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Germinal centers where B cells undergo clonal expansion and antibody affinity maturation are hypoxic microenvironments. However, the function of hypoxia-inducible factor (HIF)-1α in immunoglobulin production remains incompletely characterized. Here, we demonstrated that B cells lacking HIF-1α exhibited significantly lower glycolytic metabolism and impaired IgA production. Loss of HIF-1α in B cells affects IgA-producing B-cell differentiation and exacerbates dextran sodium sulfate (DSS)-induced colitis. Conversely, promoting HIF-1α stabilization via a PHD inhibitor roxadustat enhances IgA class switching and alleviates intestinal inflammation. Mechanistically, HIF-1α facilitates IgA class switching through acetyl-coenzyme A (acetyl-CoA) accumulation, which is essential for histone H3K27 acetylation at the Sα region. Consequently, supplementation with acetyl-CoA improved defective IgA production in Hif1a-deficient B cells and limited experimental colitis. Collectively, these findings highlight the critical importance of HIF-1α in IgA class switching and the potential for targeting the HIF-1α-dependent metabolic‒epigenetic axis to treat inflammatory bowel diseases and other inflammatory disorders., Competing Interests: Competing interests The authors declare no competing interests., (© 2024. The Author(s).)

Objectives: Metabolic changes are crucially involved in osteoclast development and may contribute to bone degradation in rheumatoid arthritis (RA). The enzyme aconitate decarboxylase 1 (Acod1) is known to link the cellular function of monocyte-derived macrophages to their metabolic status. As osteoclasts derive from the monocyte lineage, we hypothesised a role for Acod1 and its metabolite itaconate in osteoclast differentiation and arthritis-associated bone loss., Methods: Itaconate levels were measured in human peripheral blood mononuclear cells (PBMCs) of patients with RA and healthy controls by mass spectrometry. Human and murine osteoclasts were treated with the itaconate derivative 4-octyl-itaconate (4-OI) in vitro. We examined the impact of Acod1-deficiency and 4-OI treatment on bone erosion in mice using K/BxN serum-induced arthritis and human TNF transgenic (hTNFtg) mice. SCENITH and extracellular flux analyses were used to evaluate the metabolic activity of osteoclasts and osteoclast progenitors. Acod1-dependent and itaconate-dependent changes in the osteoclast transcriptome were identified by RNA sequencing. CRISPR/Cas9 gene editing was used to investigate the role of hypoxia-inducible factor (Hif)-1α in Acod1-mediated regulation of osteoclast development., Results: Itaconate levels in PBMCs from patients with RA were inversely correlated with disease activity. Acod1-deficient mice exhibited increased osteoclast numbers and bone erosion in experimental arthritis while 4-OI treatment alleviated inflammatory bone loss in vivo and inhibited human and murine osteoclast differentiation in vitro. Mechanistically, Acod1 suppressed osteoclast differentiation by inhibiting succinate dehydrogenase-dependent production of reactive oxygen species and Hif1α-mediated induction of aerobic glycolysis., Conclusion: Acod1 and itaconate are crucial regulators of osteoclast differentiation and bone loss in inflammatory arthritis., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Several recent reports have demonstrated that B cell-targeting chimeric antigen receptor (CAR) T cells offer a viable treatment option for patients with autoantibody-mediated autoimmune diseases. To present additional data on this therapy and discuss strategies for more efficient clinical translation, leading experts in CAR T cell therapy for autoimmunity from various countries, including China, Germany, and the United States, convened at the "1st International Autoimmune CAR T Innovators Summit" in Grassau, Germany, from May 10-12, 2024. The summit showcased additional insights of CAR T cell therapy in diverse autoimmune diseases and provided platforms for discussions on key questions through workshops and roundtables. Here, we summarize the recent findings and key developments reported at the summit., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024.)

Background and Objective: Patient education is an integral component of the treatment of axial spondyloarthritis (axSpA). However, the validated tools currently available for assessing disease-related knowledge are outdated and, in the case of axSpA, only available in English. The aims of this work were therefore (1) to develop a German-language tool for assessing disease-specific knowledge among axSpA patients and (2) to assess this tool in a pilot study., Methods: Available axSpA-specific tools were assessed by a panel of experts and a draft of the current G‑ASKQ7 questionnaire was agreed upon. After evaluation of face validity and subsequent adaptation, consecutive adult axSpA patients of a university hospital (Universitätsklinikum Erlangen) outpatient rheumatology department were asked to complete the questionnaire. Correlation between the patients' overall scores and other collected parameters (age, sex, and disease duration) were investigated., Results: Patients rated the developed G‑ASKQ7 questionnaire comprising seven questions as easy to understand and completed it within an average of 6.3 ± 2.0 min. The final questionnaire was completed by 65 axSpA patients (36 women; mean age 45.3 ± 12.4 years; mean disease duration 8.6 ± 7.3 years). The average G‑AKSQ7 score was 17.8/25, with significantly higher scores among women (19.0/25) than men (16.3/25; p ≤ 0.05). The question most often answered correctly (79.3 %) was question 7 concerning disease self-management, whereas question 4 on measurement of disease activity received the most incorrect answers (55.8 %). No significant correlation between disease duration (p = 0.57; Pearson's correlation coefficient, r = 0.07) or age (p  = 0.67; r = -0.05) and disease-specific knowledge was found., Conclusion: The G‑ASKQ7 represents the first German-language instrument for measuring disease-specific knowledge among axSpA patients. Routine application of this questionnaire would enable low-threshold assessment of an individual patient's knowledge requirements and thus provision of appropriate educational information. Continuous updates and further evaluation studies are required., Competing Interests: Einhaltung ethischer Richtlinien Interessenkonflikt J. Knitza gibt Berater- und Vortragtätigkeiten für die BDRh Service GmbH an. L. Schuster, J. Henes, M. Diener, F. Mühlensiepen, I. Andreica, A. Hueber und G. Schett geben an, dass kein Interessenkonflikt besteht.Die Studie wurde von der Ethikkommission der Universität Tübingen genehmigt (Votum Nr. 869/2021BO2)., (© 2024. The Author(s).)

Background: CD19-targeting chimeric antigen receptor (CAR) T-cell therapy has shown remarkable outcomes in patients with systemic lupus erythematosus. The effects of CD19-targeting CAR T cells on organ manifestations in patients with systemic sclerosis have yet to be characterised. B cells have a central role in the pathogenesis of systemic sclerosis. We present a detailed analysis of the effects of CD19-targeting CAR T-cell therapy in patients with systemic sclerosis., Methods: Six patients with severe diffuse systemic sclerosis with an insufficient response to at least two treatments were consecutively recruited at the Department of Internal Medicine 3, University Hospital Erlangen (Erlangen, Germany) to receive CD19-targeting CAR T-cell treatment (1 × 10 6 CAR T cells per kg bodyweight). Events were predefined by progression of interstitial lung disease, onset of congestive heart failure, onset of renal failure, onset of arterial hypertension, or initiation of new immunosuppressive or antifibrotic therapy. Event-free time or treatment intensification after study entry was the primary outcome. Key secondary outcomes included changes in the modified Rodnan Skin Score (mRSS), imaging (a component of the assessment of lung fibrosis), laboratory assessments, patient-reported outcomes, and a modified version of the American College of Rheumatology Composite Response Index in Systemic Sclerosis (ACR-CRISS), assessed at baseline, 3 months, 6 months, 9 months, and 12 months., Findings: Between April 20, 2022, and Nov 8, 2023, six patients with severe diffuse systemic sclerosis (median age 42 years [IQR 36-53]; four men and two women; all White European) were recruited and received CD19-targeted CAR T-cell therapy. The median follow-up time was 487 days (IQR 342-585). No events occurred within the observational period. Probability of improvement in the ACR-CRISS score increased to a median of 100% (IQR 100-100) at 6 months. Median mRSS decreased by 31% (IQR 29-38), corresponding to a median of 8 points (IQR 7-13) within 100 days. The extent of disease on CT scan decreased by a median of 4% (IQR 3-4) due to reduction of ground-glass opacities while the reticular pattern remained stable. Forced vital capacity improved by a median of 195 mL (IQR 18-275) at the latest observational timepoint., Interpretation: We provide the first evidence that CD19-targeting CAR T-cell therapy might intercept with the progression of fibrotic organ manifestations in patients with systemic sclerosis., Funding: Deutsche Forschungsgemeinschaft, Deutsche Krebshilfe, ELAN-Foundation Erlangen, IZKF Erlangen, and Bundesministerium für Bildung und Forschung., Competing Interests: Declaration of interests JA and ChB received a travel grant from Kyverna therapeutics. ChB received a research grant from Boehringer Ingelheim and speaker fees from Novartis. CaB received consulting fees from Almirall, Delcath, BMS, Immunocore, Pierre Fabre, MSD, Novartis, Regeneron, and Sanofi; honoraria from Almirall, Leo Pharma, BMS, Pierre Fabre, and MSD; travel support from Pierre Fabre; and participates on the data safety monitoring or advisory board of Miltenyi Biotech and InflaRx. FM received a research grant from Kite/Gilead and consulting fees from AbbVie, ArgoBio, AstraZeneca, BMS, Crispr Therapeutics, Janssen, Kite, and Novartis; honoraria from AbbVie, ArgoBio, AstraZeneca, BMS, Crispr Therapeutics, Janssen, Kite, Kyverna, Miltenyi, Novartis, and Sobi; and participates on the BMS and Biontech data safety monitoring or advisory board. TKr received grants, consulting fees, honoraria, and travel support from Novartis and Pfizer, as well as consulting fees and honoraria from Kiowa Kirin, payment for expert testimony from Novartis, and travel support from AbbVie. GS received honoraria from Cabaletta, Novartis, Janssen, and Kyverna. SoK received honoraria from BMS and Sobi, as well as travel support from Janssen, BMS, Sobi, Novartis, and Kite/Gilead. JHWD has consultancy relationships with and is part of the speaker or advisory board of AbbVie, Active Biotech, Anamar, ARXX, AstraZeneca, Bayer Pharma, Boehringer Ingelheim, Calliditas Therapeutics, Celgene, Galapagos, Genentech, GSK, Inventiva, Janssen, Novartis, Pfizer, Roche, and UCB; has received research funding from Anamar, Argenx, ARXX, BMS, Bayer Pharma, Boehringer Ingelheim, Cantargia, Celgene, CSL Behring, Galapagos, GSK, Inventiva, Kiniksa, Lassen, Sanofi-Aventis, RedX, and UCB; travel support from AbbVie and SOBI; and is Chief Executive Officer of 4D Science and Scientific Lead of FibroCure. AM received grants from Miltenyi Biomedicine and Kyverna, and consulting fees from BMS/Celgene, KITE/Gilead, Novartis, BioNTech, Miltenyi Biomedicine, and Century Therapeutics. AM received honoraria from BMS/Celgene, KITE/Gilead, Novartis, BioNTech, Miltenyi Biomedicine, and Century Therapeutics, and travel support from AbbVie and Janssen. RGB received grants from Kyverna and travel support from BMS and Novartis. MA received grants, honoraria, payment for expert testimony, travel support and equipment from Miltenyi Biotec; and received consulting fees, honoraria and travel support from Miltenyi Biomedicine. All other authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY-NC-ND 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Systemic Lupus Erythematosus (SLE) is a rare, heterogeneous, potentially life-threatening autoimmune disease. Presence of kidney or other major organ (brain, heart or lung) involvement are predictors of poor outcome and in a subset of patients resistant to 1st or 2nd line conventional treatment. The 10-year mortality remains around 10-15 %. Chimeric Antigen Receptors (CAR) are molecules that allow to redirect the engineered immune cells towards specific target antigens and to simultaneously boost their activation. Following breakthrough results observed in the treatment of hematological malignancies, conventional CAR T-cell therapy has recently been applied to refractory SLE patients. Compared to the use of monoclonal antibodies, anti-CD19 CAR T-cells allow to achieve deeper depletion of autoreactive B cells, notably at site of inflamed tissues and lymphoid organs (i.e. lymph node), to suppress interferon signature and to restore the immune tolerance with the reemergence of naïve B-cells with a new repertoire. All clinical data reported in SLE patients so far showed that autologous anti-CD19 CAR T-cell treatment allowed impressive short- and longer-term resolution of lupus nephritis and other severe disease-related manifestations, without major toxicities and only mild cytokine-release syndrome. These clinical effects persisted after B-cell reconstitution and were associated with normalization of double-stranded DNA antibodies and complement levels in drug-free patients until three years after the procedure. Overall, these pioneering experiences show unique clinical and immunological response to CAR T-cell therapy in SLE, and the need for extended follow-up to determine its long-term efficacy., Competing Interests: Declaration of competing interest We have no conflict of interest., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Introduction: Systemic sclerosis is a complex disease that affects various target organs, making it difficult to assess response and determine remission or relapse. A baseline Neutrophil-to-Lymphocyte Ratio (NLR) >2.95 is associated with severe progressive skin and lung disease and decreased 5-year survival in systemic sclerosis (SSc). However, it is unknown whether NLR changes in response to treatment., Objective: To retrospectively evaluate NLR changes as a biomarker for treatment response in SSc., Methods: Progressive diffuse SSc patients who were treated with autologous hematopoietic stem cell transplantation (AHSCT group), with combination therapy of rituximab and mycophenolate mofetil (combination group) or CAR-T cell therapy (CAR-T group) were recruited, along with healthy controls (HC group). NLR, modified Rodnan Skin Score (mRSS) and forced vital capacity (FVC)% predicted were repeatedly assessed over 2 years., Results: Fifteen patients were recruited in the AHSCT group, 15 in the combination group, and six patients in the CAR-T group. Baseline mean NLR was high (>2.95) in AHSCT, combination groups, and CAR-T compared with HC. All treatment arms showed a statistically significant decrease in mRSS values and an increase in FVC% at each time point up to 12 months. In a linear mixed model, NLR significantly decreased up to 24 months only in the AHSCT group. NLR correlated with mRSS and FVC exclusively in the AHSCT group. NLR increased above 3 in two patients who experienced a relapse after AHSCT., Conclusion: NLR is a simple biomarker that correlated with outcome measures in SSc following AHSCT, but not with conventional therapy or CAR-T therapy. It is suggested that a decrease in NLR following AHSCT may indicate remission, whereas an increase may be associated with exacerbation. Further research is needed to validate these novel findings., (© The Author(s) 2024. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: Guselkumab (human monoclonal antibody) selectively inhibits the interleukin (IL)-23p19 subunit., Objectives: Assess the longer-term pharmacodynamic effects of guselkumab and explore associations between such effects and clinical responses in patients with active psoriatic arthritis (PsA)., Design: DISCOVER-2 randomized 739 biologic-naïve patients with active PsA (swollen/tender joint counts each ⩾5, C-reactive protein (CRP) ⩾0.6 mg/dL) to guselkumab (100 mg every 4 weeks (Q4W) or at Weeks 0, 4, and then Q8W) or placebo. Guselkumab-randomized participants with available serum biomarker data (randomly selected to reflect demographic and disease characteristics of the DISCOVER-2 population) comprised inflammatory ( N  = 100) and collagen ( N  = 178) biomarker cohorts., Methods: Pharmacodynamic effects of guselkumab through 2 years on inflammatory and collagen biomarker levels (general linear model) and associations between biomarkers and improvements in composite measures of joint, skin, and overall disease activity (Spearman linear regression) through 2 years were assessed. The relationship between the pharmacodynamic effects of guselkumab and achieving ⩾50% improvement in the American College of Rheumatology response criteria (ACR50) was assessed using a general linear model., Results: With guselkumab, pharmacodynamic effects on inflammatory (CRP, IL-6, serum amyloid A (SAA), IL-17A, IL-17F, IL-22, and beta-defensin 2 (BD-2)) and collagen (matrix metalloproteinase-degradation type I, III, IV, and VI collagen (C1M, C3M, C4M, and C6M)) biomarker levels were sustained or enhanced through Week 100. Throughout follow-up timepoints (Week 24/52/100), decreases in CRP, IL-6, C1M, and C6M levels correlated ( r  = 0.26-0.30; p  < 0.05) with improved joint disease activity (Disease Activity in Psoriatic Arthritis); decreases in IL-17A, IL-17F, IL-22, and BD-2 levels correlated ( r  = 0.34-0.58; p  < 0.05) with improved skin disease (Psoriasis Area and Severity Index); and decreases in C1M, C3M, C4M, and C6M correlated ( r  = 0.27-0.31; p  < 0.05) with improved overall disease activity (Psoriatic Arthritis Disease Activity Score). Significantly ( p  < 0.05) greater reductions from baseline at Week 100 in CRP, IL-6, SAA, and C1M levels were observed in participants improving from Week 24 ACR50 nonresponse to Week 100 ACR50 response and were accompanied by a significant decrease in C1M from Week 24 to Week 100 versus nonresponders at both Weeks 24 and 100., Conclusion: In biologic-naïve participants with active PsA, guselkumab elicited substantial and enduring reductions in biomarkers that were associated with durable improvements in joint, skin, and overall disease activity through 2 years of DISCOVER-2., Trial Registration: NCT03158285 (clinicaltrials.gov identifier)., Competing Interests: SS: research support from Amgen, Boehringer Ingelheim, Bristol Myers Squibb, Eli Lilly, GlaxoSmithKline, Janssen, and UCB; honoraria/speaker fees from AbbVie, Amgen, AstraZeneca, Eli Lilly, GlaxoSmithKline, Janssen, Teijin Pharma, and UCB. GS: speaker fees from Janssen and Novartis. SPR: research support, consulting fees, and/or speaker fees from AbbVie, Amgen, Celgene, Eli Lilly, Janssen, Novartis, Pfizer, SUN, and UCB. MG: research support and/or consulting fees from Genentech, Gilead, Novartis, Pfizer, and Sonoma Biotherapeutics. WC and SG: employees of Janssen Research & Development, LLC; own stock or stock options in Johnson & Johnson. SDC: employee of Janssen Scientific Affairs, LLC, a Johnson & Johnson company; owns stock or stock options in Johnson & Johnson. FL: employee of Janssen Pharmaceutical Companies of Johnson & Johnson; owns stock or stock options in Johnson & Johnson. PR: Grant/research support from Janssen and Novartis; and consultant fees from Abbot, AbbVie, Amgen, Bristol Myers Squibb, Celgene, Eli Lilly, Janssen, Novartis, Pfizer, and UCB., (© The Author(s), 2024.)

A program focused on pathogenesis, clinical trial design, and nonpharmacologic mind-body therapy for of spondyloarthritis (SpA) was presented at the Spondylitis Association of America Unmet Needs Conference IV. SpA pathogenesis is incompletely understood but involves a complex set of drivers, including genetics, biomechanical stress, and microbial factors. Affected tissues may include axial and peripheral joints, entheses, skin, uvea, and intestines. The specific role of key cytokines like interleukin (IL)-23, IL-17, and tumor necrosis factor in the phases of this inflammatory process remains unclear. New insights into pathogenesis will continue to generate targets for novel therapeutics. How to optimally evaluate those therapeutics in clinical trials, and for the various manifestations of SpA, remains less clear. Future trials need better generalizability, robust subgroup analyses to assess differential responses for distinct disease manifestations, a focus on comparative efficacy, and outcomes relevant to the clinician and the patient. Additionally, study designs need to leverage available technology to facilitate subject participation in trials. In view of the interplay between biologic, physical, and psychological aspects of disease, there is increasing attention to nonpharmacologic agents, with the aim of maximizing long-term health-related quality of life through the control of symptoms and inflammation. Recent studies provide encouraging evidence that mind-body interventions such as tai chi, qigong, yoga, and meditation have benefits for patients with SpA, particularly those with pain. The advances in our understanding of pathogenesis, novel therapeutics, and nonpharmacologic interventions have revolutionized the management of SpA, but numerous questions around optimal management remain.

Objectives: Transcriptomic data demonstrated that fibroblasts are heterogeneous with functionally diverse subpopulations. Although fibroblasts are key effector cells of fibrotic diseases such as systemic sclerosis (SSc), they have not yet been characterised spatially at the cellular level. Here, we aimed to investigate fibroblast subpopulations using imaging mass cytometry (IMC) as a proteomic-based, spatially resolved omics approach., Methods: We applied IMC to deconvolute the heterogeneity of 49 969 cells including 6501 fibroblasts at the single-cell level, to analyse their spatial distribution and to characterise their cellular niches in skin sections of patients with SSc and controls in situ., Results: We identified 13 different subpopulations of fibroblasts in SSc and control skin, the proportion increases in five fibroblast subpopulations (myofibroblasts, FAP high , S1PR + , Thy1 + ;ADAM12 high ;PU.1 high and ADAM12 + ;GLI1 + fibroblasts) and decreases in three subpopulations (TFAM high , PI16 + ;FAP + and Thy1 + ;ADAM12 low fibroblasts). Several fibroblast subpopulations demonstrated spatial enrichment and altered cellular interactions in SSc. The proportion of S1PR + -fibroblast positively correlated with more extensive skin fibrosis, whereas high numbers of PI16 + ;FAP - -fibroblasts were associated with milder skin fibrosis. The frequency of aberrant cellular interaction between S1PR + and ADAM12 + ;GLI1 + -fibroblasts also positively associated with the extent of skin fibrosis in SSc., Conclusion: Using IMC, we demonstrated profound changes in composition and localisation of the majority of fibroblast subpopulations in SSc skin. These findings may provide a rationale for specific targeting of deregulated fibroblast subpopulations in SSc. Quantification of S1PR + -fibroblast and PI16 + ;FAP - -fibroblasts may offer potential for patient stratification according to severity of skin fibrosis., Competing Interests: Competing interests: A-HG received lecture fees from Boehringer Ingelheim and Abbvie. JHWD has consultancy relationships and/or has received research funding from AbbVie, Actelion, BMS, Celgene, Bayer Pharma, Boehringer Ingelheim, JB Therapeutics, Sanofi-Aventis, Novartis, UCB, GSK, Array Biopharma and Active Biotech in the area of potential treatments of SSc, is CEO of 4D Science and Scientific lead/Co-CEO of FibroCure. A-HG has received research founding from Boehringer Ingelheim. The project was supported by an unrestricted grant from the Hiller Foundation., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ on behalf of EULAR.)

B cells have a pivotal function in the pathogenesis of autoimmune diseases, such as rheumatoid arthritis, multiple sclerosis and systemic lupus erythematosus. In autoimmune disease, B cells orchestrate antigen presentation, cytokine production and autoantibody production, the latter via their differentiation into antibody-secreting plasmablasts and plasma cells. This article addresses the current therapeutic strategies to deplete B cells in order to ameliorate or potentially even cure autoimmune disease. It addresses the main target antigens in the B-cell lineage that are used for therapeutic approaches. Furthermore, it summarises the current evidence for successful treatment of autoimmune disease with monoclonal antibodies targeting B cells and the limitations and challenges of these approaches. Finally, the concept of deep B-cell depletion and immunological reset by chimeric antigen receptor T cells is discussed, as well as the lessons from this approach for better understanding the role of B cells in autoimmune disease., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ on behalf of EULAR.)