Key messages
• We are uncertain whether rituximab prevents disability worsening in people with any form of multiple sclerosis (MS).
• Rituximab may offer moderate-to-large benefit against a range of other medicines in preventing relapses in relapsing MS, both in people treated with rituximab for the first time and in those given rituximab after other medicines failed to work or became unsuitable.
• Very few people given rituximab in the studies had serious unwanted/harmful events, developed cancer, or died over 24 months' follow-up.
What is multiple sclerosis (MS)?
MS is a disease affecting the central nervous system, in which the body’s immune system mistakenly attacks the protective covering of nerve fibres, which leads to inflammation and damage. Communication between the brain and the rest of the body is affected, resulting in a wide range of symptoms. There are two main types: (1) relapsing MS, where someone has periods of relapse (worsening of symptoms) followed by remissions (improvement or complete recovery); and (2) progressive MS, where symptoms worsen over time, without distinct periods of improvement. Relapsing MS is more common.
How is MS treated?
There is no cure for MS, so the goal of treatment is to manage symptoms, reduce disease activity, slow progression, and improve quality of life. This involves giving people with MS disease-modifying treatments (DMTs), in contrast to treatments which only manage symptoms. There are different kinds of disease-modifying treatments for MS, including rituximab. Rituximab is:
• a medicine given slowly via a needle in a vein (intravenous infusion) that can suppress certain immune cells;
• included in the World Health Organization (WHO) Model List of Essential Medicines for MS, which makes rituximab available worldwide. Rituximab is not always reimbursed by health systems because it is not licensed for MS by marketing authorities;
• a highly effective treatment. It's cheaper and is given less often than other approved medicines for MS. Treatment with rituximab requires specialist care and infusion facilities, but other approved medicines do too.
What did we want to find out?
We wanted to find out the effects of rituximab on people with any form of MS on:
• disability worsening, relapse, and quality of life;
• unwanted effects, such as serious harmful effects, serious common infections, cancer, and death.
What did we do?
We searched for studies that compared rituximab with other infused medicines (e.g. natalizumab), injectable medicines (e.g. interferon beta, glatiramer acetate), and oral medicines (e.g. fingolimod, dimethyl fumarate).
We compared and summarised the results of the included studies, and rated our confidence in the evidence, based on factors such as study methods and quality.
What did we find?
We found 28 studies that involved 37,443 people with MS and lasted one or two years. The biggest study involved 8600 people and the smallest, 27 people. Most people (27,500, 73% of all participants) had a relapsing form of MS, while only 813 (2%) had a progressive form. Three studies included 9130 (24%) people with all forms of MS. Most studies originated from high-income countries. Public institutions funded 22 (79%) of the studies.
MAIN RESULTS
Relapsing forms of MS
• We do not know if rituximab has an effect on long-term disability worsening due to the short follow-up period of the studies.
• For people treated with rituximab for the first time as well as those given rituximab after other medicines failed to work or became unsuitable, rituximab may reduce the risk of relapses compared with interferon beta or glatiramer acetate, dimethyl fumarate, fingolimod, and natalizumab (evidence from 16 studies).
• Serious unwanted effects of rituximab are very few. However, we do not know if rituximab has an effect on long-term serious unwanted effects due to the short follow-up period of the studies.
• Rituximab likely increases serious common infections (i.e. hospital-treated infections) compared with other approved medicines for MS. However, the likelihood of serious common infections occurring is low in terms of the total number of people being considered.
Progressive forms of MS
We do not know if rituximab has benefits for people with primary progressive MS.
What are the main limitations of the evidence?
Our confidence in the evidence is limited because of three main factors. First, people were not randomly placed into different treatment groups in most of the studies. This means that differences between the groups could be due to differences between participants rather than between the comparison treatments. Second, we found few studies in which participants were assigned randomly to different treatment groups. These studies were small and used methods likely to introduce errors in their results. Third, results originated from short-term studies. This is an important issue for people with a lifelong disease such as MS, who need to know the long-term benefits and unwanted effects of a medicine.
How current is the evidence?
This review updates our previous review. The evidence is current to 31 December 2023.
For preventing relapses in relapsing MS, rituximab as 'first choice' and 'switching' treatment compares favourably with a wide range of approved DMTs. The protective effect of rituximab against disability worsening is uncertain. There is limited information to determine the effect of rituximab on primary progressive MS. There is limited evidence for long-term adverse events of rituximab in people with MS. Evidence for serious adverse events, cancer, and mortality was of very low certainty due to few events. There is an increased risk of serious (hospital-treated) infections with rituximab compared with other DMTs, although the absolute risk is low. High-quality (prospectively registered) NRSIs should be conducted to draw more reliable conclusions about the potential benefits and harms of rituximab in people with MS.
Multiple sclerosis (MS) is the most common neurological cause of disability in young adults. Off-label rituximab for MS is used in most countries surveyed by the International Federation of MS, including high-income countries where on-label disease-modifying treatments (DMTs) are available. This updates the 2021 version of the review.
To assess the benefits and harms of rituximab as 'first choice' and 'switching' treatment for adults with any form of MS.
We searched CENTRAL, MEDLINE, Embase, CINAHL, and three trials registers on 31 December 2023, together with reference checking and contacting study authors to identify unpublished studies.
We included randomised controlled trials (RCTs) and controlled non-randomised studies of interventions (NRSIs) comparing rituximab with placebo or another DMT for adults with any form of MS.
We followed standard Cochrane methods. We used RoB 1 to assess risk of bias in RCTs and ROBINS-I in NRSIs. We assessed the certainty of evidence for critical and important prioritised outcomes using GRADE: disability worsening, relapse, serious adverse events (SAEs), health-related quality of life (HRQoL), common infections, cancer, and mortality. We conducted separate analyses for rituximab as 'first choice' or as 'switching' treatment, relapsing or progressive MS, comparison with placebo or another DMT, and RCTs or NRSIs.
In this update, the number of study participants increased from 16,429 (15 studies) to 37,443 (28 studies; 13 new studies: 1 RCT and 12 NRSIs). The studies were conducted worldwide; most originated from high-income countries (25 studies). Public institutions funded 22 (79%) of the studies. Most studies investigated the effects of rituximab on people with relapsing MS (19 studies; 27,500 (73%) participants). We identified 12 ongoing studies.
Rituximab as 'first choice' for active relapsing MS
None of the included studies compared rituximab to placebo.
One RCT compared rituximab to dimethyl fumarate, with 24 months' follow-up. Rituximab may reduce the recurrence of relapse (odds ratio (OR) 0.16, 95% confidence interval (CI) 0.04 to 0.57; 195 participants; low-certainty evidence). The evidence is very uncertain on disability worsening and SAEs. Rituximab may result in little to no difference in upper respiratory tract infections (rate ratio (RR) 1.03, 95% CI 0.79 to 1.34; low-certainty evidence). The evidence is very uncertain for urinary tract, skin, and viral infections. HRQoL, cancer, and mortality were not reported.
One NRSI compared rituximab to other DMTs, with 24 months' follow-up. Disability worsening was not reported. Compared with interferon beta or glatiramer acetate, rituximab likely delays relapse (hazard ratio (HR) 0.14, 95% CI 0.05 to 0.39; 1 study, 335 participants; moderate-certainty evidence). Compared with dimethyl fumarate and natalizumab, rituximab may delay relapse (dimethyl fumarate: HR 0.29, 95% CI 0.08 to 1.00; 1 study, 206 participants; low-certainty evidence; natalizumab: HR 0.24, 95% CI 0.06 to 1.00; 1 study, 170 participants; low-certainty evidence). The evidence for relapse is very uncertain when comparing rituximab to fingolimod. The effect on SAEs is uncertain due to very few events in all the comparison groups. No deaths were reported. HRQoL, common infections, and cancer were not reported.
Rituximab as 'first choice' for primary progressive MS
One RCT compared rituximab to placebo, with 24 months' follow-up. Rituximab likely results in little or no difference in disability worsening (OR 0.71, 95% CI 0.45 to 1.11; 439 participants; moderate-certainty evidence). The evidence is very uncertain on relapse, SAEs, common infections, cancer, and mortality. HRQoL was not reported.
None of the included studies compared rituximab as 'first choice' treatment to other DMTs for primary or secondary progressive MS.
Rituximab as 'switching' treatment for relapsing MS
One small RCT compared rituximab to placebo, with 12 months' follow-up. Disability worsening was not reported. Rituximab may reduce recurrence of relapses (OR 0.38, 95% CI 0.16 to 0.93; 1 study, 104 participants; low-certainty evidence). The evidence is very uncertain regarding SAEs, common infections, cancer, and mortality. HRQoL was not reported.
Twelve NRSIs compared rituximab to other DMTs, with 24 months' follow-up. The evidence on disability worsening is very uncertain in comparison with interferons or glatiramer acetate, natalizumab, alemtuzumab, and ocrelizumab. Rituximab likely delays time to relapse in comparison with interferons or glatiramer acetate (HR 0.18, 95% CI 0.07 to 0.49; 1 study, 1383 participants; moderate-certainty evidence), fingolimod (HR 0.08, 95% CI 0.02 to 0.32; 1 study, 256 participants; moderate-certainty evidence), and may result in little or no difference compared with natalizumab (HR 0.96, 95% CI 0.83 to 1.10; 3 studies, 1922 participants; low-certainty evidence). The evidence is very uncertain on relapse in comparison with alemtuzumab. There is uncertainty regarding SAEs when comparing rituximab to natalizumab and fingolimod. Rituximab likely increases serious common infections when compared with interferon beta or glatiramer acetate (OR 1.71, 95% CI 1.11 to 2.62; 1 study, 5477 participants; moderate-certainty evidence) and natalizumab (OR 1.58, 95% CI 1.08 to 2.32; 2 studies, 5001 participants; moderate-certainty evidence). The evidence for common infections is very uncertain when comparing rituximab to fingolimod and ocrelizumab. Rituximab may slightly reduce the risk of cancer compared with natalizumab (HR 0.79, 95% CI 0.62 to 0.99; 2 studies, 6202 participants; low-certainty evidence), whereas the evidence is very uncertain in comparison with fingolimod. The effect of rituximab on mortality is very uncertain due to very few events in all the comparison groups. HRQoL was not reported.