creation of this article
We asked two patients who attend our specialist multiple sclerosis clinic to comment on the draft manuscript and develop the “Tips for patients” box. They highlighted the importance of early referral to a specialist multiple sclerosis team, the importance of lifestyle factors and burden of monitoring when selecting DMTs, and contraception and preconception counselling in women with multiple sclerosis.
Contributors: FDA and WJB participated in the conception and design of the article and drafting, revision, and final approval of the manuscript for publication. NAJ participated in the conception and design of the article, preparation of the table, and revision of the manuscript. WJB is guarantor.
Competing interests: We have read and understood BMJ policy on declaration of interests and declare the following interests: WJB has received speaker fees for educational activities from Merck Serono, which produces interferon beta-1a used to treat multiple sclerosis.
Provenance and peer review: Commissioned; externally peer reviewed.
Patient consent not required (patient anonymised or hypothetical).