Key messages
• Overall, we are very uncertain about the effects of treatments on relapses and slowing the worsening of disability. We did find evidence that rituximab after two years and interferon beta-1b after three years of treatment probably slightly reduce the number of people who experience relapses.
• The number of people who stop taking a drug because of harmful events is slightly higher with interferon beta-1a, and probably slightly higher with interferon beta-1b, rituximab, immunoglobulins, glatiramer acetate, natalizumab, fingolimod, siponimod, and ocrelizumab.
• Longer studies that make comparisons between treatments are needed to assess the benefits and harms of drugs acting on the immune system over time for people with progressive multiple sclerosis. Future studies should also consider other effects that are important to people with progressive multiple sclerosis, such as quality of life and ability to think, learn, remember, use judgement, and make decisions.
Background
Multiple sclerosis is caused by inflammation of the brain and spine due to an impairment of the immune system, resulting in damage that gradually limits activities of daily living. People with multiple sclerosis typically experience tiredness, pain, cramps in their muscles, and reduction or loss of sensitivity and strength in parts of their body. The appearance of symptoms is called 'relapse', and is usually followed by gradual recovery ('remission'), in what is known as 'relapsing-remitting' multiple sclerosis. When recovery doesn't happen or is incomplete between relapses, it is known as 'progressive' multiple sclerosis.
Over the years, in most people with relapsing-remitting multiple sclerosis, worsening of disability will become continuous, without recovery. This is known as 'secondary-progressive' multiple sclerosis. In about 15 out of 100 cases, multiple sclerosis shows a progressive course from the onset, without relapse and recovery. This is called 'primary progressive' multiple sclerosis.
Multiple sclerosis affects males and females in equal proportion, with onset occurring most often between the ages of 30 and 50 years.
How is multiple sclerosis treated?
Although there is no cure for multiple sclerosis, so-called disease-modifying drugs can reduce the frequency of relapses and slow or delay the progression of disability. Fewer treatments are available for progressive multiple sclerosis than for other forms of the disease, but more have been approved in recent years.
What did we want to find out?
We wanted to find out:
• which treatments produce the most benefit, in terms of the number of people with a reduction of relapses or disability worsening; and
• if any drug is better tolerated than any other drug or causes fewer unwanted effects.
What did we do?
We searched for studies that compared different disease-modifying treatments with each other or to placebo ('dummy' or sham treatment). We compared and summarised the results and rated our confidence in the evidence based on factors such as study methods and sizes.
What did we find?
We found 23 studies involving a total of 10,167 people with progressive multiple sclerosis who were treated with a disease-modifying drug or placebo for at least one year. The number of participants enrolled in the studies ranged from 27 to 1651. Most studies lasted 12 or 24 months, with only four studies lasting more than 24 months. Most of the included studies were conducted by drug companies to obtain regulatory approval to sell the drug. Twenty studies compared disease-modifying treatments to placebo, and three studies compared different disease-modifying treatments to each other.
We are confident that slightly more people stop taking interferon beta-1a because of unwanted effects when compared to placebo.
We are moderately confident that rituximab after two years and interferon beta-1b after three years of treatment slightly reduce the number of people with relapses, and slightly more people stop taking interferon beta-1b, rituximab, immunoglobulins, glatiramer acetate, natalizumab, fingolimod, siponimod, and ocrelizumab because of unwanted effects, when compared to placebo.
We are very uncertain about the effect of the other treatments studied on number of people with relapses, number of people with a worsening of disability, number of people who stop taking the drug because of unwanted effects, and number of people with serious unwanted effects.
What are the limitations of the evidence?
Our confidence in the effects of disease-modifying drugs is very limited because the evidence was based on relatively low numbers of people experiencing events like relapses and worsening of disability, and because we were concerned that the interests of drug companies may have influenced the reporting of results.
How up-to-date is this evidence?
The evidence is current to 8 August 2022.
The number of people with PMS with relapses is probably slightly reduced with rituximab at two years, and interferon beta-1b at three years, compared to placebo. Both drugs are also probably associated with a slightly higher proportion of withdrawals due to adverse events, as are immunoglobulins, glatiramer acetate, natalizumab, fingolimod, siponimod, and ocrelizumab; we have high confidence that this is the case with interferon beta-1a.
We found only low or very low certainty evidence relating to disability progression for the included disease-modifying treatments compared to placebo, largely due to imprecision. We are also uncertain about the effect of interventions on serious adverse events, also because of imprecision.
These findings are due in part to the short follow-up of the included RCTs, which lacked detection of less common severe adverse events. Moreover, the funding source of many included studies may have introduced bias into the results.
Future research on PMS should include head-to-head rather than placebo-controlled trials, with a longer follow-up of at least three years. Given the relative rarity of PMS, controlled, non-randomised studies on large samples may usefully integrate data from pivotal RCTs. Outcomes valuable and meaningful to people with PMS should be consistently adopted and measured to permit the evaluation of relative effectiveness among treatments.
In recent years a broader range of immunomodulatory and immunosuppressive treatment options have emerged for people with progressive forms of multiple sclerosis (PMS). While consensus supports these options as reducing relapses, their relative benefit and safety profiles remain unclear due to a lack of direct comparison trials.
To compare through network meta-analysis the efficacy and safety of alemtuzumab, azathioprine, cladribine, cyclophosphamide, daclizumab, dimethylfumarate, diroximel fumarate, fingolimod, fludarabine, glatiramer acetate, immunoglobulins, interferon beta 1-a and beta 1-b, interferon beta-1b (Betaferon), interferon beta-1a (Avonex, Rebif), laquinimod, leflunomide, methotrexate, minocycline, mitoxantrone, mycophenolate mofetil, natalizumab, ocrelizumab, ofatumumab, ozanimod, pegylated interferon beta-1a, ponesimod, rituximab, siponimod, corticosteroids, and teriflunomide for PMS.
We searched CENTRAL, MEDLINE, and Embase up to August 2022, as well as ClinicalTrials.gov and the WHO ICTRP.
Randomised controlled trials (RCTs) that studied one or more treatments as monotherapy, compared to placebo or to another active agent, for use in adults with PMS.
Two review authors independently selected studies and extracted data. We performed data synthesis by pair-wise and network meta-analysis. We assessed the certainty of the body of evidence according to GRADE.
We included 23 studies involving a total of 10,167 participants.
The most frequent (39% of studies) reason for a rating of high risk of bias was sponsor role in study authorship and data management and analysis. Other concerns were performance, attrition, and selective reporting bias, with 8.7% of studies at high risk of bias for all three of these domains.
The common comparator for network analysis was placebo.
Relapses over 12 months: assessed in one study (318 participants). None of the treatments assessed showed moderate or high certainty evidence compared to placebo.
Relapses over 24 months: assessed in six studies (1622 participants). The number of people with clinical relapses is probably trivially reduced with rituximab (risk ratio (RR) 0.60, 95% confidence interval (CI) 0.19 to 1.95; moderate certainty evidence). None of the remaining treatments assessed showed moderate or high certainty evidence compared to placebo.
Relapses over 36 months: assessed in four studies (2095 participants). The number of people with clinical relapses is probably trivially reduced with interferon beta-1b (RR 0.82, 95% CI 0.73 to 0.93; moderate certainty evidence). None of the remaining treatments assessed showed moderate or high certainty evidence compared to placebo.
Disability worsening over 24 months: assessed in 11 studies (5284 participants). None of the treatments assessed showed moderate or high certainty evidence compared to placebo.
Disability worsening over 36 months: assessed in five studies (2827 participants). None of the treatments assessed showed moderate or high certainty evidence compared to placebo.
Serious adverse events: assessed in 15 studies (8019 participants). None of the treatments assessed showed moderate or high certainty evidence compared to placebo.
Discontinuation due to adverse events: assessed in 21 studies (9981 participants). The number of people who discontinued treatment due to adverse events is trivially increased with interferon beta-1a (odds ratio (OR) 2.93, 95% CI 1.64 to 5.26; high certainty evidence). The number of people who discontinued treatment due to adverse events is probably trivially increased with rituximab (OR 4.00, 95% CI 0.84 to 19.12; moderate certainty evidence); interferon beta-1b (OR 2.98, 95% CI 1.92 to 4.61; moderate certainty evidence); immunoglobulins (OR 1.95, 95% CI 0.99 to 3.84; moderate certainty evidence); glatiramer acetate (OR 3.98, 95% CI 1.48 to 10.72; moderate certainty evidence); natalizumab (OR 1.02, 95% CI 0.55 to 1.90; moderate certainty evidence); siponimod (OR 1.53, 95% CI 0.98 to 2.38; moderate certainty evidence); fingolimod (OR 2.29, 95% CI 1.46 to 3.60; moderate certainty evidence), and ocrelizumab (OR 1.24, 95% CI 0.54 to 2.86; moderate certainty evidence). None of the remaining treatments assessed showed moderate or high certainty evidence compared to placebo.