Rituximab in secondary progressive multiple sclerosis: a meta‐analysis

Pasin Intarakhao; Taksaporn Laipasu; Jiraporn Jitprapaikulsan; Natnasak Apiraksattayakul; Punchika Kosiyakul; Sasitorn Siritho; Naraporn Prayoonwiwat; Tatchaporn Ongphichetmetha

doi:10.1002/acn3.52186

. 2024 Aug 26;11(10):2707–2718. doi: 10.1002/acn3.52186

Rituximab in secondary progressive multiple sclerosis: a meta‐analysis

Pasin Intarakhao ¹, Taksaporn Laipasu ¹, Jiraporn Jitprapaikulsan ^2,³, Natnasak Apiraksattayakul ², Punchika Kosiyakul ², Sasitorn Siritho ^2,⁴, Naraporn Prayoonwiwat ^2,³, Tatchaporn Ongphichetmetha ^2,^3,^5,^✉

PMCID: PMC11514939 PMID: 39186371

Abstract

Objective

To evaluate the efficacy of rituximab (RTX) in stabilizing disability progression in secondary progressive multiple sclerosis (SPMS).

Methods

A systematic review was conducted, encompassing studies from inception to April 2023, utilizing the MEDLINE and EMBASE databases. Inclusion criteria comprised studies with a minimum of 3 SPMS patients receiving intravenous RTX in at least one infusion, with a follow‐up duration of at least 6 months. Primary outcome measures included changes in Expanded Disability Status Scale (EDSS) scores. Mean differences in pre‐ and post‐RTX EDSS scores were analyzed using a random‐effects model. Meta‐regression examined age at RTX initiation, pre‐RTX EDSS scores, disease duration, and outcome reported time as variables. Secondary outcomes assessed changes in the annualized relapse rate (ARR).

Results

Thirteen studies, involving 604 SPMS patients, met the inclusion criteria. Following a mean follow‐up of 2 years, the mean difference in EDSS scores (ΔEDSS = EDSS_pre‐RTX − EDSS_post‐RTX) was −0.21 (95% CI −0.51 to 0.08, p = 0.16), indicating no significant variation. Multivariable meta‐regression identified significant associations between EDSS score mean difference and pre‐RTX EDSS scores, disease duration at RTX initiation, and outcome reported time. However, age at RTX initiation showed no significant association. Pre‐ and post‐RTX ARR data were available for 245 out of 604 SPMS patients across seven studies, revealing a mean difference in ARR (ΔARR = ARR_pre‐RTX − ARR_post‐RTX) of 0.74 (95% CI 0.19–1.29, p = 0.008).

Interpretation

RTX demonstrates efficacy in reducing relapse frequency and exhibits potential in stabilizing disability progression over a 2‐year follow‐up, particularly among individuals with shorter disease duration.

Introduction

Multiple sclerosis (MS) is an idiopathic inflammatory demyelinating disease of the central nervous system (CNS). Most patients initially present with relapsing–remitting multiple sclerosis (RRMS). ¹ Previous studies have shown that 60% to 90% of these patients eventually progress to secondary progressive MS (SPMS), marked by disability progression independent of clinical relapses. ²

The pathophysiology of MS differs between relapsing–remitting and progressive phases. ³ RRMS is marked by acute focal inflammation driven by peripheral immune processes, while the progressive phase involves diffuse chronic‐active inflammation and neurodegeneration within the CNS. ⁴ , ⁵ , ⁶ Evidence indicates that RRMS and SPMS may not have clear boundaries, with progression independent of relapse activity (PIRA) potentially starting early in the disease. ⁷ , ⁸ , ⁹ , ¹⁰ This suggests MS as a continuum of inflammatory and degenerative processes. Current disease‐modifying therapies (DMTs) targeting peripheral inflammation show limited effectiveness in SPMS, emphasizing the need for treatments that can penetrate the blood–brain barrier and address compartmentalized CNS inflammation. ⁶

Studies highlight B‐lymphocytes' significant role in MS pathogenesis, especially in SPMS, where follicle‐like structures are found in the meninges. ¹¹ , ¹² Rituximab (RTX), a chimeric monoclonal anti‐CD20 antibody, is used off‐label for RRMS due to its cost‐effectiveness in preventing relapses, though data on its impact on SPMS disability progression are limited. ¹¹ , ¹³ , ¹⁴ , ¹⁵ , ¹⁶ , ¹⁷ , ¹⁸ , ¹⁹ , ²⁰ , ²¹ , ²² , ²³ , ²⁴ , ²⁵ Despite this, RTX treatment has been linked to reduced B‐lymphocytes in cerebrospinal fluid, suggesting it might either lower B‐lymphocyte migration across CNS barriers or directly deplete CNS B‐lymphocytes, potentially offering therapeutic benefits for SPMS. ²⁶ , ²⁷ , ²⁸ , ²⁹

This systematic review and meta‐analysis aimed to evaluate the efficacy of RTX in stabilizing disability progression and mitigating disease activity among patients with SPMS, as well as to assess the safety of RTX.

Materials and Methods

The systematic review protocol was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta‐Analysis (PRISMA) 2020 Statement ³⁰ and was registered with PROSPERO, the International Prospective Register of Systematic Reviews (https://www.crd.york.ac.uk/prospero/, identifier: CRD42023408426).

Search strategy

The search strategy followed the PICOS criteria (Population, Intervention, Comparator, Outcome, Study design) (Table S1). Two independent reviewers (P.I. and T.L.) systematically searched MEDLINE and EMBASE from inception to April 2023. Additionally, hand searches of reference lists, protocols, abstracts, and gray literature were conducted. Search strategies for each database incorporated medical subject headings (MeSH), EMBASE subject headings (EMTREE), and free‐text terms relevant to SPMS and RTX, as outlined in the Supplementary Materials.

Study screening

The study screening process included deduplication of records identified through the search strategy, initially performed using Covidence software and then manually rechecked. Titles and abstracts were independently screened by two reviewers (P.I. and T.L.). Any discrepancies were resolved by a third investigator (T.O.).

Study selection

Full‐text articles were obtained to assess eligibility, with two independent reviewers (P.I. and T.L.) conducting the assessment. Any discrepancies in the selection process were resolved by a third investigator (T.O.). Authors of abstracts were contacted via email at least twice to acquire full‐text articles or additional data.

Eligibility criteria

Studies were included if they (1) included adult participants aged ≥18 years with SPMS, (2) administered intravenous RTX regardless of dosing regimen, with at least one infusion, (3) reported both pre‐ and post‐RTX EDSS scores. ²⁷ or changes in EDSS scores after RTX initiation, with a minimum follow‐up duration of 6 months, and (4) were retrospective or prospective studies with a minimum sample size of 3. Studies were excluded if they (1) administered other DMTs or immunosuppressants simultaneously with RTX, excluding corticosteroids, (2) did not provide clear reports on EDSS outcomes among SPMS patients, (3) were categorized as news, letters, books, documentation, or reviews, and (4) were published in languages other than English.

Data extraction

Two reviewers (P.I. and T.L.) independently extracted the following data: (1) characteristics of included studies, including study design, years of publication, countries where studies were conducted, eligibility criteria, definitions of SPMS in the studies (if mentioned), and the number of study participants, (2) characteristics of study participants, including sex distribution, age at RTX initiation, disease duration, pre‐RTX EDSS scores, pre‐RTX annualized relapse rate (ARR), and pre‐RTX magnetic resonance imaging (MRI) activity using contrast‐enhancing lesions (CELs) as an indicator, (3) characteristics of study interventions, including RTX dosing regimen and duration of RTX treatment, and (4) characteristics of study outcomes, including outcome reports, outcome reported time, post‐RTX EDSS scores, post‐RTX ARR, post‐RTX MRI activity, proportion of patients with confirmed disability progression post‐RTX, time to first confirmed disability progression, and adverse events observed in participants treated with RTX.

Risk of bias assessment

Two independent reviewers (P.I. and T.L.) utilized the modified Newcastle–Ottawa quality assessment scale (NOS) to evaluate the quality of the included studies. This scale includes two domains: the selection of participants and the ascertainment of outcomes in cohort studies. ³¹ Since all the outcomes collected were pre‐ and post‐RTX treatment effects among participants receiving RTX exclusively, the comparability domain was not applicable. Any discrepancies in the assessment were resolved by the third investigator (T.O.). Additionally, a funnel plot was employed to visualize potential publication bias in the included studies.

Efficacy and safety measures

The primary outcome considered was the changes in EDSS scores from baseline (pre‐RTX EDSS scores) to after RTX initiation (post‐RTX EDSS scores). The secondary outcomes included the changes in ARR from baseline (pre‐RTX ARR) to after RTX initiation (post‐RTX ARR), the proportion of participants with CELs after RTX initiation, the proportion of participants with confirmed disability progression after RTX initiation, time to first confirmed disability progression, and the proportion of participants experiencing RTX‐related adverse events.

Statistical analysis

For the qualitative analysis, categorical variables were presented as proportions and percentages, while continuous variables were expressed as means, weighted for the sample size of each study. The mean difference (with 95% confidence intervals [CIs]) with the standard deviation (SD), calculated from the mean EDSS scores and mean ARR pre‐ and post‐RTX, was used to assess the effect size. The mean differences were pooled using the inverse variance method, and the analysis was conducted using a random‐effects model, visually depicted with Forest plots. When mean and SD of the outcome measures were not provided, they were calculated from the median and interquartile range (IQR) using formulas provided by Wan et al. ³² When individual data for EDSS scores and/or ARR were available, mean and SD were computed. All statistical evaluations were performed using Cochrane's Review Manager (RevMan) 5.4 and STATA/MP 17.0 (Stata Corp, College Station, TX, USA). The I ² index was utilized to assess heterogeneity across studies, with I ² values of 0%–25%, 26%–75%, and 75%–100% corresponding to low, moderate, and high levels of heterogeneity, respectively. ³³

Subgroup analyses were performed using: (1) pre‐RTX EDSS scores of 5.0, which indicates patients capable of walking without aid for around 200 meters, and signifies a moderate level of disability, with patients experiencing notable limitations in mobility and daily activities, ²⁷ as a cut‐off point (Subgroup analysis 1), (2) disease duration of 10 years, as a cut‐off point (Subgroup analysis 2), (3) pre‐RTX ARR of 1.00, as a cut‐off point (Subgroup analysis 3), and (4) outcome reported time of 2 years, as a cut‐off point (Subgroup analysis 4).

Meta‐regression was conducted using age at RTX initiation, pre‐RTX EDSS scores, disease duration, and outcome reported time as variables. Leave‐one‐out sensitivity analysis was employed to assess heterogeneity between studies.

Results

Search result

An initial search yielded 12,715 studies from the MEDLINE/PubMed and EMBASE databases. After removing 1390 duplicate articles, 11,203 irrelevant articles, and 65 articles with unavailable full‐text or the required data, 57 articles underwent full‐text reviews. Applying the exclusion criteria led to the elimination of another 44 articles (Fig. 1). Consequently, 13 studies met the criteria for inclusion in the analysis.

Flow diagram of the selection process according to PRISMA guidelines.

Study population and qualitative analysis

Among the 13 included studies, there were two randomized controlled trials, one nonrandomized experimental study, and 10 retrospective cohort studies. The NOS score, excluding the comparability aspect, ranged from 6 to 8 (median: 6), suggesting an overall moderate quality of study (Table S3).

A total of 604 patients with SPMS were included in the study. Full demographic data, clinical characteristics, details of treatment received, and outcomes of each study were provided in Table 1. Of the 604 participants, 397 (65.7%) were female, with a mean age at RTX initiation of 44.6 ± 6.0 years. RTX was administered after a mean disease duration of 14.2 ± 4.0 years. The most commonly administered dosing regimen of intravenous RTX was 1000 mg given 14 days apart, with subsequent doses ranging from 500 to 1000 mg every 6–9 months (Table S5). The mean reported outcome time was 24.2 ± 13.1 months.

Table 1.

Characteristics of included studies.

References	Country	Study design	Total number of SPMS patients, n	Age, mean ± SD, years	Number of females, n (%)	MS disease duration, mean ± SD, years
Salzer et al. (2016) ²⁴	Sweden	Retrospective cohort study	198	49.1 ± 8.5	126 (63.6)	19.1 ± 7.9
Naegelin et al. (2019) ²⁶	Switzerland	Retrospective cohort study	54	49.0 ± 9.6	32 (59)	18.6 ± 9.3
Casanova et al. (2018) ²⁷	Spain	Retrospective cohort study	10	41.9 ± 10.1	9 (90)	14.7 ± 10.4
Etemadifar et al. (2019) ²⁰	Iran	Randomized controlled trial	39	31.9 ± 7.7	35 (89.7)	7.6
Leonidou et al. (2019) ¹⁹	Cyprus	Retrospective cohort study	17	47.3 ± 9	9 (52.9)	15.0 ± 6.5
Linden et al. (2019) ²³	Sweden	Retrospective cohort study	45	49.2 ± 8.8	30 (66.7)	19.6 ± 7.8
Moghadasi et al. (2019) ²²	Iran	Retrospective cohort study	60	41.2 ± 6.8	38 (63.3)	12.8 ± 5.8
Airas et al. (2020) ²⁵	Finland	Retrospective cohort study	25	47.8 ± 9.5	14 (56)	18.2 ± 8.1
Cheshmavar et al. (2020) ¹⁸	Iran	Randomized controlled trial	43	40.95 ± 8.3	34 (79.1)	12.0 ± 6.6
Megherbi et al. (2021) ²⁸	Algeria	Retrospective cohort study	23	46.8 ± 4.7	12 (52.2)	9.8 ± 4.4
Patil et al. (2021) ²¹	India	Retrospective cohort study	32	38.7 ± 11.6	21 (65.6)	8.8 ± 7.6
Torgauten et al. (2021) ²⁶	Norway	Retrospective cohort study	23	54.9 ± 10.3	14 (60.9)	15.2 ± 9.1
Salehizadeh et al. (2022) ¹⁷	Iran	Nonrandomized experimental study	35	41.4 ± 8.6	23 (65.7)	12.9 ± 6.0

References	Duration of RTX, mean ± SD, months	Outcome reported time, months	Pre‐RTX EDSS scores, mean ± SD	Pre‐RTX ARR, mean ± SD	Pre‐RTX CELs, n (%)
Salzer et al. (2016) ²⁴	24.8 ± 14.7	24	5.38 ± 1.37	NR	47 (23.9)
Naegelin et al. (2019) ²⁶	46.3 ± 30.7	42	6.02 ± 1.32	NR	NR
Casanova et al. (2018) ²⁷	14.1 ± 12.4	Mean ± SD = 14.8 ± 12.5	5.20 ± 1.48	0.50 ± 0.53	NR
Etemadifar et al. (2019) ²⁰	24.0	24	3.80 ± 0.58	1.97 ± 0.43	NR
Leonidou et al. (2019) ¹⁹	12.0	12	6.00 ± 1.25	NR	NR
Linden et al. (2019) ²³	NR Number of RTX infusion, median (range) = 6 (1–9)	Mean ± SD = 41.4 ± 17.7	4.25 ± 1.36	NR	11 (24.4)
Moghadasi et al. (2019) ²²	NR Number of RTX infusion, mean ± SD = 2.43 ± 0.77	Mean ± SD = 10.6 ± 3.7	5.85 ± 0.44	0.32 ± 0.54	13 (21.7)
Airas et al. (2020) ²⁵	Median (range) = 1.7 (0.6–3.8) months Number of RTX infusion, median (range) = 3 (2–6)	24	5.75 ± 1.27	0.29 ± 0.39	NR
Cheshmavar et al. (2020) ¹⁸	12.0	12	3.09 ± 0.95	1.33 ± 0.52	8 (18.6)
Megherbi et al. (2021) ²⁸	28.4 ± 9.3	Mean ± SD = 28.4 ± 9.3	5.75 ± 0.78	1.30 ± 0.93	NR
Patil et al. (2021) ²¹	NR Number of RTX infusion, median (range) = 3 (2–12)	Mean ± SD = 50.3 ± 30.5	4.50 ± 1.21	0.80 ± 1.00	11 (34.3)
Torgauten et al. (2021) ²⁶	NR Number of RTX infusion, mean ± SD = 3.2 ± 1.8	18.7	5.63 ± 1.17	0.34 ± 0.39	NR
Salehizadeh et al. (2022) ¹⁷	NR	12	5.80 ± 1.77	NR	NR

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ARR, annualized relapse rate; CELs, contrast‐enhancing lesions; EDSS, Expanded Disability Status Scale; IV, intravenous; mg, milligram; MRI, magnetic resonance imaging; MS, multiple sclerosis; NR, not reported; n, number; RTX, rituximab; SD, standard deviation; SPMS, secondary progressive multiple sclerosis.

Efficacy outcomes

Effect of RTX on the mean EDSS scores

Mean EDSS scores before and after RTX were available for 604 patients across 13 studies (Table 2). ¹³ , ¹⁴ , ¹⁵ , ¹⁶ , ¹⁷ , ¹⁸ , ¹⁹ , ²⁰ , ²¹ , ²² , ²³ , ²⁴ , ²⁶ Overall, the difference in mean EDSS scores before versus after RTX (post‐RTX EDSS scores subtracted from pre‐RTX EDSS scores) was −0.21 (95% CI −0.51 to 0.08, p = 0.16, Fig. 2), which did not reach statistical significance. Sensitivity analysis revealed that no single study influenced the overall mean difference in EDSS scores, with estimates ranging from −0.13 (95% CI −0.41 to 0.15) to −0.28 (95% CI −0.58 to 0.03) (Fig. S1). High between‐study heterogeneity was observed (I ² = 79%).

Table 2.

Outcomes of included studies.

References	Post‐RTX EDSS scores, mean ± SD	Post‐RTX ARR, mean ± SD	Post‐RTX CELs, n (%)
Salzer et al. (2016) ²⁴	5.88 ± 1.37	0.04	NR
Naegelin et al. (2019) ²⁶	5.57 ± 1.32	NR	NR
Etemadifar et al. (2019) ²⁰	4.00 ± 0.95	0.02 ± 0.43	NR
Leonidou et al. (2019) ¹⁹	5.50 ± 1.25	NR	NR
Linden et al. (2019) ²³	5.50 ± 1.36	NR	NR
Moghadasi et al. (2019) ²²	5.71 ± 0.66	0.10 ± 0.35	NR
Airas et al. (2020) ²⁵	6.00 ± 1.02	0.08 ± 0.28	NR
Cheshmavar et al. (2020) ¹⁸	4.02 ± 0.91	0.56 ± 0.73	3 (7)
Casanova et al. (2021) ²⁷	5.85 ± 0.88	NR	NR
Megherbi et al. (2021) ²⁸	5.00 ± 2.07	0.26 ± 0.33	NR
Patil et al. (2021) ²¹	4.50 ± 1.69	0.10 ± 0.45	2 (6)
Torgauten et al. (2021) ²⁶	6.13 ± 1.17	0.04 ± 0.39	3 (13)
Salehizadeh et al. (2022) ¹⁷	5.76 ± 1.44	NR	NR

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ARR, annualized relapse rate; CELs, contrast‐enhancing lesions; EDSS, Expanded Disability Status Scale; NR, not reported; n, number; RTX, rituximab; SD, standard deviation.

The forest plot for mean difference in Expanded Disability Status Scale (EDSS) scores after rituximab (RTX) treatment in patients with SPMS. Error bars represent 95% confidence interval.

To address this high heterogeneity and investigate potential differences in RTX efficacy among participant subgroups, we conducted subgroup and multivariable meta‐regression analyses. The subgroup analysis focusing on participants with disabling disease (i.e., pre‐RTX EDSS scores ≥5.0, n = 445/604) revealed an EDSS score mean difference of −0.02 (95% CI −0.33 to 0.29, p = 0.91), indicating no significant difference between pre‐ and post‐RTX EDSS scores, with moderate heterogeneity (I ² = 69%). However, among participants with a pre‐RTX EDSS scores <5.0, the EDSS score mean difference was −0.61 (95% CI −1.15 to −0.07), reaching statistical significance (p = 0.03), indicating a significant increase in post‐RTX EDSS scores from baseline, with high heterogeneity (I ² = 81%) (Fig. S2).

Additionally, the subgroup analysis on disease duration demonstrated the robustness of RTX in stabilizing EDSS scores, especially among those with disease duration of <10 years, with an EDSS score mean difference of −0.05 (95% CI −0.49 to 0.39, p = 0.82) (Fig. S3). The subgroup analyses on pre‐RTX ARR and outcome reported time also confirmed the efficacy of RTX in stabilizing EDSS scores among both subgroups of pre‐RTX ARR (<1.00 vs. ≥1.00) (Fig. S4) and outcome reported time (<2 years vs. ≥2 years) (Fig. S5).

The multivariable meta‐regression analysis indicated that RTX efficacy, as assessed by EDSS score mean difference, was significantly associated with pre‐RTX EDSS scores (b = 0.5670, 95% CI 0.4069–0.7271, p = 0.000), disease duration at RTX initiation (b = −0.0826, 95% CI −0.1488 to −0.0167, p = 0.014), and outcome reported time (b = 0.0136, 95% CI 0.0008–0.02636, p = 0.037), but not with age at RTX initiation (b = −0.0128, 95% CI −0.0550 to 0.0294, p = 0.553). Publication bias was detected through an asymmetrical funnel plot (Fig. S6).

Effect of RTX on the proportion of participants with confirmed disability progression and time to confirmed disability progression

Two studies reported confirmed disability progression (CDP) as an outcome. ²³ , ²⁶ A retrospective cohort study by Casanova et al. defined confirmed worsening or improvement of disability as a decrease or increase of one point in EDSS (if EDSS < 6.0) or 0.5 points (if EDSS ≥ 6.0). The proportion of participants with confirmed worsening and improvement of disability over 2 years of RTX treatment was 33.3% and 26.6%, respectively. ²³ Another study using propensity score matching by Naegelin et al. defined CDP as an increase in the EDSS score (1.5 steps for an EDSS score of 0, 1 step for scores between 1 and 5, and 0.5 steps for scores of ≥ 5.5) occurring 12 or more months after baseline, which was confirmed by a second examination conducted 12 months later. Over a period of 2 years, the proportion of participants with CDP was 12.5% in the RTX‐treated group compared to 25% in the matched control group. Time to CDP was also compared between participants receiving and not receiving RTX, with the results showing that time to CDP was longer in the RTX‐treated group than in the matched control group (hazard ratio = 0.49, 95% CI 0.26–0.93, p = 0.03). ²⁶

Effect of RTX on the mean ARR

Pre‐ and post‐RTX ARR data were available for 245 out of 604 SPMS patients across seven studies (Table 2). ¹⁴ , ¹⁶ , ¹⁷ , ¹⁸ , ²¹ , ²² , ²⁴ The random‐effects model meta‐analysis revealed a mean difference in ARR before versus after RTX (post‐RTX ARR subtracted from pre‐RTX ARR) of 0.74 (95% CI 0.19–1.29, p = 0.008, Fig. 3). However, the analysis indicated high heterogeneity (I ² = 97%). To assess the robustness of the findings, we conducted a leave‐one‐out sensitivity analysis by excluding the study by Etemadifar et al., ¹⁶ resulting in a decrease of I ² to 82%. Despite this exclusion, the effect size remained statistically significant (0.05, 95% CI 0.26–0.74, p < 0.0001) (Fig. S7). Notably, Etemadifar et al.'s inclusion criteria focused on participants with high baseline disease activity, leading to a notably higher pre‐RTX ARR compared to other studies. Furthermore, examination of the funnel plot revealed no substantial evidence of publication bias (Fig. S8). Due to the limited number of studies with available ARR data, subgroup analyses were not performed.

The forest plot for mean difference in annualized relapse rate (ARR) after rituximab (RTX) treatment in patients with SPMS. Error bars represent 95% confidence interval.

Effect of RTX on the MRI activity

Pre‐RTX MRI activity was reported in five studies. ¹⁴ , ¹⁷ , ¹⁸ , ¹⁹ , ²⁰ Contrast‐enhancing lesions (CELs) were identified in 90 out of 378 participants (23.8%) (Table 2). Only three studies mentioned post‐RTX MRI activity, ¹⁴ , ¹⁷ , ²² with a proportion of participants with CELs of 8 out of 98 (8.2%). Two studies reported both pre‐ and post‐RTX MRI activity. The proportion of participants with CELs decreased from 18.6% to 7%, ¹⁴ and from 34.3% to 6%. ¹⁷

Safety outcomes

Adverse events associated with RTX administration among SPMS participants were reported in only four studies, involving 145 participants (Table 3). ¹⁴ , ²¹ , ²² , ²⁶ Overall, 30 out of 145 participants (20.7%) experienced RTX‐related adverse events. These events included lower urinary tract infection (5/30, 16.7%), infusion‐related reactions (4/30, 13.3%), unspecified serious infection (4/30, 13.3%), pneumonia or urinary tract infection (3/30, 10%), hypogammaglobulinemia (2/30, 6.7%), upper respiratory infection (2/30, 6.7%), varicella zoster infection (2/30, 6.7%), pneumonia (1/30, 3.3%), bacterial vaginitis (1/30, 3.3%), transient dyspnea (1/30, 3.3%), mildly increased liver enzyme (1/30, 3.3%), leukocytoclastic vasculitis (1/30, 3.3%), and other unspecified adverse events (3/30, 10%). However, data regarding adverse events specifically within the SPMS subgroup in the other nine studies were unavailable.

Table 3.

Adverse events from RTX of included studies.

References	Adverse events, number of participants with specific adverse events/total number of study participants of each study (%)
Salzer et al. (2016) ²⁴	NR
Naegelin et al. (2019) ²⁶	Leukocytoclastic vasculitis 1/54 (1.9), herpes zoster infection 1/54 (1.9), pneumonia or urinary tract infections 3/54 (5.6)
Casanova et al. (2018) ²⁷	NR
Etemadifar et al. (2019) ²⁰	NR
Leonidou et al. (2019) ¹⁹	NR
Linden et al. (2019) ²³	NR
Moghadasi et al. (2019) ²²	NR
Airas et al. (2020) ²⁵	Lower urinary tract infection 5/25 (20), pneumonia 1/25 (4), upper respiratory infection 1/25 (4), others 3/25 (12)
Cheshmavar et al. (2020) ¹⁸	Moderate–severe allergic reaction 2/43 (4.7), upper respiratory infection and distress 1/43 (2.3), varicella zoster infection 1/43 (2.3), bacterial vaginitis 1/43 (2.3), transient dyspnea 1/43 (2.3), mildly increased liver enzymes 1/43 (2.3)
Megherbi et al. (2021) ²⁸	NR
Patil et al. (2021) ²¹	NR
Torgauten et al. (2021) ²⁶	Any adverse event 8/23 (34.8), any infusion‐related adverse event 2/23 (8.7), serious infections 4/23 (17), hypogammaglobulinemia 2/23 (8.7)
Salehizadeh et al. (2022) ¹⁷	NR

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NR, not reported; n, number; RTX, rituximab.

Discussion

This study represents the first systematic review and meta‐analysis aimed at assessing the efficacy of RTX in stabilizing disability progression among patients with SPMS, utilizing changes in pre‐ and post‐RTX EDSS scores as the primary outcome measure. The analysis revealed that post‐RTX EDSS scores did not significantly differ from pre‐RTX EDSS scores among the overall SPMS population, with a mean difference of −0.21 (95% CI −0.51 to 0.08, p = 0.16). This suggests a potential benefit of RTX in stabilizing disability progression in SPMS. Furthermore, the leave‐one‐out sensitivity analysis demonstrated that no individual study disproportionately influenced the overall mean difference in EDSS scores.

Furthermore, meta‐regression analysis unveiled significant associations between favorable EDSS effect sizes and several factors. Firstly, a shorter disease duration before RTX initiation, as previously observed in Siponimod trials, ³⁴ was correlated with more favorable outcomes. This finding aligns with previous studies demonstrating that early initiation of high‐efficacy DMTs (within 2 years of disease onset) reduces disability progression. ³⁵ , ³⁶ , ³⁷ Secondly, a longer outcome reporting time was found to be crucial for detecting EDSS score changes, particularly among patients with slowly progressive MS. ³⁸ Interestingly, a higher baseline EDSS score was associated with greater stabilization of EDSS scores after RTX treatment, contradicting findings from a previous study. ³⁹ Studies have demonstrated that the benefits of DMTs on disability progression are more pronounced when initiating each DMT at lower baseline EDSS scores, particularly scores below 3.0, compared to higher baseline EDSS scores. ⁴⁰ , ⁴¹ The discrepancy between our meta‐regression result and previous studies may be attributed to the relatively short duration of outcome reporting in our study, with a mean reported time of 24.2 ± 13.1 months. It is worth noting that the time to a one‐point increase in the EDSS scores has been shown to vary depending on the baseline EDSS scores, with longer durations observed in the EDSS scores >6.0 group. ⁴²

The majority of studies included in this meta‐analysis utilized a retrospective cohort study design, evaluating the effect of RTX treatment by comparing pre‐ and post‐RTX EDSS scores, lacking a comparison group. Consequently, data on SPMS patients not receiving RTX and experiencing disability progression at the natural rate were unavailable. To address this gap, we compared the efficacy of RTX in slowing or stabilizing EDSS score changes with findings from a randomized placebo‐controlled trial. In this trial, evaluating the efficacy of interferon β‐1a, the placebo group demonstrated an annual increase in EDSS of 0.272. ⁴³ Notably, these study patients shared similar characteristics with our cohort, including age, disease duration, and EDSS at onset, reflecting typical SPMS patients. Inferentially, the rate of EDSS changes was higher among SPMS patients not receiving disease‐modifying therapies (0.272 EDSS points per year) compared to those receiving RTX in our meta‐analysis (0.21 EDSS points per 2 years).

Additionally, this meta‐analysis confirms RTX's effectiveness in reducing inflammation, showing a significant decrease in ARR, even in patients in the progressive phase. Furthermore, the observed reduction in MRI activity supports RTX's efficacy in halting inflammation. Although there were no major RTX‐associated adverse events, complications were documented in 30 out of 145 patients (20.7%), primarily related to infections and infusion‐related reactions.

The primary focus of this meta‐analysis lies in discerning whether the efficacy of RTX in stabilizing disability progression predominantly targets relapse‐associated disability or progression independent of relapse activity (PIRA). ⁴⁴ PIRA, denoting disability accrual independent of relapse occurrence, is intricately linked to neurodegenerative processes and diffuse inflammation, emerging early in RRMS, and gaining prominence as the disease advances. Notably, the EMA guideline for SPMS underscores the importance of assessing DMTs' efficacy against disability progression by predominantly targeting SPMS patients exhibiting recent evidence of PIRA without active inflammation. ⁴⁵ However, due to limitations in our dataset concerning clinical relapses and MRI activity, subgroup analysis or meta‐regression to ascertain their impact on RTX's efficacy in stabilizing disability progression could not be performed. Furthermore, the diverse criteria for defining PIRA across studies, alongside variations in disability assessment methods and tools, present challenges in utilizing PIRA as a definitive outcome measure in this meta‐analysis. ¹⁰ , ⁴⁶

This study has several limitations. Firstly, due to data incomparability across studies, quantitative analyses of key outcomes such as SPMS patients with confirmed disability progression at specific time points were not feasible. Secondly, most studies were observational, resulting in variations in RTX dosing and outcome reporting. Thirdly, inconsistent definitions of SPMS led to heterogeneous patient populations. ⁴⁷ , ⁴⁸ Fourthly, the lack of a placebo arm hindered direct comparison of RTX efficacy to natural disease progression. Additionally, short follow‐up periods may have limited capturing RTX's full effect, particularly among patients with slow progression rates. ⁴² Furthermore, the lack of measurement of CD19 B‐lymphocytes in most studies prevented evaluation of the achievement of peripheral CD19 B‐lymphocyte suppression from the given RTX dosing regimen. The sensitivity of EDSS scores in detecting disability progression in MS has recently been questioned, as it primarily reflects ambulatory function. ⁴⁹ Given the nonlinear nature of the EDSS scale, changes in EDSS scores do not uniformly represent changes in disability. Moreover, low sample sizes and high heterogeneity could contribute to regression to the mean. Lastly, potential publication bias and selection bias, where RTX was more likely prescribed to patients with earlier and faster disease progression, are additional concerns.

To summarize, RTX appears to stabilize the rate of disability progression, as assessed by EDSS scores, in SPMS, particularly among those with a shorter disease duration. SPMS patients with active disease activity, both clinically and radiologically, may derive greater benefit from RTX, which can reduce clinical relapses and MRI activity, thus potentially decreasing relapse‐associated disability progression. Clinicians should carefully reassess the degree of relapse‐associated disability progression (likely reduced by RTX due to fewer relapses) and PIRA (only partially treated by RTX) in every RRMS patient transitioning to the progressive phase to determine whether continuing RTX is warranted, considering the balance between benefits and the risks of infection and hypogammaglobulinemia. There remains a significant unmet need for more effective therapies targeting the progressive mechanisms in MS.

For future research, randomized controlled trials (RCTs) comparing RTX to placebo should be conducted in both SPMS patients with and without disease activity. These trials should focus on early RTX initiation within the first few years after the onset of the progressive phase and involve patients with low baseline EDSS scores, with long‐term follow‐up. Moreover, these trials should evaluate disability progression using functional composite scores that encompass comprehensive neurological domains. Additionally, incorporating biomarkers such as volumetric MRI, optical coherence tomography (OCT), neurofilament light chain (NfL), or glial fibrillary acidic protein (GFAP) could provide valuable insights into treatment efficacy and disease progression. ⁵⁰ , ⁵¹ , ⁵² , ⁵³ , ⁵⁴

Our findings offer valuable insights into the therapeutic profile of RTX in SPMS. RTX demonstrates a clear ability to reduce relapse frequency and shows promise in stabilizing disability progression over the medium term (2 years), while maintaining a favorable safety profile. Considering the observed benefits, continuation of RTX treatment in MS patients upon reaching the progressive phase could be a viable option, particularly for those with active disease activity.

Author Contributions

P.I., T.L., J.J., and S.S. contributed with conception and design, research operation, data collecting, analysis and interpretation of data, discussion of the results, drafting of the manuscript or revising it critically for important intellectual content, and final approval of the manuscript submitted. N.A. and P.K. contributed with research operation, data collecting, analysis, and interpretation of data. N.P. contributed with revising of the manuscript. T.O. contributed with conception and design, research operation, data collecting, analysis and interpretation of data, discussion of the results, drafting of the manuscript or revising it critically for important intellectual content, final approval of the manuscript submitted, and supervision.

Funding Information

None

Conflicts of Interest

The authors declare that they have no known competing financial interests or personal relationships that could have influenced the work reported in this paper.

Supporting information

Table S1. Description of PICOS criteria.

Table S2. Search term.

Table S3. The quality assessment of enrolled twelve studies using the modified Newcastle‐Ottawa scale.

Table S4. Eligibility criteria of each study.

Table S5. Rituximab dosing regimen of each study.

Figure S1. The leave‐one‐out meta‐analysis summary for changes in EDSS.

Figure S2. The forest plot for changes in EDSS, grouped by pre‐RTX EDSS.

Figure S3. The forest plot for changes in EDSS, grouped by disease duration.

Figure S4. The forest plot for changes in EDSS, grouped by pre‐RTX ARR.

Figure S5. The forest plot for changes in EDSS, grouped by outcome reported time.

Figure S6. The funnel plot for publication bias analysis, including twelve studies that were enrolled in the analysis of changes in Expanded Disability Status Scale.

Figure S7. The forest plot for changes in ARR excluding Etemadifar et al.

Figure S8. Funnel plot for publication bias analysis including six studies that were enrolled in the analyzing of changes in annualized relapse rate.

ACN3-11-2707-s001.docx^{(1.9MB, docx)}

Acknowledgments

None

Data Availability Statement

The data that support the findings of this study are available from the corresponding author upon reasonable request.

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