Treatment for multiple sclerosis (MS), a chronic inflammatory disease of the central nervous system, has changed drastically in the last thirty years. Several different disease-modifying therapies ...are now available, with off-label use of the B-cell-depleting antibody rituximab becoming an increasingly popular choice, as more and more studies report on its effectiveness.
To summarize the current state of evidence for rituximab as a treatment for relapsing-remitting MS (RRMS).
A structured literature search was conducted in PubMed, focusing on peer-reviewed studies of adult populations with RRMS. Ongoing trials with rituximab in MS were identified through Clinicaltrials.gov and additional references were identified through review articles.
Despite promising results for rituximab as a treatment of MS, the market-authorization holder switched focus from rituximab and discontinued the industry-sponsored trials programme. However, several observational studies, smaller clinical trials, and one large investigator-initiated randomized-controlled trial have continued to report fewer clinical relapses, fewer contrast-enhancing lesions on magnetic resonance imaging, and better drug survival with rituximab, compared with MS-approved alternatives.
Rituximab should be considered as both a first-line and second-line therapy option for most MS patients with active, non-progressive disease. However, as an off-label therapy for MS, regulatory approval remains a barrier for wider adoption in many countries.
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IMPORTANCE: Although highly effective disease-modifying therapies for multiple sclerosis (MS) have been associated with an increased risk of infections vs injectable therapies interferon beta and ...glatiramer acetate (GA), the magnitude of potential risk increase is not well established in real-world populations. Even less is known about infection risk associated with rituximab, which is extensively used off-label to treat MS in Sweden. OBJECTIVE: To examine the risk of serious infections associated with disease-modifying treatments for MS. DESIGN, SETTING, AND PARTICIPANTS: This nationwide register-based cohort study was conducted in Sweden from January 1, 2011, to December 31, 2017. National registers with prospective data collection from the public health care system were used. All Swedish patients with relapsing-remitting MS whose data were recorded in the Swedish MS register as initiating treatment with rituximab, natalizumab, fingolimod, or interferon beta and GA and an age-matched and sex-matched general population comparator cohort were included. EXPOSURES: Treatment with rituximab, natalizumab, fingolimod, and interferon beta and GA. MAIN OUTCOMES AND MEASURES: Serious infections were defined as all infections resulting in hospitalization. Additional outcomes included outpatient treatment with antibiotic or herpes antiviral medications. Adjusted hazard ratios (HRs) were estimated in Cox regressions. RESULTS: A total of 6421 patients (3260 taking rituximab, 1588 taking natalizumab, 1535 taking fingolimod, and 2217 taking interferon beta/GA) were included, plus a comparator cohort of 42 645 individuals. Among 6421 patients with 8600 treatment episodes, the mean (SD) age at treatment start ranged from 35.0 (10.1) years to 40.4 (10.6) years; 6186 patients were female. The crude rate of infections was higher in patients with MS taking interferon beta and GA than the general population (incidence rate, 8.9 95% CI, 6.4-12.1 vs 5.2 95% CI, 4.8-5.5 per 1000 person-years), and higher still in patients taking fingolimod (incidence rate, 14.3 95% CI, 10.8-18.5 per 1000 person-years), natalizumab (incidence rate, 11.4 95% CI, 8.3-15.3 per 1000 person-years), and rituximab (incidence rate, 19.7 95% CI, 16.4-23.5 per 1000 person-years). After confounder adjustment, the rate remained significantly higher for rituximab (HR, 1.70 95% CI, 1.11-2.61) but not fingolimod (HR, 1.30 95% CI, 0.84-2.03) or natalizumab (HR, 1.12 95% CI, 0.71-1.77) compared with interferon beta and GA. In contrast, use of herpes antiviral drugs during rituximab treatment was similar to that of interferon beta and GA and lower than that of natalizumab (HR, 1.82 1.34-2.46) and fingolimod (HR, 1.71 95% CI, 1.27-2.32). CONCLUSIONS AND RELEVANCE: Patients with MS are at a generally increased risk of infections, and this differs by treatment. The rate of infections was lowest with interferon beta and GA; among newer treatments, off-label use of rituximab was associated with the highest rate of serious infections. The different risk profiles should inform the risk-benefit assessments of these treatments.
Objective
Although off‐label use of rituximab is a common alternative to disease‐modifying therapies (DMTs) approved for multiple sclerosis (MS) in several countries, the impact of this on treatment ...cost‐effectiveness is not well known.
Methods
We evaluated the relative cost‐effectiveness of rituximab and MS‐approved DMTs in a register‐based cohort study of Swedish residents with relapsing–remitting MS, aged 18–65 years, starting treatment with rituximab, natalizumab, fingolimod, or dimethyl fumarate between January 2010 and July 2016, and followed through July 2021 (n = 5,924). By linking the population‐based Swedish MS register to several Swedish health care and demographic registers, we estimated health care costs in relation to number of relapses, over 5 years from treatment start. Differences between treatments were estimated in inverse probability of treatment‐weighted regression models, adjusting for a broad range of potential confounders covering demographics, medical history, and MS‐related clinical characteristics.
Results
Off‐label rituximab was associated with both lower total health care costs (mean cost savings ranged $35,000–$66,000 vs. each approved DMT), and fewer relapses (mean number of prevented relapses ranged 0.12–0.22), per started therapy over 5 years. Results were robust to variations in discounting and pricing of health care visits, with the main driver of cost‐savings being the price of the index drug itself.
Interpretation
The cost‐effectiveness of rituximab dominated the MS‐approved alternatives. Off‐label, low‐dose rituximab should be considered for persons with MS and could reduce barriers to treatment, especially in resource‐limited settings. ANN NEUROL 2024;95:1099–1111
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4.
Rituximab in multiple sclerosis Salzer, J.; Svenningsson, R.; Alping, P. ...
Neurology,
11/2016, Volume:
87, Issue:
20
Journal Article
Objective
Many JC virus antibody‐positive relapsing–remitting multiple sclerosis (RRMS) patients who are stable on natalizumab switch to other therapies to avoid progressive multifocal ...leukoencephalopathy.
Methods
We compared outcomes for all RRMS patients switching from natalizumab due to JC virus antibody positivity at 3 Swedish multiple sclerosis centers with different preferential use of rituximab and fingolimod (Stockholm, n = 156, fingolimod 51%; Gothenburg, n = 64, fingolimod 88%; Umeå, n = 36, fingolimod 19%), yielding a total cohort of N = 256 (fingolimod 55%).
Results
Within 1.5 years of cessation of natalizumab, 1.8% (rituximab) and 17.6% (fingolimod) of patients experienced a clinical relapse (hazard ratio for rituximab = 0.10, 95% confidence interval CI = 0.02–0.43). The hazard ratio (favoring rituximab) for adverse events (5.3% vs 21.1%) and treatment discontinuation (1.8% vs 28.2%) were 0.25 (95% CI = 0.10–0.59) and 0.07 (95% CI = 0.02–0.30), respectively. Furthermore, contrast‐enhancing lesions were found in 1.4% (rituximab) versus 24.2% (fingolimod) of magnetic resonance imaging examinations (odds ratio = 0.05, 95% CI = 0.00–0.22). Differences remained when adjusting for possible confounders (age, sex, disability status, time on natalizumab, washout time, follow‐up time, and study center).
Interpretation
Our findings suggest an improved effectiveness and tolerability of rituximab compared with fingolimod in stable RRMS patients who switch from natalizumab due to JC virus antibody positivity. Although residual confounding factors cannot be ruled out, the shared reason for switching from natalizumab and the preferential use of either rituximab or fingolimod in 2 of the centers mitigates these concerns. Ann Neurol 2016;79:950–958
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OBJECTIVE:To investigate the safety and efficacy of rituximab in multiple sclerosis (MS).
METHODS:In this retrospective uncontrolled observational multicenter study, off-label rituximab-treated ...patients with MS were identified through the Swedish MS register. Outcome data were collected from the MS register and medical charts. Adverse events (AEs) grades 2–5 according to the Common Terminology Criteria for Adverse Events were recorded.
RESULTS:A total of 822 rituximab-treated patients with MS were identified557 relapsing-remitting MS (RRMS), 198 secondary progressive MS (SPMS), and 67 primary progressive MS (PPMS). At baseline, 26.2% had contrast-enhancing lesions (CELs). Patients were treated with 500 or 1,000 mg rituximab IV every 6–12 months, during a mean 21.8 (SD 14.3) months. During treatment, the annualized relapse rates were 0.044 (RRMS), 0.038 (SPMS), and 0.015 (PPMS), and 4.6% of patients displayed CELs. Median Expanded Disability Status Scale remained unchanged in RRMS (p = 0.42) and increased by 0.5 and 1.0 in SPMS and PPMS, respectively (p = 0.10 and 0.25). Infusion-related AEs occurred during 7.8% of infusions and most were mild. A total of 89 AEs grades ≥2 (of which 76 infections) were recorded in 72 patients. No case of progressive multifocal leukoencephalopathy was detected.
CONCLUSIONS:This is the largest cohort of patients with MS treated with rituximab reported so far. The safety, clinical, and MRI findings in this heterogeneous real-world cohort treated with different doses of rituximab were similar to those reported in previous randomized controlled trials on B-cell depletion therapy in MS.
CLASSIFICATION OF EVIDENCE:This study provides Class IV evidence that for patients with MS, rituximab is safe and effective.
Objective
Novel, highly effective disease‐modifying therapies have revolutionized multiple sclerosis (MS) care. However, evidence from large comparative studies on important safety outcomes, such as ...cancer, is still lacking.
Methods
In this nationwide register‐based cohort study, we linked data from the Swedish MS register to the Swedish Cancer Register and other national health care and census registers. We included 4,187 first‐ever initiations of rituximab, 1,620 of fingolimod, and 1,670 of natalizumab in 6,136 MS patients matched for age, sex, and location to 37,801 non‐MS general population subjects. Primary outcome was time to first invasive cancer.
Results
We identified 78 invasive cancers among treated patients: rituximab 33 (incidence rate IR per 10,000 person‐years = 34.4, 95% confidence interval CI = 23.7–48.3), fingolimod 28 (IR = 44.0, 95% CI = 29.2–63.5), and natalizumab 17 (IR = 26.0, 95% CI = 15.1–41.6). The general population IR was 31.0 (95% CI = 27.8–34.4). Adjusting for baseline characteristics, we found no difference in risk of invasive cancer between rituximab, natalizumab, and the general population but a possibly higher risk with fingolimod compared to the general population (hazard ratio HR = 1.53, 95% CI = 0.98–2.38) and rituximab (HR = 1.68, 95% CI = 1.00–2.84).
Interpretation
In this first large comparative study of 3 highly effective MS disease‐modifying therapies, no increased risk of invasive cancer was seen with rituximab and natalizumab, compared to the general population. However, there was a borderline‐significant increased risk with fingolimod, compared to both the general population and rituximab. It was not possible to attribute this increased risk to any specific type of cancer, and further studies are warranted to validate these findings. ANN NEUROL 2020;87:688–699
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To investigate the association between infections and disability worsening in people with multiple sclerosis (MS) treated with either B-cell depleting therapy (rituximab) or ...interferon-beta/glatiramer acetate (IFN/GA).OBJECTIVETo investigate the association between infections and disability worsening in people with multiple sclerosis (MS) treated with either B-cell depleting therapy (rituximab) or interferon-beta/glatiramer acetate (IFN/GA).This cohort study spanned from 2000 to 2021, using data from the Swedish MS Registry linked to national health care registries, comprising 8,759 rituximab and 7,561 IFN/GA treatment episodes. The risk of hospital-treated infection was estimated using multivariable Cox models. The association between infections and increase in Expanded Disability Status Scale (EDSS) scores was assessed using a doubly robust generalized estimating equations model. Additionally, a piece-wise exponential model analyzed events of increased disability beyond defined cut-off values, controlling for relapses, and MRI activity.METHODSThis cohort study spanned from 2000 to 2021, using data from the Swedish MS Registry linked to national health care registries, comprising 8,759 rituximab and 7,561 IFN/GA treatment episodes. The risk of hospital-treated infection was estimated using multivariable Cox models. The association between infections and increase in Expanded Disability Status Scale (EDSS) scores was assessed using a doubly robust generalized estimating equations model. Additionally, a piece-wise exponential model analyzed events of increased disability beyond defined cut-off values, controlling for relapses, and MRI activity.Compared with IFN/GA, rituximab displayed increased risk of both inpatient- and outpatient-treated infections (hazard ratio HR, 2.08; 95% confidence interval CI, 1.50-2.90 and HR, 1.37; 95% CI, 1.13-1.67, respectively). An inpatient-treated infection was associated with a 0.19-unit increase in EDSS (95% CI, 0.12-0.26). Degree of worsening was greatest for progressive MS, and under IFN/GA treatment, which unlike rituximab, was more commonly associated with MRI activity. After controlling for relapses and MRI activity, inpatient-treated infections were associated with disability worsening in people with relapsing-remitting MS treated with IFN/GA (HR, 2.01; 95% CI, 1.59-2.53), but not in those treated with rituximab.RESULTSCompared with IFN/GA, rituximab displayed increased risk of both inpatient- and outpatient-treated infections (hazard ratio HR, 2.08; 95% confidence interval CI, 1.50-2.90 and HR, 1.37; 95% CI, 1.13-1.67, respectively). An inpatient-treated infection was associated with a 0.19-unit increase in EDSS (95% CI, 0.12-0.26). Degree of worsening was greatest for progressive MS, and under IFN/GA treatment, which unlike rituximab, was more commonly associated with MRI activity. After controlling for relapses and MRI activity, inpatient-treated infections were associated with disability worsening in people with relapsing-remitting MS treated with IFN/GA (HR, 2.01; 95% CI, 1.59-2.53), but not in those treated with rituximab.Compared to IFN/GA, rituximab doubled the infection risk, but reduced the risk of subsequent disability worsening. Further, the risk of worsening after hospital-treated infection was greater with progressive MS than with relapsing-remitting MS. Infection risk should be considered to improve long term outcomes. ANN NEUROL 2024.INTERPRETATIONCompared to IFN/GA, rituximab doubled the infection risk, but reduced the risk of subsequent disability worsening. Further, the risk of worsening after hospital-treated infection was greater with progressive MS than with relapsing-remitting MS. Infection risk should be considered to improve long term outcomes. ANN NEUROL 2024.
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To assess safety outcomes for the induction therapies alemtuzumab and autologous hematopoietic stem cell transplantation (AHSCT) compared to noninduction disease-modifying therapies.
We performed a ...population-based cohort study linking the Swedish Multiple Sclerosis Register to national health care registers. Alemtuzumab, AHSCT, and a matched reference group of noninduction therapies (natalizumab, dimethyl fumarate, rituximab, fingolimod) were included if started between 2008 and 2017. Main outcomes were death, thyroid disease, nonthyroid autoimmune disease, and infection.
We identified 132 alemtuzumab-treated and 139 AHSCT-treated (68% high-dose cyclophosphamide and anti-thymocyte globulin ATG, 32% BCNU, etoposide, cytosine-arabinoside, and melphalan/ATG) patients, together with 2,486 matched patients treated with noninduction therapies. Four patients in the alemtuzumab group died (incidence rate IR per 1,000 person-years 8.6, 95% confidence interval CI 2.3-22.0) compared to 1 patient in the AHSCT group (IR 1.7, 95% CI 0.0-9.6), and the mortality rate in the reference group was 0.7 (95% CI 0.3-1.3). Thyroid disease was most frequent in the alemtuzumab group (IR 109, 95% CI 75-154) but also occurred more often for AHSCT (IR 34, 95% CI 18-56) compared to the reference (IR 5.3 95% CI 3.9-7.1). The incidence of nonthyroid autoimmune disease was similar in all groups. IR for infection diagnosed ≥6 months from therapy initiation was 53 (95% CI 30-87) for alemtuzumab, 108 (95% CI 75-150) for AHSCT, and 51 (95% CI 46-57) for the reference.
We confirmed a high incidence of thyroid disease in alemtuzumab- and, to a smaller extent, AHSCT-treated patients and found a higher incidence of infection for AHSCT compared to both alemtuzumab and noninduction therapies. The incidence of nonthyroid autoimmune disease was low for both therapies.
This study provides Class III evidence of an increased risk of thyroid disease with alemtuzumab and an increased risk of infection with AHSCT treatment.
Multiple Sclerosis (MS) is a chronic autoimmune disorder of the central nervous system,characterized by the accumulation of demyelinating inflammatory lesions. Milder casesexist, but most patients ...eventually develop severe neurological symptoms and disability.However, this dire prognosis is likely to change with the increasing availability of modern,highly effective disease-modifying therapies (DMTs). The rapid development of new therapies for MS has resulted in a quickly changingtreatment landscape. Recently, the use of off-label rituximab has become the most usedDMT for MS in Sweden. In addition to the purely pharmacological therapies, autologoushaematopoietic stem cell transplantation (AHSCT) has emerged as an option for patientswith severe disease. The aim of this PhD project was to investigate risk-benefit aspects of DMTs for MS witha special focus on rituximab. Study I was a cohort study comparing the effectiveness of rituximab and fingolimod inpatients switching from natalizumab due to JC-virus positivity. In 256 patients, fewerrelapses and contrast-enhancing lesions were observed in the rituximab group, within thefirst 1.5 years of the therapy switch. The rituximab group also reported fewer adverseevents and better drug survival, compared with fingolimod. Rituximab appears to be thesuperior choice in this patient population and likely for highly active MS in general. Study II was a validation of the Swedish MS Register, the main data source for MSresearch in Sweden. Among 3012 patients, data on treatment and Expanded Disability Status Scale (EDSS) was reasonably complete. Observations of Magnetic ResonanceImaging (MRI) were often missing or incomplete, but could partly be recovered fromthe medical records. Missingness varied by MS clinic and treatment. The proportionof missing was higher for the older injectable therapies, compared with newer DMTs,which has implications for comparative studies. Study III was a cohort study assessing cancer risk in patients treated with rituximab,natalizumab, or fingolimod. Among 7477 therapy starts, we identified 78 cancers. Aftercontrolling for possible confounding, we found an increased risk of cancer for thefingolimod group, compared with both the rituximab group and the general population.It was not possible to assess if any specific type of cancer was driving this difference.No increased risk was found for rituximab or natalizumab, compared with the generalpopulation. These findings were in line with previous studies of rituximab in rheumatoidarthritis, but interestingly with a lower risk of breast cancer on rituximab than in the trialprogramme for ocrelizumab. Study IV was a cohort study assessing safety outcomes for patients treated with theinduction therapies AHSCT or alemtuzumab. Among 271 patients, one death occurred inthe AHSCT group and four deaths occurred in the alemtuzumab group. The mortality ratefor AHSCT was lower in our study than in most previous reports. AHSCT was associatedwith an increased risk of infection that diminished a few months after treatment. Theincidence of thyroid disease with alemtuzumab was higher in our study than previouslyreported in clinical trials, but in line with other observational data.
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