Systematic review of the efficacy of rituximab in the management of central nervous system involvement among adults with Sjögren’s disease

Abstract

Introduction

Sjögren’s disease is an autoimmune condition that may have neurological involvement. Rituximab is a monoclonal antibody against CD20 that has shown potential in the management of central and peripheral neuropathy in lymphomas and some autoimmune disease. There is limited data on the efficacy of rituximab on central nervous system (CNS) involvement in Sjögren’s disease. The aim of this systematic review was to assess the effects of rituximab on CNS involvement among adults with Sjögren’s disease.

Materials and methods

The PubMed, Scopus, and Web of Science medical databases were searched and the related articles were included in the review based on the inclusion and exclusion criteria. All articles published in English language that reported the effect of rituximab in the management of CNS involvement in Sjögren’s disease were included and reviewed.

Results

Of the primary retrieved 173 articles, three (N = 62) were included in the review. All the studies were cohort studies and reported the effects of rituximab on CNS involvement as secondary analysis. Rituximab was administered in combination of other medications. Data synthesis revealed that rituximab, especially in combination with other medications, might have beneficial effects in severe and refractory CNS involvement in Sjögren’s disease.

Conclusions

Rituximab administration should be limited to severe and refractory CNS involvements in Sjögren’s disease. However, due to the scarcity of articles and low level of confidence, further studies should be conducted to reach a definite conclusion.

Background

Sjögren’s disease is an autoimmune disease that involves multiple systems [1]. Sjögren’s disease was historically divided into primary and associated types based on the etiology [2]. Primary Sjögren’s disease is more prevalent among females and the age of unset and age at diagnosis for primary Sjögren’s disease is 34–57 and 40–67 years, respectively [3]. Although the main finding in Sjögren’s disease is salivary involvement, systemic involvement might occur in 30 to 50% of the patients [4]. Neurologic involvement in Sjögren’s disease is hard to determine and can complicate the treatment as these involvements may proceed glandular involvement [5]. Neurological involvement has been reported to range between 8.5 and 70% [6–8]. The wide prevalence range might be due to the use of different tools for the diagnosis. The prevalence of central nervous system (CNS) involvement in Sjögren’s disease has also been reported to range between 2.5 and 48% in primary Sjögren’s disease [7]. There is female dominance in CNS involvement in primary Sjögren’s disease and the manifestations can be in the form of focal or diffused cerebral or spinal lesions [9–11]. CNS involvement in secondary Sjögren’s disease is very much related to the nature of the underlying disease and may completely differ from the presentations found in primary Sjögren’s disease and therefore the prevalence is not well reported [12–14].

CNS involvement in Sjögren’s disease can result in a diverse range of symptoms, including headache, seizures, deficits in sensory and motor neurons, movement disorders, Multiple Sclerosis-like symptoms, optic nerve neuropathy, aseptic meningitis, cognitive disorders, and psychological manifestations [8, 10]. Due to the variety of CNS symptoms in Sjögren’s disease, the efficacy of different treatments on each symptom differ [13]. The emergence of monoclonal antibodies has provided hopes for a better management of autoimmune diseases, including CNS involvement in Sjögren’s disease [13].

Rituximab is a monoclonal antibody against CD20 that has been approved as a treatment agent for disease and conditions including non-Hodgkin’s lymphoma that are CD20 positive, chronic lymphocytic leukemia (CLL), small lymphocytic leukemia (SLL), rheumatoid arthritis (RA), microscopic polyangiitis (MP), granulomatosis with polyangiitis (GPA), and pemphigus vulgaris (PV) [12]. Rituximab induces cell death through antibody- and complement-dependent cell-mediated cytotoxicity, antibody dependent phagocytosis, and direct effect of receptor binding [15]. Furthermore, rituximab reduces B Cell function that might be a mechanism of its action in the treatment of autoimmune diseases [16]. Rituximab has shown beneficial effects in the treatment of CNS involvement in lymphoma, Myelin oligodendrocyte glycoprotein (MOG) antibody disease (MOG-AD), and chronic infammatory demyelinating polyradiculoneuropathy (CIDP), and severe CNS involvement in systemic lupus erythematosus [17]. Although rituximab was found to be effective in the management of peripheral nervous system involvement in Sjögren’s disease [18], there is scarcity of scientific evidence regarding its efficacy in the management of CNS involvement in Sjögren’s disease and the findings of the studies have been controversial [19]. Therefore, the aim of this systematic review was to evaluate the published articles on the effects of rituximab administration on CNS involvement in Sjögren’s disease. The findings of this review could be used to provide an evidence-based conclusion on its efficacy in the management of CNS involvement in Sjögren’s disease.

Materials and methods

This systematic review was conducted on published articles in medical PubMed, Scopus, and Web of Science databases until 15 March 2025. The keywords were selected based on the Patient Intervention Comparison Outcome (PICO) method and included Sjögren’s disease as population, rituximab as intervention, and central nervous system, and neurologic as outcome. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guideline was used to conduct this systematic review. the search strategy was first developed in PubMed using the keywords, their synonyms, and Medical Subject Heading (MeSH) terms combined with Boolean operators. After reaching the final terms, the syntax in PubMed was modified to perform search in Scopus and Web of Science. The search term selection and search strategy are presented in Tables 1 and 2. The eligibility criteria for the studies were any human study that included data on the effect of rituximab in the management of CNS involvement in Sjögren’s disease in English language. Besides the mentioned databases, gray literature including Google Scholar and references of the included articles and reviews were also searched for relevant articles. Reviews, case reports, seminar proceedings, abstracts, commentaries and letter to editors as well as articles with unavailable full texts were excluded.

Table 1.

Keywords selected based on the PICO

PICO	Keywords	Search terms
Patient	Sjögren’s disease	Sjögren’s syndrome Sicca syndrome Gougerot syndrome
Intervention	Rituximab	Rituximab Mabthera Rituxan Anti-CD20 antibodies
Comparison	Standard care	-
Outcome	CNS involvement	Central Nervous System CNS Neurologic Neuropsychiatric

Table 2.

Search strategy in pubmed, scopus, and web of scinece

WOS	Search Query	Results
1	ALL=(rituximab*)	52,237
2	ALL=(anti-CD20 antibody)	7547
3	ALL=(anti-CD20 antibodies)	7540
4	ALL=(anti CD20 antibody)	8561
5	ALL=(anti CD20 antibodies)	8549
6	ALL=(antiCD20 antibodies)	97
7	ALL=(antiCD20 antibody)	97
8	ALL=(mabthera)	353
9	ALL=(Rituxan)	427
10	#1 OR #2 OR #3 OR #4 OR #5 OR #6 OR #7 OR #8 OR #9	55,547
11	ALL=(Sjögren*)	31,384
12	ALL=(sicca syndrome)	3239
13	ALL=(Gougerot*syndrome)	0
14	#11 OR #12 OR #13	32,192
15	ALL=(central nervous system*)	311,176
16	ALL=(CNS)	236,593
17	ALL=(neurologic*)	656,386
18	ALL=(neuropsychiatric)	60,883
19	#15 OR #16 OR #17 OR #18	1,111,873
20	#10 AND #14 AND #19	55
PubMed	Search Query	Results
1	rituximab	34,188
2	anti-CD20 antibody	5549
3	MabThera	34,201
4	Rituxan	34,238
5	(((rituximab) OR (anti-CD20 antibody)) OR (MabThera)) OR (Rituxan)	36,159
6	Sjögren’s Syndrome	22,644
7	sicca syndrome	3036
8	Gougerot’s syndrome	10
9	((Sjögren’s Syndrome) OR (sicca syndrome)) OR (Gougerot’s syndrome)	23,496
10	Central Nervous System	1,714,518
11	“central nervous system“[MeSH Terms] OR (“central“[All Fields] AND “nervous“[All Fields] AND “system“[All Fields]) OR “central nervous system“[All Fields] OR “CNS”	1,767,655
12	neurological involvement	88,018
13	neuropsychiatric	57,277
14	(((“central nervous system“[MeSH Terms] OR (“central“[All Fields] AND “nervous“[All Fields] AND “system“[All Fields]) OR “central nervous system“[All Fields] OR “CNS”) OR (neurological involvement))) OR (neuropsychiatric)	1,863,215
15	(((((rituximab) OR (anti-CD20 antibody)) OR (MabThera)) OR (Rituxan)) AND (((Sjögren’s Syndrome) OR (sicca syndrome)) OR (Gougerot’s syndrome))) AND ((((“central nervous system“[MeSH Terms] OR (“central“[All Fields] AND “nervous“[All Fields] AND “system“[All Fields]) OR “central nervous system“[All Fields] OR “CNS”) OR (neurological involvement))) OR (neuropsychiatric))	46
Scopus	Search query	Results
	TITLE-ABS-KEY ((“rituximab*” OR “anti-CD20 antibody” OR “anti-CD20 antibodies” OR “anti CD20 antibody” OR “anti CD20 antibodies” OR “antiCD20 antibodies” OR “antiCD20 antibody” OR “mabthera” OR “Rituxan”) AND (“Sjögren*” OR “sicca syndrome”) AND (“central nervous system*” OR “CNS” OR “neurologic*” OR “neuropsychiatric”)	72

The retrieved articles from the databases were combined into one dataset using the Endnote X9 software (Clarivate). The software was used to remove duplicate and screen title and abstracts. Screening of the retrieved articles was performed in two steps. The first step was screening for title and abstract based on the inclusion and exclusion criteria and the second step was reviewing the full text of the remaining articles from the first step. Data were then extracted from the included articles in the second step for synthesis. Two researchers performed the screening independently in each step. At the end of each step, the results of the screening by the researchers were compared and disagreement was resolved based on consensus between the researchers. In case of missing information or incomplete data, the corresponding authors of the manuscripts were contacted through email to provide data. In case no response was received from the corresponding authors, the research team decided whether to include or exclude the article based on the availability of the presented data. The flow diagram of the study is presented in Fig. 1.

Fig. 1.

The flow diagram of the systematic review

Of the primary identified 173 articles from three databases, including PubMed (n = 46), Scopus (n = 72) and Web of Science (n = 55), 108 duplicated publications were excluded leaving 65 articles for title and abstract screening. Based on the screening, 52 articles were excluded due to irrelevance, study type, or language incompatibility leaving 13 studies for full text evaluation. One study was excluded due to unavailable full text. Review of full text of the remaining 12 articles resulted in the exclusion of 9 articles due to unavailable data on the outcome or exposure (n = 6), no CNS involvement in the patients (n = 1), and no follow up data (n = 1) leaving three articles for data extraction.

Quality assessment

The quality assessment of the finally included studies were evaluated using the Joanna Briggs Institute (JBI) quality assessment tool for cohort studies. JBI is a validated tool that can be used to assess the methodological quality of studies in a systematic review [20]. The methodological quality is mainly evaluated in terms of the clarity of the study design, risk of bias, and measures to reduce bias in the results. Due to the small number of included articles, no article was excluded due to poor quality; however, the JBI score was used in interpreting the synthesized data. The quality assessment of the articles in presented in Table 3.

Table 3.

Quality assessment of the articles using the Joanna Briggs Institute quality assessment tool

Questionnaire item	Feldman et al. 2019	Flores-Chávez et al. 2018	Mekinian et al. 2012
Were the two groups similar and recruited from the same population?	Yes	Yes	Yes
Were the exposures measured similarly to assign people to both exposed and unexposed groups?	Yes	Yes	Yes
Was the exposure measured in a valid and reliable way?	Yes	Yes	Yes
Were confounding factors identified?	Yes	No	No
Were strategies to deal with confounding factors stated?	No	Not applicable	No
Were the groups/participants free of the outcome at the start of the study (or at the moment of exposure)?	Yes	Unclear	Yes
Were the outcomes measured in a valid and reliable way?	Yes	Yes	Yes
Was the follow up time reported and sufficient to be long enough for outcomes to occur?	Yes	Yes	Yes
Was follow up complete, and if not, were the reasons to loss to follow up described and explored?	Yes	Unclear	Yes
Were strategies to address incomplete follow up utilized?	No	Unclear	No
Was appropriate statistical analysis used?	Yes	No	No

Data synthesis

Data from each included article was extracted using a researcher-made checklist in Excel and included characteristics of the article (First author and publication year), design of the study, sample size, main outcomes, and the results of the study. Due to the heterogeneity of the outcome measures, study duration, and patient characteristics, meta-analysis could not be performed and the findings of the studies were summarized in this systematic review and decision was made based on the quality assessment of the articles, sample size of the articles.

Results

Three studies (N = 62) were included in this systematic review. Summary of the included studies are presented in Table 4. All the studies were cohort studies with participants with Sjögren’s disease and CNS involvement ranging from 17 to 28 patients.

Table 4.

Summary of the included studies

Author (year)	Study design	Sample size	Intervention/Exposure	Duration	Outcomes	Findings
Feldman et al. (2019) [21]	Retrospective cohort	27 patients with neurologic symptoms (17 Sjogren’s disease)	rituximab+corticosteroid+cyclophosphamide+IVIG	2–7 months	Physicial neurological assessmet, imaging, electrophysiological evaluation, and pathology findings	No overall association between rituximab and neurological improvement
Flores-Chávez et al. (2018) [22]	Retrospective cohort	208 pateints with severe life-threatening systemic disease (based on ESSDAI) 28 cases of CNS involvement	Rituximab+IVIG	10 years (1–14 years)		Symptoms improved in 20–30% of patients who received rituximab and IVIG
Mekinian et al. (2012) [23]	Cohort	17 Sjogren’s disease patients	Rituximab+IVIG	13 months (6–58 months)	Physician neurological assessment, Rankin score, European Sjögren’s Disease Activity Index (ESSDAI)	Response rate was higher in CNS involvement + vasculitis or cryoglobulinaemia (9/10, 90%) than sole CNS involvement (2/7, 29%, p = 0.03) after three months. Rankin and ESSDAI improved in patients with cryoglobulinaemia or vasculitis. Neurological symptoms improved in 11 patients (65%) at 3 months. Of the 11 patients, 9 (53%) treatment effect remained at 6 months.

Feldman et al. (2019) conducted a retrospective cohort study on 27 patients with neurologic symptoms including 17 patients with Sjögren’s disease in a single-center study in the United States [21]. The study duration ranged between 2 and 7 months. Of the 17 patients, only one patient with Sjogren’s disease with systemic polyneuropathy diagnosed with cryoglobulinemia associated neuropathy and had concomitant immune thrombocytopenic purpura (ITP) and monoclonal gammopathy of undetermined significance (MGUS) received rituximab in combination with corticosteroid, cyclophosphamide, and Intravenous Immune Globulin (IVIG). Neurological evaluation was performed based on signs and symptoms, radiology, elecrophysiological and pathological assessment. The patient neurological status improved after the medication. All patients with cryoglobulinemia including the patients with Sjögren’s disease improved after medication. However, the duration of medication in the patient with Sjögren’s disease was not mentioned in the study.

Flores-Chávez et al. (2018) conducted a retrospective cohort on 208 patients who were identified with severe life-threatening systemic disease using the European League Against Rheumatism Sjögren’s disease activity index (ESSDAI) in a multicenter registry in Spain [22]. Of the 208 patients, CNS involvement was determined in 28 patients [22]. The mean follow up duration of the study was 10 years (1–14 years). Three patients with CNS involvement received rituximab and IVIG. The study did not directly report the response rate of CNS involvement; however, the overall response rate with rituximab and IVIG was reported to range between 20 and 30% [22].

Mekinian et al. (2012) conducted a cohort study on 11 patients with CNS involvement due to Sjögren’s disease (median follow duration was 13 months [6–58 months]) [23]. CNS involvement was evaluated using MRI imaging and revealed diffused abnormalities in the white matter. The main clinical manifestations were multiple sclerosis-like (n = 6, 54%), spastic paraparesis and sphincter dysfunction (n = 3, 27%), and focal neurological manifestations (n = 3, 27%), and transverse myelitis (n = 1, 0.9%). All patients received rituximab was. No effect was observed for rituximab in the management of multiple sclerosis-like manifestations (n = 6). On the other hand, rituximab was effective in improving walking distance in the patient with transverse myelitis after three months. Of the two patients with anxiety and depression, rituximab was effective in one patient who also had cognitive decline after three months, while rituximab was not effective in the management of and cognitive decline in another two patients. MRI re-evaluation was performed for 6 patients that showed no improvement at 6 months. Eight patients received 1 g rituximab repeated 15 days later. The adverse effects were mild arterial hypertension episodes (n = 2), severe acute reaction at infusion cite at the second dose injection (n = 1), which resulted in RTX discontinuation, severe cutaneous infection (n = 1). Cytomegalovirus infection was reported 18 months after rituximab administration in a 74-year-old patient with acquired hypogammaglobulinaemia and mycophenolate mofetil.

Discussion

Quality of evidence

This systematic review included cohort studies on patients with Sjögren’s disease with other comorbidities that evaluated the effects of rituximab administration on CNS involvement based on laboratory, imaging, and clinical examination. None of the studies were intended to assess the effects of rituximab on CNS involvement; therefore the reported findings were secondary findings. For this reason, the sample size in none of the studies was appropriate for a generalizable finding. However, the findings of the studies are synthesized based on their quality of evidence.

Although the study by Feldman et al. (2019) was a cohort study on 27 patients, of whom only one patient received rituximab that improved CNS involvement. Although various measurements were performed for the patients to assess CNS involvement, Feldman et al. (2019) did not mention whether all evaluation methods were done for all patients, including the patient who received rituximab. Furthermore, the administration dose, duration of administration and follow up period was not mentioned for the patient. As the patient received corticosteroid, cyclophosphamide, and IVIG, the effects on CNS improvement could not be linked solely to rituximab [21]. The study also failed to indicate whether patients had primary or secondary Sjögren’s disease; however, the authors mentioned Sjögren’s disease as a coexisting condition with cryoglobulinemia [21]. Therefore, the quality of evidence in relation to the effect of rituximab on CNS involvement was considered poor.

Flores-Chávez et al. (2018) evaluated the effects of rituximab in combination to IVIG on CNS involvement in three patients with Sjögren’s disease. Although the exact effect was not reported, the overall 10-year response rate to rituximab with IVIG could be between 20 and 30% [22]. Although the study did not state the dose and duration of administration, the long follow up period of the study may indicate the long term rituximab administration along with IVIG could be beneficial in reducing CNS involvement in severe disease. However, the quality of evidence could not be good.

Mekinian et al. (2012) also evaluated the effects of rituximab on CNS involvement in 11 patients with Sjögren’s disease. The follow up duration in the Mekinian et al. (2012) study was medium term (13 months) and the findings indicated that although the effects of rituximab on CNS involvement was depended on the clinical manifestations. Mekinian et al. (2012) stated that the best treatment response was seen in patients with transverse myelitis symptoms while rituximab did not improve MRI findings among those who performed follow up (6/11 patients). The administration dose of rituximab was one gram repeated after 15 days. Acute side effects were seen in five patients (45.5%) of whom, adverse effects were severe in three patients (60%) but rituximab administration was stopped only in one patient (20%). One long-term adverse effect was reported in an elderly patient in the form of cytomegalovirus infection [23]. The quality of evidence in the study was acceptable.

Overall, it can be hypothesized that rituximab administration could have a borderline effect on CNS involvement in Sjögren’s disease. This effect might be more prominent in patients with severe CNS involvement and in combination with other medications including IVIG. Similar to the findings of the reviewed studies, a case report by Ging et al. (2019) reported improvements in CNS involvement in a 58-year-old female with Sjögren’s disease and fulminant CNS function impairment [24]. However, the patient in the case report primarily underwent plasmapheresis and received cyclophosphamide and corticosteroid monthly for 7 months and then received rituximab every 6 months [24]. The administration dose of rituximab was not stated but the patient’s CNS involvement (primarily flaccid tetraplegia and seizures) was resolved within three months and she experienced no replaces during 1.5 years of follow up with no adverse effect [24]. The findings of the case report in terms of the effectiveness of rituximab administration in severe CNS involvement along with other medications were in line with the overall findings of this systematic review. In another case report by Kudsi et al. (2023), IV rituximab administration at the dose of 375 mg/m2 every two weeks resolved headache, which was resistant to prednisolone and methotrexate, in a 48-year old woman with Sjögren’s disease and prevented relapse for two years [25]. This finding was in contrast to the overall findings of this systematic review and indicated that rituximab could effectively manage less severe but refractory CNS symptoms. In a review of five case reports by Jaskólska et al. (2025) on the CNS involvement in Sjögren’s disease, rituximab (1 g twice daily every two weeks followed by 1 g daily every 6 months as maintenance) and prednisolone were administered to only to one patient (62-year-old female) and improved the CNS symptoms [8]. However, the review did not comment on the efficacy of rituximab in the management of CNS involvement [8]. The current guidelines that indicated rituximab in refractory cases of CNS involvement, especially in patients with cryoglobulinemia and vasculitis-related CNS involvement have based their recommendations on small studies, case series, and case reports [9, 26]. These recommendations may be affected by reporting bias and the small sample size of the studies may prevent generalizing the findings. Therefore, it is suggested that prospective cohorts or randomized clinical trials be conducted on the effect of rituximab, its effective administration (initial and maintenance doses) and safety of administration in the management of CNS involvement in Sjögren’s disease.

Considering the sample size of the included studies, the assessment of CNS involvement findings as secondary outcome, and observational study design, the level of evidence of the findings of this systematic review was low. However, this systematic review gathered low-level evidence from observational studies in order to provide a better understanding on the possible effects of rituximab on CNS involvement in Sjögren’s disease. Therefore, it is recommended that further interventional studies evaluate the effects of rituximab alone or in combination with other medications on CNS involvement in Sjögren’s disease. The findings of this systematic review can serve as a primary hypothesis for the effects of rituximab on CNS involvement in Sjögren’s disease in designing further studies on this topic.

Conclusions

The findings of the current systematic review were in line with the previous recommendations that rituximab could have potential benefits if administered in combination with other medications in patients with Sjögren’s disease and refractory or severe CNS involvement. However, due to the scarcity of data and small sample sizes and possibility of bias, further well-designed observational or interventional studies are needed to justify the use and safety of rituximab in the management of CNS involvement in Sjögren’s disease.

Abbreviations

CIDP

Chronic inflammatory demyelinating polyradiculoneuropathy

CLL

Chronic lymphocytic leukemia

CNS

Central nervous system

ESSDAI

European League Against Rheumatism Sjögren's syndrome disease activity index

GPA

Granulomatosis with polyangitis

ITP

Immune thrombocytopenic purpura

IVIG

Intravenous immunoglobulin

MeSH

Medical Subject Heading

MOG

Myelin oligodendrocyte glycoprotein

MOG-AD

Myelin oligodendrocyte glycoprotein antibody disease

MP

Microscopic polyangitis

PICO

Patient, intervention, comparison, outcome

PV

Pemphigus vulgaris

RA

Rheumatoid arthritis

SLL

Small lymphocytic leukemia

WOS

Web of Science

Author contributions

MS conceptualized and supervised the study. AJE designed and improved the search strategy and conducted the search. AJE and MS performed the screening of the retrieved articles. AJE provided the first draft of the manuscript. MS improved the academic writing of the manuscript. All authors read and approved the final draft of the manuscript for submission.

Funding

This study was not funded by any organization of institution.

Data availability

No datasets were generated or analysed during the current study.

Declarations

Ethics approval and consent to participate

Since this study was a systematic review, no consent was obtained from patients. Based on the institutional regulations, systematic reviews do not require to obtain ethics approval. However, the protocol for the systematic review was registered in the PROSPERO website (Code: CRD420251029094).

Consent for publication

Not applicable.

Competing interests

The authors declare no competing interests.