---
title: "B-cell centrality and therapeutic response in autoimmune diseases: systematic review overview"
id: "frontiers-in-immunology-10-b-cell-centrality-dictates-therapeutic-efficacy-across-autoimmune-diseases-a"
canonical_url: "https://medichelpline.com/clinical-feed/frontiers-in-immunology-10-b-cell-centrality-dictates-therapeutic-efficacy-across-autoimmune-diseases-a"
content_type: "clinical_feed_article"
specialty: "Infectious Disease"
source_name: "Frontiers in Immunology"
source_url: "https://www.frontiersin.org/articles/10.3389/fimmu.2026.1906254"
published_at: "2026-09-10T00:00:00.000Z"
evidence_level: "Journal Feed"
license: "CC-BY-NC-4.0 / Informational Use"
---
# B-cell centrality and therapeutic response in autoimmune diseases: systematic review overview
## Provenance & Clinical Metadata
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- **Specialty:** [Infectious Disease](https://medichelpline.com/clinical-feed/infectious-disease.md)
- **Primary Source:** Frontiers in Immunology
- **Source URL:** [Original Journal Publication](https://www.frontiersin.org/articles/10.3389/fimmu.2026.1906254)
- **Published At:** 2026-09-10T00:00:00.000Z
- **Evidence Rating:** Journal Feed
## Executive GIST (TL;DR)
- The source provided is a Frontiers in Immunology article titled "B-cell centrality dictates therapeutic efficacy across autoimmune diseases: a systematic review." The accessible content in the provided source is limited to website navigation and journal section listings; the article body and review content were not included. - From the title alone it is clear the review examines the role of **B cells** in determining therapeutic outcomes across multiple autoimmune conditions, and that it uses a systematic review approach. No further methodological details (search strategy, inclusion criteria, data sources, number of studies reviewed, or analysis methods) were available in the provided source. - No study results, comparative efficacy data, specific therapies, or disease-specific conclusions were present in the supplied text. Therefore, no evidence-based findings, effect sizes, or recommendations can be extracted from the provided material. - Key expected areas likely addressed by the original review—based on the title—would include the centrality of **B-cell** biology to autoimmunity, differential responses to B-cell–targeted therapies across diseases, and implications for precision treatment. However, these points were not reported in the available source text. - The provided source included only journal navigation elements and section lists (e.g., Autoimmune Disorders, B Cell Biology, Multiple Sclerosis and Neuroimmunology), which confirm journal scope but not article content. - Because primary review details are missing from the supplied source, readers and clinicians should consult the full text at the journal site or contact the publisher for the complete systematic review to obtain valid clinical data, methods, and conclusions. - Any attempt to summarize study-specific outcomes, population details, or therapeutic comparisons would require access to the article body; such specifics were not reported and therefore are not included here. - The lack of accessible content also prevents assessment of review quality (risk of bias assessment, PRISMA adherence) or appraisal of clinical applicability. - For clinical decision-making, clinicians should seek the original article and supporting primary studies cited therein before altering practice based on the review’s title alone. - Contacting Frontiers in Immunology or using the provided DOI/URL to retrieve the full article is recommended for complete information and verification of findings.
## Clinical Analysis & Structured Key Points
Frontiers | B-cell centrality dictates therapeutic efficacy across autoimmune diseases: a systematic review SYSTEMATIC REVIEW article Front. Immunol. , 10 September 2026 Sec. Autoimmune Disorders Volume 17 - 2026 | https://doi.org/10.3389/fimmu.2026.1906254 Published in Frontiers in Immunology Autoimmune Disorders 7 impact factor 11.3 citescore Part of a Research Topic Modulating B cell subsets: Future therapeutics for autoimmune diseases Submission open 62k views 30 articles Editor & Reviewers Edited by C W Chris Wincup Reviewed by Y G Yekta Ghane A C Alessandro Conforti Outline Figures and Tables Figure 1 View in article Figure 2 View in article Figure 3 View in article Figure 4 View in article Table 1 Disease mechanistic basis and therapeutic strategies. View in article Table 2 Characteristics of clinical trials evaluating B-cell-targeted therapy in autoimmune diseases. View in article Table 3 Study population, eligibility criteria, and B-cell therapy specifications. View in article Table 4 Clinical, laboratory, and safety outcomes of B-cell-targeted therapies. View in article Table 5 Ongoing B-cell-directed therapy trials in autoimmune diseases. View in article SYSTEMATIC REVIEW article Front. Immunol. , 10 September 2026 Sec. Autoimmune Disorders Volume 17 - 2026 | https://doi.org/10.3389/fimmu.2026.1906254 B-cell centrality dictates therapeutic efficacy across autoimmune diseases: a systematic review V H Vishakha Hooda 1 H G Harsh Goel 2 T M Taruna Madan 3 A S Alpana Sharma 3 * 1. Department of Medical Oncology, All India Institute of Medical Sciences, New Delhi, India 2. Laboratory Oncology Unit, Dr. B.R. Ambedkar Institute Rotary Cancer Hospital, All India Institute of Medical Sciences, New Delhi, India 3. Division of Development Research, Indian Council of Medical Research, New Delhi, India See more Article metrics View details Abstract Background: B cells play a critical role in autoimmunity through autoantibody production, plasma cell differentiation, antigen presentation, cytokine secretion, and germinal center responses. The clinical efficacy, durability, and safety profiles vary across autoimmune diseases. Therefore, the objective is to assess B-cell therapeutic responses and their correlation with disease pathology in autoimmunity. Methods: Embase, Web of Science, and PubMed were systematically screened for clinical trials published between 2020 and July 2025. A total of 24 clinical trials across five autoimmune conditions—pemphigus vulgaris, myasthenia gravis, rheumatoid arthritis, systemic sclerosis, and Sjögren’s syndrome—were evaluated for B-cell-targeted therapy. Interventions included B-cell depletion therapy, CAR-T cell therapy, BTK inhibition, rituximab and its biosimilars, and combination strategies. Results: Across 24 clinical trials, more than 3,500 participants were included. We observed that autoantibody-mediated diseases pemphigus vulgaris and myasthenia gravis had the most superior and durable immune response to B-cell depletion by rituximab and inebilizumab, respectively. BTK inhibition showed rapid but non-durable responses. Immune complex diseases like rheumatoid arthritis and systemic sclerosis showed improvement in activity scores and partial response, and no clinical remission after treatment with rituximab and its biosimilars. The next-generation approach BCMA-directed CAR T-cell therapy showed promising results with potential durability in myasthenia gravis. Combination therapy using belimumab and rituximab resulted in a significantly better clinical outcome than monotherapy in Sjögren’s syndrome. Overall, B-cell therapy safety profiles showed no severe adversity and were well tolerated. Conclusions: The success of B-cell therapeutics appears to align with B-cell contribution, disease biology, and the depth of B-cell targeting in autoimmune conditions. Precision targeting is needed to effectively combat autoimmune diseases. Introduction B cells or B lymphocytes are important immune cell subsets around which the whole immune system revolves. From producing antibodies against pathogens to secreting key cytokines, not only do they help other immune cells in their optimal functioning, but they also serve as antigen-presenting cells to T cells ( 1 ). B cells are produced in the bone marrow wherein they develop variable immunoglobulin receptors to target diverse groups of pathogens by neutralization, opsonization, antibody-mediated and cell-mediated cytotoxicity, or promoting phagocytosis ( 2 , 3 ). During this process, self-reactive B cells are either suppressed or eliminated to develop tolerance against self-antigens. However, like many biological processes, the tolerance against autoreactive B cells is not infallible, leading to autoimmunity and other malignancies. Autoreactive B cells, therefore, directly—by producing autoantibodies—or indirectly—by secreting cytokines and engaging with T cells as antigen-presenting cells—produce abnormal immune response contributing to autoimmune pathology ( 4 ). Therefore, in the 1900s, B-cell depletion was adopted as one of the approaches to target autoimmunity ( 5 ). Owing to disease heterogeneity and the patient’s variability to treatment response, B-cell depletion therapy is of many types. B-cell-targeted therapeutics involves direct depletion of B cells using monoclonal antibodies such as anti-CD20 [rituximab (RTX)] and indirect depletion by targeting activation markers, cytokines, or co-stimulatory markers to dampen B-cell responses ( Figure 1 ) ( 6 – 9 ). Figure 1 B-cell developmental stages and corresponding therapeutic targets. Image depicting schematic representation of B-cell stages from progenitor B cell (Pro B), precursor B cell (Pre B), transitional, naïve, germinal center, memory, plasmablast, and plasma cells along with common B-cell therapeutic targets like CD19, CD20, CD38, CD22, BAFF, and BCMA and their corresponding B-cell therapy. Direct depletion by mAb may include RTX, ocrelizumab, ofatumumab, and ublituximab, which targets CD20 on B cells ( 10 ). In rheumatoid arthritis (RA), RTX is approved for patients whose disease remains active despite TNF inhibitor therapy, where it has been shown to deliver long-term control of inflammation and joint symptoms ( Table 1 ) ( 25 , 26 ). In pemphigus vulgaris (PV), CD20 blockade has become a standard first-line therapy for moderate-to-severe cases, frequently leading to sustained remission ( 27 , 28 ). Studies in primary Sjögren’s syndrome (pSS) have yielded mixed findings, though some have reported symptom relief and partial restoration of glandular function ( 29 , 30 ). In systemic sclerosis (SSc), RTX treatment has been linked to a measurable reduction in skin thickening and preservation of lung capacity ( 31 , 32 ). Its use in myasthenia gravis (MG), particularly in refractory disease, is expanding, with encouraging patient responses documented ( 33 ). Table 1 Autoimmune condition Mechanism of autoimmunity Major autoantibodies and targets Non-B-cell therapies B-cell-targeted therapies References Pemphigus vulgaris Loss of cellular adhesion in epidermis of skin and mucosa leading to blistering Anti-desmoglein 1/3 Corticosteroids, intravenous immunoglobulin, azathioprine, mycophenolate mofetil, cyclophosphamide, methotrexate, cyclosporine Rituximab, ianalumab, DSG3-CAART cells, rilzabrutinib, tirabrutinib ( 11 – 15 ) Rheumatoid arthritis Inflammation in joints caused by B and T cells and cytokine disruption (TNF-α, IL-6) Anti-citrullinated protein antibodies, rheumatoid factor targeting Fc region of IgG NSAIDs, corticosteroids, DMARDs, TNF inhibitors, JAK inhibitors Rituximab, ofatumumab, belimumab, atacicept, tabalumab, ianalumab, telitacicept, rozibafusp alfa ( 16 , 17 ) Sjögren’s syndrome Abnormal accumulation of lymphocytes in exocrine glands; Hyperactivation of B cells and formation of ectopic germinal center Anti-Ro/La targeting ribonucleoprotein complexes Glucocorticoids, leflunomide, methotrexate, azathioprine, mycophenolate, or cyclophosphamide Ianalumab, Belimumab, telitacicept, CAR-T cells, rituximab ( 11 , 18 , 19 ) Myasthenia gravis Loss of neuromuscular transmission Anti-AChR/MuSK targeting receptors at neuromuscular junction Anticholinesterase inhibitors, corticosteroids, immunosuppressants, β-adrenergic agonists, azathioprine, tacrolimus, mycophenolate mofetil, methotrexate, cyclophosphamide, eculizumab, efgartigimod, intravenous immunoglobulin Rituximab, inebilizumab, belimumab, telitacicept, CAR-T cells, MuSK-CAART cells ( 11 , 20 , 21 ) Systemic sclerosis Vascular injury and overactivation of fibroblast causing fibrosis Anti-topoisomerase I/centromere/RNA polymerase III Mycophenolate mofetil, methotrexate, PDE5 inhibitors, tocilizumab, prostacyclin Rituximab, inebilizumab, belimumab ( 11 , 22 – 24 ) Disease mechanistic basis and therapeutic strategies. Therapies such as inebilizumab and obexelimab act against CD19, a surface marker present from early B-cell development through the plasmablast stage, thus targeting a broader segment of the B-cell lineage than CD20-directed mAb that targets mature B cells ( 34 ). In PV, inebilizumab has been associated with fewer blistering episodes and lower pathogenic autoantibody concentrations ( 35 ). Bruton’s tyrosine kinase (BTK) inhibitors like fenebrutinib, rilzabrutinib, tirabrutinib, evobrutinib, and tolebrutinib disrupt intracellular signaling downstream of the B-cell receptor. By interrupting these pathways, they limit B-cell activation, clonal expansion, and antigen presentation without inducing full depletion ( 11 , 36 , 37 ). Initial clinical results point to reduced inflammatory activity and, in some cases, functional gains in RA, SSc, and pSS ( 36 – 39 ). Furthermore, CAR T-cell therapy directed at CD19 is emerging as a potential option for severe autoimmune diseases unresponsive to conventional treatment ( 40 ). Pilot studies in systemic lupus erythematosus (SLE) and MG have reported rapid near-complete elimination of B cells, accompanied by long-lasting remission ( 41 – 43 ). Nonetheless, significant risks including cytokine release syndrome and neurotoxicity necessitate rigorous safety oversight ( 44 ). Despite advancements in therapeutic strategies for autoimmunity, critical understanding of comparative B-cell therapeutics and their efficacy and durability across autoimmune conditions remains limited. Moreover, autoimmune conditions are mediated by different immune mechanisms and are not equally contributed by B cells, underscoring the need of disease-wise evaluation. Therefore, the objective of this review is to comprehensively assess efficacy and durability along with safety profiles of B-cell therapeutics such as B-cell depletion, B-cell signaling modulation, CAR-T cells, and combinatorial therapy across five different autoimmune conditions. Methods This systematic review was conducted using PRISMA guidelines 2020 ( 45 ). Data sources and search strategy For this review, a comprehensive literature search was performed using Embase, Web of Science, and PubMed databases for the articles published from 2020 to 2025 until July 2025. A filter including only randomized control trials, clinical trials, and studies was utilized during the process. The search strategy added in the Supplementary Material included the following listed MeSH terms and the keywords: B-cell-targeted therapies, B-cell therapies, anti cd20, anti cd19, RTX, ocrelizumab, ofatumumab, ublituximab, inebilizumab, B-cell trials, belimumab, and CART B cell ( Supplementary Table 1 ). All these terms were used only after adding the autoimmune diseases under consideration such as B-cell-targeted therapies in PV, B-cell-targeted therapies in RA, and so on. The autoimmune diseases reviewed in this study are PV, RA, Sjögren’s syndrome (SS), SSc, and MG. Inclusion and exclusion criteria The literature search was performed by two independent researchers to avoid bias and discrepancies while ensuring accuracy. We included only randomized controlled trials and clinical trials where the primary endpoint was assessing the effectiveness of B-cell therapy in humans suffering from the above-mentioned autoimmune disorders. We excluded non-human studies, animal studies, conference abstracts, case reports, observational studies, meta-analyses, and reviews. Data screening and inclusion Following the use of MeSH terms, a total of 979 studies were obtained, out of which 49 studies were initially found eligible for further screening. However, after employing the inclusion and exclusion criteria, 24 studies (5 PV, 13 RA, 1 SS, 2 SyS, and 3 MG) were found suitable to be included in this review ( Figure 2 ). In our study, we included the baseline characteristics such as patient number, age, sex, study design, location, and prior therapies, and outcome data such as complete response, partial response, overall survival, primary endpoint, secondary endpoint, key result, and other complications. Figure 2 PRISMA flowchart mapping study selection process for systematic review. Risk of bias assessment The quality of the included reports was assessed by two reviewers independently using the Cochrane Risk of Bias 2 (RoB2) tool and the ROBINS-I tool. The RoB2 tool assesses any bias across five domains: (D1) bias arising from the randomization process, (D2) bias due to deviations from intended interventions, (D3) bias due to missing outcome data, (D4) bias in measurement of the outcome, and (D5) bias in selection of the reported result, and then scored as low risk of bias, some concerns, or high risk of bias. An overall risk of bias further determines the quality of the study. ROBINS-I for non-randomized trials evaluate bias resulting from confounding factors, selection of study subjects, intervention, deviations from intended interventions, missing data, outcome measurement, and selection of reported results. We have harmonized and visually summarized the risk of bias assessment of both RoB2 and ROBINS-I using a unified traffic light plot for better comparison. Detailed information of RoB has been shared in the Supplementary Material . Results This review evaluated 24 reports across five autoimmune conditions—PV, RA, MG, SSc, and SS. Risk of bias across studies The risk of bias was evaluated using the Cochrane RoB 2 tool for randomized controlled trials and ROBINS-I for non-randomized single-arm trials. Out of 24 reports assessed, 11 were at low risk of bias, 11 studies had some concerns, and 2 studies were classified as high risk of bias ( Figure 3 ). However, on individual domain assessment, D1, which is based on a randomization process that has inadequate information regarding randomization and concealment, demonstrated 18 studies with low risk of bias, 3 studies with some concern, and 3 non-randomized studies assessed by ROBINS-I with high risk due to absence of randomization and bias due to selection or confounding. D2 based on deviations demonstrated 5 studies with some concerns and 1 study with high risk due to the open-label study design and variable interventions while the remaining 18 studies were at low risk. D3 and D5 based on missing outcomes and selection of reported results showed few studies with some concerns while others with low risk. D4 based on outcome measures were also primarily low risk with two studies each of some concern and high risk. Overall RoB assessment suggests that most of the included reports were methodologically robust and with low risk or some concerns of bias. Figure 3 Risk of bias assessment. Traffic light plot presenting quality of reports included in the systematic review carried out using the Cochrane RoB2 tool and ROBINS-I. Red = high/serious risk, yellow = some concerns/moderate risk, and green = low risk. n = 24. Pemphigus vulgaris According to the inclusion and exclusion criteria for this review, five clinical studies examining B-cell-targeted treatments for PV were found suitable ( 46 – 50 ). This included two phase 2 single-arm studies and three phase 3 randomized controlled trials ( Table 2 ). Studies were multicentric spanning Europe, USA, Japan, and Australia, and follow-up periods varied from 24 weeks to 7 years. Three phase 3 trials, a US-based randomized trial, and two RITUX3 trials directly compared RTX with common immunosuppressive treatments like mycophenolate mofetil (MMF) and prednisone, respectively ( 46 – 48 ). The remaining studies used open-label, uncontrolled designs to evaluate two novel BTK inhibitors—tirabrutinib and rilzabrutinib ( 49 , 50 ). Table 2 Disease Author (year) Journal Trial registration Phase Funding source Study design Intervention/comparator Blinding Follow-up duration Location Pemphigus vulgaris Maho-Vaillant M et al. (2021) ( 46 ) J Invest Dermatol NCT00784589 (RITUX3) Phase 3 Not reported Randomized controlled trial (1:1) Rituximab vs. prednisone Open-label 36 months Multicenter; France Werth VP et al. (2021) ( 47 ) N Engl J Med NCT02383589 Phase 3 Not reported Randomized controlled trial (1:1) Rituximab vs. mycophenolate mofetil Double-blind, double-dummy 52 weeks Multicenter; USA Tedbirt B et al. (2024) ( 48 ) JAMA Dermatol NCT00784589 (RITUX3) Phase 3 French Society of Dermatology Randomized controlled trial (1:1) Rituximab vs. prednisone Open-label 7 years Multicenter; France Murrell DF et al. (2021) ( 49 ) Br J Dermatol NCT02704429 Phase 2 Principia Biopharma (Sanofi) Single-arm (“BELIEVE” study) Rilzabrutinib (single arm) Not blinded 24 weeks Multicenter; Australia, Croatia, France, Greece, Israel Yamagami J et al. (2021) ( 50 ) J Dermatol Sci NCT03762265 Phase 2 Ono Pharmaceutical (Japan) Single-arm, uncontrolled Tirabrutinib (single arm) Not blinded 52 weeks Multicenter; Japan Rheumatoid arthritis Takeuchi T et al. (2023) ( 51 ) Ann Rheum Dis NCT03605251 Phase 2 Taiho Pharmaceutical Randomized, parallel-group TAS5315 vs. placebo Double-blind 12 and 36 weeks Multicenter; Japan Li J et al. (2022) ( 52 ) Rheumatology (Oxford) NCT04192617 Phase 2 SinoMab BioScience Randomized (1:1:1), multi-dose SM03 (low/high dose) vs. placebo Double-blind 24 weeks Multicenter; China Zeng X et al. (2022) ( 53 ) Arthritis Res Ther NCT03522415 Phase 3 Shanghai Henlius Biotech Randomized HLX01 vs. placebo Double-blind 48 weeks Multicenter; China Smolen JS et al. (2020) ( 54 ) Rheumatology (Oxford) NCT01274182 Phase 2 Hexal AG; Sandoz Randomized Sandoz rituximab vs. reference RTX Double-blind 24–52 weeks Multicenter; Europe, USA, South America and Asia Burmester G et al. (2020) ( 55 ) Clin Pharmacol Drug Dev NCT02792699 Phase 3 Amgen Inc. Randomized (1:1:1) ABP 798 vs. RTX-US/EU Double-blind 52 weeks Multicenter; Europe and USA Maharaj N et al. (2024) ( 56 ) Arthritis Res Ther NCT0426877 Phase 3 Dr. Reddy’s Laboratories Randomized DRL_RI vs. RTX-US/EU Double-blind 26 weeks Multicenter; Europe and USA De Meyst E et al. (2024) ( 57 ) Trials NCT06003283 Not reported Investigator-initiated Parallel-group superiority RCT Rituximab (dose-optimized, fixed-interval) vs. standard RTX Open-label 104 weeks Multicenter; Belgium Haridas et al. (2020) ( 58 ) BioDrugs NCT02296775 Phase 1/2 Dr. Reddy’s Laboratories Ltd. Randomized, parallel-group DRL RI (RTX biosimilar) vs. Rituxan (RTX‑US) vs. MabThera (RTX‑EU) Double-blind 24 and 52 weeks Multicenter; India and Ukraine Rivellese et al. (2023) ( 59 ) The Lancet Rheumatology 2014-003529-16 (STRAP); 2017-004079-30 (STRAP-EU) Phase 3 UK Medical Research Council and Versus Arthritis Randomized (1:1:1), parallel-group Rituximab vs. etanercept vs. tocilizumab Open-label (blinded joint assessors and pathology review) 16 and 48 weeks Multicenter; UK, Belgium, Italy, Portugal, and Spain Humby et al. (2021) ( 60 ) The Lancet ISRCTN97443826; EudraCT 2012-002535-28 Phase 4 UK-NIHR Randomized controlled trial Rituximab vs. tocilizumab Open-label (blinded joint assessors) 48 weeks Multicenter; UK, Belgium, Italy, Portugal and Spain Conaghan et al. (2023) ( 61 ) Lancet Rheumatology NCT0263
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