Myasthenia gravis (MG) is an autoimmune disease caused by dysfunction at the neuromuscular junction. Current studies on MG are increasingly focusing on the involvement of B cell immunophenotypes in the development of the disease. Nonetheless, the specific correlation between B cells and MG still needs to be fully clarified. From published GWAS studies, we gathered summary results on B cell immunophenotypes and MG. We performed a Two-sample Mendelian randomization (MR) analysis to investigate the potential causal relationship between B cells and MG. The primary estimation was done by using IVW and the Wald ratio. To assess pleiotropy and heterogeneity, a range of tests were utilized, including the Cochran Q test, MR-Egger intercept analysis, and the MR-PRESSO test. Next, we explored the potential for a reverse connection between B cells and MG using reverse MR analysis. Subsequently, in order to control for any potential confounding variables among the B cells, we carried out a multivariable MR analysis. Finally, we conducted co-localization analysis to examine the correlation between B cells and MG. Additionally, we repeated the above analysis process for two different MG subtypes. A total of 15 B cells were found to be significantly associated with MG, 7 B cells showed significant association with Early-onset MG, and 13 B cells showed significant association with Late-onset MG, as identified by MR analysis. We verified the reliability of the results by examining heterogeneity or pleiotropy. The Reverse MR analysis showed that there is bidirectional causality between 4 B cells and Early-onset MG, as well as between 2 B cells and Late-onset MG. To prevent confusion among B cells, we utilized multivariable MR analysis and identified that only 7 B cell immunophenotypes had independent effects on MG, while 4 B cell immunophenotypes had independent effects on Late-onset MG. None of the B cells had independent effects on Early-onset MG. Through colocalization analysis, it was found that two B-cell variants (rs75787009, rs354026) were associated with MG, along with two variants (rs138791329, rs11882257) were linked to Late-onset MG. Our results indicate a connection between B cells and the risk of MG, underscoring the possibility of using B-cell depletion therapy as a treatment option for MG patients based on genetic factors. Nevertheless, further research is needed to explore the specific mechanisms involved in this association.

The multiple sclerosis (MS) therapeutic landscape has evolved over time. We conducted a knowledge graph-guided analysis of MS-specific disease-modifying therapy (DMT) prescription trends using longitudinal real-world clinical data. We utilized registry-linked electronic health records (EHR) data from two large independent healthcare systems encompassing both academic and community practices (2004-2022). We applied a novel and efficient Knowledge-driven Online Multimodal Automated Phenotyping (KOMAP) algorithm to identify patients diagnosed with MS and evaluated algorithm performance against chart-reviewed and registry-recorded diagnosis labels. To assess temporal trends in DMT prescriptions, we combined the two cohorts and constructed time-varying temporal knowledge graphs using the patient-level EHR data segmented by calendar year. For each year, we analyzed co-occurrence patterns between DMTs and MS diagnosis by using Shifted Positive Pointwise Mutual Information transformation and singular value decomposition to generate embeddings. We computed patient-wise cosine similarities and confidence intervals. The phenotyping algorithm achieved robust performance in predicting MS diagnosis (AUROC: MGB=0.994, UPMC=0.922), identifying 29,169 MS patients in the combined dataset. Among commonly used standard-effectiveness DMTs, prescriptions for interferon-beta (slope=-0.018±0.011, p<0.001) and glatiramer acetate (slope=-0.013±0.012, p=0.026) and fumarates (slope=-0.031±0.010, p<0.001) declined after 2013. Use of S1P receptor modulators (slope=-0.026±0.016, p=0.005) declined after 2015. Among commonly used higher-effectiveness DMTs, B-cell depletion therapies (slope=0.051±0.027, p<0.001), particularly ocrelizumab (slope=0.020±0.016, p<0.001), showed a marked increase since 2017. Natalizumab usage peaked in 2012 (slope pre-2012 =0.063±0.012, p pre-2012 <0.001; slope post-2012 =-0.027±0.008, p post-2012 <0.001). Other DMT classes such as cell proliferation inhibitors, chemotherapy agents, and purine blockers, showed low usage during follow-up. Real-world evidence from two large EHR-based MS cohorts highlights distinct temporal shifts in the MS therapeutic landscape toward higher-effectiveness DMTs, particularly B-cell depletion therapy. Accurate identification of patients diagnosed with multiple sclerosis (MS) from real-world clinical data is essential for tracking longitudinal prescription patterns at scale and understanding the evolution of the MS therapeutic landscape.Leveraging electronic health records (EHR) data, our knowledge graph-guided unsupervised algorithm accurately and efficiently identified MS patients from two large, independent healthcare systems.Temporal analysis using knowledge graph-guided methods revealed major shifts in MS-related disease-modifying therapy (DMT) prescriptions, including a decline in early injectable use and increased adoption of B-cell depletion therapies.These findings confirm a growing preference for higher-effectiveness DMTs in MS and provide a scalable framework for evaluating long-term treatment patterns across healthcare systems.

Rheumatoid arthritis (RA) is the most common inflammatory joint disease worldwide. T-cell inhibitors, tumor necrosis factor inhibitors, interleukin inhibitors (ILIs), Janus kinase inhibitors, and B-cell depletion therapy are indicated as second-line therapy and are prescribed for other inflammatory autoimmune conditions (ankylosing spondylitis, psoriatic arthritis, psoriasis, Crohn disease, ulcerative colitis) co-occurring in an estimated 7% to 20% of patients with RA but are routinely excluded from RA studies. There is a lack of real-world evidence documenting treatment patterns in the large segment of patients with RA with inflammatory autoimmune comorbidities. To describe RA medication utilization patterns among biologic-naive patients, with and without similarly treated comorbidities. This retrospective cohort study uses administrative health claims from a large national health insurer between 2016 and 2022. Persistence, medication possession ratio (MPR), and utilization patterns were measured for patients with and without similarly treated comorbidities. Differences in means were calculated using a t-test, and Cox proportional hazards regression modeling was used to estimate persistence and hazard ratio (HR). A total of 22,946 patients with RA persisted on the index therapy for an average of 368.2 days (SD, 436). MPR varied across drug classes, with ILIs having the highest MPR at 0.95 (SD, 0.10) and B-cell depletion class having the lowest at 0.82 (SD, 0.19). Patients with RA with psoriatic arthritis were more likely to end the episode with therapy gap restart (HR, 1.1; CI, 1.02-1.22), yet patients with RA with psoriasis were less likely to experience a therapy gap restart (HR, 0.91; CI, 0.83-0.99). Among patients with RA initiated on ILIs, those with psoriasis are more likely to stop or switch compared with those without psoriasis (HR, 1.19; CI, 1.02-1.39). Among patients with RA initiated on Janus kinase inhibitors, those with psoriatic arthritis were more likely to stop or switch therapy compared with patients with RA without psoriatic arthritis (HR, 1.27; CI, 1.02-1.59). RA medication utilization varied significantly and may be influenced by comorbidities differently across RA drug classes. More research is needed to understand why therapies like tumor necrosis factor inhibitors persist longer in patients with RA with ulcerative colitis yet are discontinued earlier in patients with psoriatic arthritis.

Given the efficacy of B-cell depletion therapy in systemic lupus erythematosus (SLE) treatment and the capacity of engineered natural killer (NK) cells in B-cell elimination, we explored the potential of genetically modified NK cells to target CD19 for the treatment of SLE. Peripheral blood-derived NK cells were engineered with CAR.CD19/interleukin (IL)-15 (XB-19.15) or CAR.CD19 alone. In vitro assays tested cytotoxicity, proliferation (Ki-67), and cytokine release (IL-15/interferon-gamma [IFN-γ]] against CD19+ cells (Raji, Nalm6, SLE B-cell). In vivo models included Nalm6-luc xenografts, humanised CD34+ mice, and SLE peripheral blood mononuclear cells xenografts to assess efficacy, persistence, and safety. A phase 1 trial enrolled 3 patients with refractory SLE receiving XB-19.15 as a proof-of-concept study. XB-19.15 showed superior cytotoxicity, sustained IL-15 secretion, and enhanced proliferation in vitro. In the mouse model, XB-19.15 showed significant dose-dependent tumour regression of Nalm-6 and B-cell depletion of humanised mice with long-term persistence in various lymphoid organs. The total levels of hIgG and anti-dsDNA antibodies were decreased in XB-19.15-treated groups with deep clearance of B-cell and plasma cells of bone marrow and spleen in the SLE xenograft model, indicating potential attenuation of SLE. Three patients received XB-19.15 achieved improvement in disease activity and reset of B-cell repertoires without severe adverse events. XB-19.15 enables potent, durable B-cell depletion and immune resetting in SLE with off-the-shelf utility and favourable safety. Preclinical and early clinical data support further trials to optimise dosing and confirm long-term efficacy.

This case report presents a 34-year-old immunocompro­mised male with multiple sclerosis on long-term B-cell depletion therapy, developing severe acute myocarditis (AM) complicated by life-threatening arrhythmias. The initial presentation mimicked acute coronary syndrome (ACS) and pulmonary pathology, delaying diagnosis. Cardiac magnetic resonance imaging (CMR) was cru­cial for confirming diffuse myocardial involvement and guiding management. This case emphasizes the value of early CMR in immunosuppressed patients with atypical presentation, where conventional diagnostic tools may be insufficient.

BackgroundNeuromyelitis optica spectrum disorder (NMOSD), driven by AQP4-IgG-producing B cells, is effectively managed with B cell depletion therapy (BCDT), such as rituximab (RTX). Although BCDT may reset the B cell compartment, its effects on B cell receptor (BCR) repertoire, clonality, isotype distribution, and somatic hypermutation (SHM) remain poorly understood. To examine how BCDT alters BCR features by comparing BCR repertoires between patients with NMOSD treated with RTX and azathioprine (AZA).MethodsFrom a prospective cohort, we recruited patients with NMOSD, including those on AZA (n = 11) and those 6–12 months post-RTX treatment (n = 9). Immunoglobulin heavy-chain libraries were generated from peripheral blood mononuclear cells and sequenced using Illumina MiSeq (2 × 300 bp). BCR features analyzed included isotype frequencies, D50 diversity index, top 10% clone fraction, SHM rates, and IGHV and IGHJ gene usage.ResultsAge (median 50 years) and disability scores were similar between the groups. In the RTX group, the median time since the last infusion was 9 months. RTX treatment led to a naïve B cell-dominant profile, with significantly reduced IgG1–IgG4 levels and unchanged IgA levels. Clonality was reduced, especially within the IgG isotype. SHM frequency was similar between groups, with no significant differences observed across individual isotypes. RTX also resulted in marked depletion of IGHV3-23, IGHV3-11, and IGHV3-73, along with IgG subclass-specific reductions in IGHV1-18, IGHV1-3, IGHV1-46, IGHV1-69, and IGHJ4.ConclusionSix to twelve months after RTX treatment, patients with NMOSD display a rejuvenated BCR repertoire characterized by naïve B cell predominance, reduced class-switched clonality, and selective loss of V gene segments. These findings support the mechanism by which BCDT resets pathogenic memory B cells and offer benchmarks for monitoring B cell reconstitution in NMOSD.

Effectiveness of Anti-CD20 B cells depleting therapy versus conventional treatment in severe Anti-N-methyl-d-aspartate receptor encephalitis: A real-world multi-center prospective cohort study

The pathogenesis of immune-mediated necrotizing myopathy: Progress and therapeutic implications.

Corrigendum to “Deep cervical lymph node volume decreases following B-cell depletion therapy”

We describe a case of tumefactive demyelinating lesion (TDL) that occurred during B-cell depletion therapy by ofatumumab and discuss its pathogenesis through serial magnetic resonance imaging and biopsied histopathology. Ten months after initiating subcutaneous ofatumumab following two episodes of transverse myelitis, the patient developed a large tumefactive lesion with closed-ring contrast-enhancement and intralesional microhemorrhages and was diagnosed as having a TDL by brain biopsy. After repeated intravenous methylprednisolone and plasma exchanges, the TDL gradually shrank, although a perilesional hypointense ring remained on susceptibility-weighted images. TDLs can occur even during B-cell depletion therapy; however, the underlying mechanism is not fully elucidated.

The deep cervical lymph nodes (dCLNs) are sites of immune presentation and B-cell maturation from the brain, and potentially involved in mechanisms of neuroinflammation. We hypothesized a reduction in dCLN volume following B-cell depletion therapy. In a retrospective cohort, we segmented bilateral dCLN from T2-FLAIR MRI at “prebaseline,” “baseline,” and “post-B-cell depletion” timepoints. Using a multivariable mixed-effect regression model, we find no changes in dCLN volumes between prebaseline and baseline timepoints (p > 0.05), but a significant decrease of 158 mm3 following ocrelizumab infusion (t = −3.3, p = 0.005). Baseline use of a disease-modifying therapy was also significantly associated with a smaller dCLN volume and attenuated the effects of B-cell depletion. These results are congruent with therapeutic mechanisms, although other alternative explanations for reductions in dCLN volumes cannot be ruled out based on this data. Deep CLN represent potential imaging biomarkers of pharmacological or clinical utility and warrant further investigation.

Bullous pemphigoid is an autoimmune disease that predominantly affects older adults. It is characterized by autoantibodies against the hemidesmosome proteins BP180 and/or BP230, and elevated levels of serum IgE, eosinophils, and chemokines in skin lesions. It typically presents pruritic, eczematous, excoriated, urticarial-like lesions; the treatments include high-potency topical corticosteroids, oral prednisone, immunosuppressants, doxycycline, dapsone, B-cell depletion therapy, intravenous immunoglobulin, as well as biologic drugs. In this report, we present the case of 63- year-old patient with a previous diagnostic of systemic arterial hypertension who developed multiple tense vesicle and bullas at photo exposed skin areas.

Fibrillary glomerulonephritis (FGN) is characterized by a severe renal prognosis. There is no uniformity of consensus regarding therapeutic treatment. Several reports on the effectiveness of rituximab have been published but showed different rates of renal response. This paper aims to evaluate the clinical and histological effects of two rituximab-based regimens in fibrillary glomerulonephritis. Twenty-one patients with a diagnosis of FGN managed in a single center (1996-2023) were identified. Seventeen patients who, since 2010, were treated with anti-CD20 antibodies were included in the present study. Eleven patients were treated with rituximab monotherapy (Group 1), 6 with the Intensive B-cell depletion therapy protocol (IBCDT) (Group 2), which consists of a combination of rituximab, IV cyclophosphamide, and steroids. At baseline mean serum creatinine and proteinuria were 2.0mg/dl and 3.7g/day, respectively. In Group 1, four patients achieved a response; in Group 2, five out of six patients achieved a response (P =.0064). Responder patients had a percentage of sclerotic glomeruli ≤40. Eight patients underwent a second biopsy due to recurrence or failure to respond to a previous therapy line. The present study confirms that FGN is primarily a B-cell-driven disease and provides evidence that FGN can be effectively managed by achieving a profound depletion of CD20+ B lymphocytes; the disease is highly progressive and probably requires prolonged maintenance treatment; and, last, early diagnosis is critical for long-term outcome because a significant glomerular sclerosis at the time of the first biopsy precludes the possibility of reversing or stabilizing the course of the disease.

Long-term outcome in Wiskott-Aldrich syndrome and X-linked thrombocytopenia patients: an observational -prospective multi-center study of the Italian Primary Immune Deficiency Network (IPINET).

Disease-modifying therapies (DMTs) are critical for managing autoimmunity such as multiple sclerosis (MS), yet concerns exist regarding their impact on viral infections. B-cell depletion (α-CD20) and IFN-β are 2 DMTs with seemingly opposing effects on viral infections. Pre-vaccine COVID-19 data linked B-cell depletion to worse outcomes, while IFN-β is believed to offer protection to viral infection. The mechanisms underlying the interactions between these DMTs and infection have yet to be fully elucidated. Our goal was to determine the modulatory effects of α-CD20 and IFN-β, administered individually or in combination, during acute respiratory viral infections in mice. In our study, B-cell depletion was achieved by administering α-CD20 antibodies 3 times every 5 days, starting 7 days before influenza A virus (IAV) infection. IFN-β was administered on days 1 and 2 p.i. α-CD20 administered alone exacerbated infection outcomes. At day 9 postinfection, mice treated with α-CD20 had elevated viral RNA, accompanied by greater weight loss, impaired viral clearance, heightened myeloid cell infiltration in the lungs, and elevated systemic inflammatory cytokines in the blood. Notably, T-cell responses to IAV were not inhibited by α-CD20. IFN-β monotherapy failed to confer significant protection against viral infection, but when combined with α-CD20, it reversed the exacerbated effects of B-cell depletion by reducing viral load, improving morbidity, limiting neutrophil infiltration, and restoring cytokine homeostasis. These findings suggest IFN-β's capacity to counteract the deleterious impacts of α-CD20 on respiratory viral infections, offering potential treatment strategies for autoimmune diseases during viral outbreaks.

Abstract Background: B cell depletion therapy (BCDT), such as monoclonal antibodies, bispecific T cell engagers(TCE) and CAR-T,has an extensive history of effectively treating B cell malignancies. Certain BCDT monoclonal antibodies,e.g. rituximab,are also approved to treat autoimmune diseases(ADs), however demonstrate poor B cells depletion in deep tissue which may limit the long-term disease control or remission in patients. Recently, anti-CD19 CAR-T, through thorough depletion and “resetting” of B cell populations, have achieved multi-year drug-free remission in systemic lupus erythematosus (SLE),idiopathic inflammatory myopathy(IIM)and systemic sclerosis(SSc). Here, we developed a trispecific TCE CC312, targeting CD3 and CD28 on T cells and CD19 on B cells. Consistent with CAR-T, CC312 showed potent T cell activation and B cell depletion in a prior study in B cell malignancies. In the current study, the potential of CC312 in treating ADs was explored in translational models and in the clinical setting. Methods: B cell killing of CC312 was assessed in ex vivo cytotoxicity assays using PBMC isolated from AD patients. T cell activation, proliferation and differentiation were also evaluated with patient PBMC. The in vivo efficacy for SLE was investigated in mice engrafted with SLE patient PBMC. In addition, clinical safety, tolerability, and efficacy of CC312 in refractory SLE, IIM, SSc, and other B cell-related ADs was evaluated in an ongoing investigator-initiated clinical trial. Results: In vitro,CC312 induced a concentration-dependent potent depletion of B cells in PBMCs derived from donors with ADs, with EC50 in pM range across donors and disease types. Compared with anti-CD3/CD19 bispecific benchmark, CC312 significantly enhanced T cell activation, proliferation, and memory T cell differentiation due to CD28 co-stimulation. In vivo, CC312 thoroughly depleted peripheral B and plasmablast cells,as well as eliminated IgG and anti-dsDNA in serum. At the end of this study, neither IgG deposits nor CD20+B cell infiltrates were observed within kidney tissues. In the ongoing clinical study of ADs, CC312 is well-tolerated, with no Grade 3+ CRS or ICANS. Even at the lowest dose level(5 μg/dose), peripheral B cells and B cell subgroups can be comprehensively depleted, accompanied with improvement or remission of disease. Conclusion: CC312’s capacity to potently and thoroughly eliminate B cells has been demonstrated in in vitro and in vivo studies as well as in the clinical setting, indicating the potential benefit in treating B cell-related ADs. As the first CD28 co-stimulatory TCE to be explored in ADs, additional clinical studies will be conducted to further evaluate the efficacy and safety in autoimmune patients. Citation Format: Yingfeng Huang, Ruixia Zhang, Xiaofang Zhang, Zhen Jing, Caizhi Zhao, Fangfang Pan, Beibei Zheng, Ruixue Dai, Li Zeng. CC312, a trispecific CD19-targeting co-stimulatory T cell engager, for the treatment of B cell malignancies and autoimmune diseases [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 3513.

The Risk of Hepatitis B and Tuberculosis Reactivation in Patients with Neuromyelitis Optica Spectrum Disorder Treated with B-Cell Depletion Therapy (P7-8.010)

B-cell depletion therapy reduces retinal inflammation in experimental autoimmune uveoretinitis.

B-cell depletion therapy is employed in a variety of clinical contexts from auto-immune diseases to malignancy. Prior research on patients with prior B-cell depletion treatment has suggested a mortality risk in patients hospitalized with COVID-19 however previous case–control studies have differed in their methods of patient comparison. Patients previously treated with B-cell-depletion hospitalized with COVID-19 were compared to matched controls in the Johns Hopkins Health System between March 1, 2020 and November 30, 2021. The primary outcome was 30-day all-cause mortality. Secondary outcomes included time to severe illness or death and time to clinical improvement. To eliminate bias due to imbalanced covariates, each patient who had previously received B-cell depletion therapy was matched with patients who had not received therapy based on age, sex, race, WHO severity score, admission date, COVID-19 specific treatment, and vaccination status. Propensity scores were calculated from a multivariable logistic regression model and performed on the matched sets, using B-cell depletion as the outcome, where the propensity score was the probability of receiving B-cell depletion therapy. The propensity score included matched covariates as well as smoking status, medical comorbidities, and vaccination status. Cox proportional-hazards regression models were applied on the matched sets to perform time to death, time to severe illness or death, and time to clinical improvement analyses. 50 patients were identified who had received B-cell depletion therapy and were compared to 186 matched controls. Patients treated with B-cell depletion experienced 30-day mortality of 6.0% compared to 3.8% in controls, adjusted hazard ratio (aHR) 1.45 (95% CI 0.30 to 6.95). B-cell-depleted patients experienced a longer time to clinical improvement, aHR 0.65 (95% CI 0.45–0.94). In this cohort, patients treated with B-cell depletion experienced a higher mortality rate compared to matched controls however this was not statistically significant. This group also experienced a prolonged time to clinical improvement based on WHO severity score.

B-cell depletion (BCD) therapies ( e.g., ocrelizumab, ofatumumab, rituximab) and natalizumab (NTZ) are highly effective disease-modifying therapies (DMTs) for multiple sclerosis (MS). However, no randomized clinical trial and only limited observational studies compared the two DMT classes. We compared BCD and NTZ in managing MS patient-reported disability progression using registry-linked electronic healthcare record (EHR) data. The study population of an EHR cohort of MS patients included a subset enrolled in a clinic-based MS registry that provided gold-standard outcome labels. To estimate average treatment effects, we applied a doubly-robust semi-supervised approach to analyze all (not only registry) patients and comprehensively adjusted for confounders that included not only a priori standard features but also knowledge graph-derived EHR features. While gold-standard disability outcomes were available in registry patients, we imputed the baseline pre-treatment and post-treatment disability status for non-registry patients. We categorized patient-reported disability progression status as "sustained worsening", "sustained improvement", or "no sustained change" based on 3 or more observations or imputations of Patient Determined Disease Steps (PDDS) scores within 3 years after target treatment initiation as the primary endpoint. In this MS cohort (n=1,738, Age=46±13 years, Non-Hispanic White=86.71%), there was no significant difference between BCD (n=1,245, 71.63%) and NTZ (n=495, 28.37%) in mitigating sustained worsening (ATE=0.012, 95% CI [-0.123, 0.102], p=.803) or promoting sustained improvement (ATE=-0.0823, 95% CI [-0.194, 0.022], p=.172) of patient-reported disability. Sensitivity analyses using a 2-year window after treatment initiation confirmed no difference in sustained worsening (ATE=-0.0141, 95% CI [-0.107, 0.080], p=.895) or sustained improvement (ATE=-0.0713, 95% CI [-0.263, 0.026], p=.245) between BCD and NTZ. In power analysis, the semi-supervised approach increased statistical power compared to the standard approach of using gold-standard data alone. This real-world comparative effectiveness analysis based on a novel doubly- robust semi-supervised approach found no difference between BCD and NTZ in managing MS disability progression. The scarcity of patient-reported disability outcomes in routine clinical care hinders analysis based on real-world patient-reported outcomes, while evaluation of sustained disability accumulation requires long-term follow-up in clinical trials.Using a large registry-linked electronic healthcare record cohort and a novel semi- supervised, doubly-robust method, we conducted a causal inference study to compare sustained change in patient-reported disability in people with MS.The semi-supervised approach effectively leverages additional data from patients without observed outcome information and increases the statistical power of the comparative effectiveness study while retaining robustness properties in the causal analysis.There was no statistically significant difference between B-cell depletion therapy and natalizumab in sustained patient-reported disability outcomes up to 3-years after treatment initiation.