Objective Osteoporosis causes fractures which further increase the disease burden of rheumatoid arthritis (RA), however, osteoporosis treatment rates remain low. While several studies have reported that biologic or targeted synthetic disease‐modifying antirheumatic drugs (b/tsDMARDs) can prevent or improve osteoporosis in RA, our large‐scale, real‐world study showed that 1 year‐b/tsDMARDs use did not arrest osteoporosis progression. This study aimed to examine longer‐term changes in bone mineral density (BMD). Methods BMD was observed for up to 5 years in patients receiving b/tsDMARDs for active RA. The primary endpoint was change in BMD (T‐score), and the secondary endpoint was change in T‐score‐related factors. Results In total, 797 patients (anti‐osteoporosis (–), n = 645; anti‐osteoporosis (+), n = 152) were included, with a median 3.1‐year follow‐up (2,489 patient‐years). Clinical disease activity index (CDAI) improved in both groups (26.0/24.4 → 6.6/6.8). T‐scores decreased significantly in the femoral neck and radius in the anti‐osteoporosis (‐) group but not in the anti‐osteoporosis (+) group [anti‐osteoporosis (–): mean change –0.11/–0.33, both p < 0.001; anti‐osteoporosis (+):–0.01/–0.10, p = 0.830/0.071]. Overall, 460 patients (58%) experienced a decrease in T‐score. A high baseline T‐score correlated with a subsequent decrease, while longer osteoporosis treatment duration correlated with an increase. Unexpectedly, the duration of b/tsDMARD use and mean CDAI during observation were not associated with BMD maintenance. Conclusion Even when RA activity was controlled with b/tsDMARDs, BMD still decreased. This study emphasizes the importance of considering osteoporosis as an independent aspect of RA, beyond inflammation control. image
{"title":"Biological/targeted synthetic DMARDs do not arrest bone loss in patients with rheumatoid arthritis: a long‐term multicenter observational study","authors":"Takafumi Aritomi, Koshiro Sonomoto, Shingo Nakayamada, Hiroaki Tanaka, Atsushi Nagayasu, Satoshi Kubo, Ippei Miyagawa, Ayako Yamaguchi, Naoaki Ohkubo, Yasuyuki Todoroki, Yurie Satoh‐Kanda, Masanobu Ueno, Ryuichiro Kanda, Yuya Fujita, Masashi Funada, Hidenori Sakai, Satsuki Matsunaga, Hiroaki Tanaka, Masayuki Shinojima, Hiroki Kawamura, Kazuki Takahashi, Miyabi Ando, Kazuki Haru, Yusuke Miyazaki, Kentaro Hanami, Masao Nawata, Shunsuke Fukuyo, Keisuke Nakatsuka, Mikiko Tokunaga, Kazuyoshi Saito, Yoshiya Tanaka","doi":"10.1002/art.70125","DOIUrl":"https://doi.org/10.1002/art.70125","url":null,"abstract":"Objective Osteoporosis causes fractures which further increase the disease burden of rheumatoid arthritis (RA), however, osteoporosis treatment rates remain low. While several studies have reported that biologic or targeted synthetic disease‐modifying antirheumatic drugs (b/tsDMARDs) can prevent or improve osteoporosis in RA, our large‐scale, real‐world study showed that 1 year‐b/tsDMARDs use did not arrest osteoporosis progression. This study aimed to examine longer‐term changes in bone mineral density (BMD). Methods BMD was observed for up to 5 years in patients receiving b/tsDMARDs for active RA. The primary endpoint was change in BMD (T‐score), and the secondary endpoint was change in T‐score‐related factors. Results In total, 797 patients (anti‐osteoporosis (–), n = 645; anti‐osteoporosis (+), n = 152) were included, with a median 3.1‐year follow‐up (2,489 patient‐years). Clinical disease activity index (CDAI) improved in both groups (26.0/24.4 → 6.6/6.8). T‐scores decreased significantly in the femoral neck and radius in the anti‐osteoporosis (‐) group but not in the anti‐osteoporosis (+) group [anti‐osteoporosis (–): mean change –0.11/–0.33, both p < 0.001; anti‐osteoporosis (+):–0.01/–0.10, p = 0.830/0.071]. Overall, 460 patients (58%) experienced a decrease in T‐score. A high baseline T‐score correlated with a subsequent decrease, while longer osteoporosis treatment duration correlated with an increase. Unexpectedly, the duration of b/tsDMARD use and mean CDAI during observation were not associated with BMD maintenance. Conclusion Even when RA activity was controlled with b/tsDMARDs, BMD still decreased. This study emphasizes the importance of considering osteoporosis as an independent aspect of RA, beyond inflammation control. <jats:boxed-text content-type=\"graphic\" position=\"anchor\"> <jats:graphic xmlns:xlink=\"http://www.w3.org/1999/xlink\" mimetype=\"image/png\" position=\"anchor\" specific-use=\"enlarged-web-image\" xlink:href=\"graphic/art70125-toc-0001-m.png\"> <jats:alt-text>image</jats:alt-text> </jats:graphic> </jats:boxed-text>","PeriodicalId":129,"journal":{"name":"Arthritis & Rheumatology","volume":"36 1","pages":""},"PeriodicalIF":13.3,"publicationDate":"2026-03-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147373865","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Kevin J. Sheridan, Emma R. Dorris, Maria Inês Pimenta, Jemma Falkov, Matthew Fisher, Sam Pledger, Hector Devey, Munitta Muthana, Denis C. Shields, Richard E Mains, Betty A Eipper, Christopher D. Buckley, Anthony G. Wilson
Objectives Both susceptibility to, and severity of, rheumatoid arthritis (RA) is associated with the rs26232 C allele. Our primary aim was to identify the biological mechanism underlying this association. Methods Expression of surrounding genes was compared between rs26232 genotypes. Publicly available databases were used to correlate expression with RA inflammation and single cell synovial distribution. Inhibition of gene expression and activity was achieved using siRNA and a pharmacology agent and effects on RA synovial fibroblasts (RASFs) characteristics in vitro were assayed. The amidated secretome of synovial fibroblasts were characterised by mass spectrometry and ELISA. Effects of amidated peptides on macrophage polarity were determined using a RASF‐macrophage co‐culture module. Results rs26232 C is associated with low expression of peptidylglycine alpha‐amidating monooxygenase ( PAM ) in multiple tissues including RASFs. Synovial PAM is highly expressed in RASFs but not immune cells and levels are inversely correlated with synovial and systemic levels of inflammation. Inhibition of PAM in RASFs increased tissue damaging activities such as invasiveness in vitro . The most abundant amidated peptides secreted by RASFS were adrenomedullin (ADM) and proadrenomedullin N‐terminal peptide (PAMP). Incubation of RASFs with either peptide inhibited IL‐6 and ‐8 and increased TGF‐β production, and reduced invasiveness in vitro . Inhibition of amidation in a RASF‐macrophage co‐culture model skewed the macrophages to pro‐inflammatory MerTK ‐ phenotypes. Conclusions Genetically determined low PAM reduces the anti‐inflammatory and tissue damaging activities of ADM and PAMP mediated by macrophages and RASFs explaining the association of rs26232 C with RA severity.
{"title":"Tissue Damage in Rheumatoid Arthritis is Genetically linked to Low Peptidylglycine Alpha‐Amidating Monooxygenase Activity in Synovial Fibroblasts","authors":"Kevin J. Sheridan, Emma R. Dorris, Maria Inês Pimenta, Jemma Falkov, Matthew Fisher, Sam Pledger, Hector Devey, Munitta Muthana, Denis C. Shields, Richard E Mains, Betty A Eipper, Christopher D. Buckley, Anthony G. Wilson","doi":"10.1002/art.70123","DOIUrl":"https://doi.org/10.1002/art.70123","url":null,"abstract":"Objectives Both susceptibility to, and severity of, rheumatoid arthritis (RA) is associated with the rs26232 C allele. Our primary aim was to identify the biological mechanism underlying this association. Methods Expression of surrounding genes was compared between rs26232 genotypes. Publicly available databases were used to correlate expression with RA inflammation and single cell synovial distribution. Inhibition of gene expression and activity was achieved using siRNA and a pharmacology agent and effects on RA synovial fibroblasts (RASFs) characteristics <jats:italic>in vitro</jats:italic> were assayed. The amidated secretome of synovial fibroblasts were characterised by mass spectrometry and ELISA. Effects of amidated peptides on macrophage polarity were determined using a RASF‐macrophage co‐culture module. Results rs26232 C is associated with low expression of peptidylglycine alpha‐amidating monooxygenase ( <jats:italic>PAM</jats:italic> ) in multiple tissues including RASFs. Synovial <jats:italic>PAM</jats:italic> is highly expressed in RASFs but not immune cells and levels are inversely correlated with synovial and systemic levels of inflammation. Inhibition of <jats:italic>PAM</jats:italic> in RASFs increased tissue damaging activities such as invasiveness <jats:italic>in vitro</jats:italic> . The most abundant amidated peptides secreted by RASFS were adrenomedullin (ADM) and proadrenomedullin N‐terminal peptide (PAMP). Incubation of RASFs with either peptide inhibited IL‐6 and ‐8 and increased TGF‐β production, and reduced invasiveness <jats:italic>in vitro</jats:italic> . Inhibition of amidation in a RASF‐macrophage co‐culture model skewed the macrophages to pro‐inflammatory MerTK <jats:sup>‐</jats:sup> phenotypes. Conclusions Genetically determined low <jats:italic>PAM</jats:italic> reduces the anti‐inflammatory and tissue damaging activities of ADM and PAMP mediated by macrophages and RASFs explaining the association of rs26232 C with RA severity.","PeriodicalId":129,"journal":{"name":"Arthritis & Rheumatology","volume":"15 1","pages":""},"PeriodicalIF":13.3,"publicationDate":"2026-03-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147373913","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Zhenghao He,Weijia Wang,Qianwen Li,Shihao Ding,Mingxia Wang,Ming Hong
OBJECTIVETo investigate peripheral immune reconstitution following BCMA-CD19 dual-targeting CAR-T therapy in patients with Systemic lupus erythematosus (SLE).METHODSSingle-cell RNA sequencing (scRNA-seq) and parallel B and T cell receptor (BCR/TCR) sequencing were performed on peripheral blood mononuclear cells (PBMCs) from five SLE patients before infusion and after peripheral B-cell reconstitution (median 90 days post-infusion). These data were integrated with public datasets from seven SLE patients treated with CD19 single-targeting CAR-T and three healthy controls for comparative analysis (total N=15 subjects; 176,182 single cells analyzed).RESULTSDual-targeting CAR-T induced marked depletion of B-lineage populations, including plasma-lineage clusters that persisted after CD19 therapy. Specifically, Cluster 2 decreased from 10.70% to 2.67% and Cluster 3 from 9.55% to 3.12% in the dual-targeting cohort, whereas Cluster 3 increased (6.78% to 12.19%) in the single-targeting comparator. In B cells, dual targeting produced greater suppression of RIG-I/MDA5 and type I interferon transcriptional programs than single-targeting therapy. BCR repertoires shifted toward an IGHM-dominant (49.83% to 89.19%, P < 0.05), naïve-biased profile, with contraction of PRE-enriched class-switched clones and restoration of diversity toward healthy-like profiles. Clinical improvement was significant (mean SLEDAI decreased from 9.6 to 2.4, P < 0.05), paralleling these molecular changes.CONCLUSIONSBCMA-CD19 dual CAR-T therapy was associated with deeper depletion of plasma-lineage compartments and a tendency toward more pronounced reversal of SLE-associated molecular signatures. This exploratory finding suggests a potential advantage of dual targeting in achieving a more comprehensive humoral reset in SLE, which warrants further direct comparative studies to determine clinical superiority.
{"title":"Dual-Targeting BCMA-CD19 CAR-T Cell Therapy in Systemic Lupus Erythematosus: Single-Cell and Immune Repertoire Analysis Reveals Mechanisms of Immune Reconstitution.","authors":"Zhenghao He,Weijia Wang,Qianwen Li,Shihao Ding,Mingxia Wang,Ming Hong","doi":"10.1002/art.70117","DOIUrl":"https://doi.org/10.1002/art.70117","url":null,"abstract":"OBJECTIVETo investigate peripheral immune reconstitution following BCMA-CD19 dual-targeting CAR-T therapy in patients with Systemic lupus erythematosus (SLE).METHODSSingle-cell RNA sequencing (scRNA-seq) and parallel B and T cell receptor (BCR/TCR) sequencing were performed on peripheral blood mononuclear cells (PBMCs) from five SLE patients before infusion and after peripheral B-cell reconstitution (median 90 days post-infusion). These data were integrated with public datasets from seven SLE patients treated with CD19 single-targeting CAR-T and three healthy controls for comparative analysis (total N=15 subjects; 176,182 single cells analyzed).RESULTSDual-targeting CAR-T induced marked depletion of B-lineage populations, including plasma-lineage clusters that persisted after CD19 therapy. Specifically, Cluster 2 decreased from 10.70% to 2.67% and Cluster 3 from 9.55% to 3.12% in the dual-targeting cohort, whereas Cluster 3 increased (6.78% to 12.19%) in the single-targeting comparator. In B cells, dual targeting produced greater suppression of RIG-I/MDA5 and type I interferon transcriptional programs than single-targeting therapy. BCR repertoires shifted toward an IGHM-dominant (49.83% to 89.19%, P < 0.05), naïve-biased profile, with contraction of PRE-enriched class-switched clones and restoration of diversity toward healthy-like profiles. Clinical improvement was significant (mean SLEDAI decreased from 9.6 to 2.4, P < 0.05), paralleling these molecular changes.CONCLUSIONSBCMA-CD19 dual CAR-T therapy was associated with deeper depletion of plasma-lineage compartments and a tendency toward more pronounced reversal of SLE-associated molecular signatures. This exploratory finding suggests a potential advantage of dual targeting in achieving a more comprehensive humoral reset in SLE, which warrants further direct comparative studies to determine clinical superiority.","PeriodicalId":129,"journal":{"name":"Arthritis & Rheumatology","volume":"55 1","pages":""},"PeriodicalIF":13.3,"publicationDate":"2026-03-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147359244","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Haerin Jang, Norzawani Buang, Catherine Sutherland, Wanseon Lee, Lauren Overend, Tarran S Rupall, Katie L Burnham, Matthew C Pickering, Marina Botto, Emma E Davenport
Objective: Rituximab, a CD20+ B cell depletion therapy, is frequently used to treat systemic lupus erythematosus (SLE). However, variability in patient response highlights the need for a deeper understanding of the underlying immune cell dynamics of B cell depletion and repopulation.
Methods: We conducted longitudinal single-cell profiling of nine SLE patients treated with rituximab from pretreatment to up to 15 months post-treatment. These were compared to eight healthy controls. We profiled 169,513 immune cells via single-cell RNA, surface protein, B cell receptor (BCR), and T cell receptor (TCR) sequencing and bulk BCR repertoire sequencing.
Results: Significant depletion of naïve, memory, and age-associated B cells (ABCs) was observed early post-treatment, followed by later repopulation of mainly transitional B cells. A fraction of antigen-experienced B cells, particularly in non-responders, persisted through the depletion. BCR repertoire analysis revealed reduced diversity and persistent clones in antigen-experienced cells at early post-treatment, but these effects were not long-lasting. Notably, repopulated naïve B cells in rituximab responders exhibited reduced NF-κB pathway activation, aligning with lower BAFF-R surface protein levels. In non-B cells, we identified 27 DEGs across 7 immune cell subtypes post-rituximab, with regulatory CD4 T cells and double negative (DN) T cells showing the most changes. Responders specifically had increased expression of genes related to cytotoxicity, MHC class II antigen presentation, and T cell activation in CD4 T central memory (TCM) and DN T cells.
Conclusion: Our longitudinal profiling provides single-cell resolution of the shifts in immune cell dynamics following B cell depletion.
{"title":"Single-cell level characterization of B cell depletion and repopulation following rituximab in systemic lupus erythematosus.","authors":"Haerin Jang, Norzawani Buang, Catherine Sutherland, Wanseon Lee, Lauren Overend, Tarran S Rupall, Katie L Burnham, Matthew C Pickering, Marina Botto, Emma E Davenport","doi":"10.1002/art.70116","DOIUrl":"https://doi.org/10.1002/art.70116","url":null,"abstract":"<p><strong>Objective: </strong>Rituximab, a CD20<sup>+</sup> B cell depletion therapy, is frequently used to treat systemic lupus erythematosus (SLE). However, variability in patient response highlights the need for a deeper understanding of the underlying immune cell dynamics of B cell depletion and repopulation.</p><p><strong>Methods: </strong>We conducted longitudinal single-cell profiling of nine SLE patients treated with rituximab from pretreatment to up to 15 months post-treatment. These were compared to eight healthy controls. We profiled 169,513 immune cells via single-cell RNA, surface protein, B cell receptor (BCR), and T cell receptor (TCR) sequencing and bulk BCR repertoire sequencing.</p><p><strong>Results: </strong>Significant depletion of naïve, memory, and age-associated B cells (ABCs) was observed early post-treatment, followed by later repopulation of mainly transitional B cells. A fraction of antigen-experienced B cells, particularly in non-responders, persisted through the depletion. BCR repertoire analysis revealed reduced diversity and persistent clones in antigen-experienced cells at early post-treatment, but these effects were not long-lasting. Notably, repopulated naïve B cells in rituximab responders exhibited reduced NF-κB pathway activation, aligning with lower BAFF-R surface protein levels. In non-B cells, we identified 27 DEGs across 7 immune cell subtypes post-rituximab, with regulatory CD4 T cells and double negative (DN) T cells showing the most changes. Responders specifically had increased expression of genes related to cytotoxicity, MHC class II antigen presentation, and T cell activation in CD4 T central memory (TCM) and DN T cells.</p><p><strong>Conclusion: </strong>Our longitudinal profiling provides single-cell resolution of the shifts in immune cell dynamics following B cell depletion.</p>","PeriodicalId":129,"journal":{"name":"Arthritis & Rheumatology","volume":" ","pages":""},"PeriodicalIF":10.9,"publicationDate":"2026-03-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147363487","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
OBJECTIVEAggressive fibroblast-like synoviocytes (FLS) drive synovial hyperplasia, extracellular matrix (ECM) remodeling, and pannus formation in rheumatoid arthritis (RA). However, the pathogenic FLS subpopulations and their upstream regulators remain incompletely defined. This study aimed to (i) identify FLS subpopulation(s) responsible for synovial hyperplasia, ECM remodeling and pannus development; (ii) elucidate the molecular mechanisms regulating their pathogenic activation, and (iii) explore therapeutic strategies targeting FLS activation and pannus-associated neovascularization in RA.METHODSWe integrated bulk RNA-sequencing, proteomics, and single-cell transcriptomics to identify pathogenic FLS subpopulation(s) in RA synovium. Functional assays were conducted to assess the effects of AEBP1 and POSTN expression on FLS activation, ECM remodeling, and angiogenesis. Bioinformatic analyses and cell biological experiments were adopted to identify the upstream regulator responsible for AEBP1 expression in FLS. We subsequently investigated the pathological impact of TWIST1-AEBP1-POSTN axis in CIA mice model.RESULTSWe identified a pathogenic POSTN+ FLS subgroup selectively enriched within the sublining layer of synovium that exhibited robust ECM remodeling and fibrogenic features. Mechanistically, we showed that AEBP1 was selectively elevated in these cells, where it activated TGF-β signaling to drive fibroblast activation, migration and proliferation. Besides, AEBP1 also induced POSTN expression, which was responsible for neovascularization. Further, inflammatory signalings induced TWIST1 expression, which directly regulated AEBP1 transcription in FLS. Intra-articular modulation of AEBP1 in CIA mice had opposite effects on synovial hyperplasia, bone erosion, and pannus formation. Moreover, the pharmacological inhibition of TWIST1 by harmine reduced AEBP1 and POSTN expression, limited the expansion of pathogenic THY1+ FLS, and alleviated joint pathology.CONCLUSIONOur study suggests that POSTN+ FLS located in the synovial sublining contribute to RA progression through the TWIST1-AEBP1-POSTN axis. Accordingly, targeting of this axis may offer a novel and effective approach for RA treatment.
{"title":"TWIST1-Mediated Induction of AEBP1 in Fibroblast-like Synoviocytes Activates TGF-β Signaling to Drive Angiogenesis and Promote Rheumatoid Arthritis.","authors":"Zhenyu Li,Minglong Cai,Wei Huang,Xi Wen,Yujing Li,Jun Sun,Chen Zhu,Chao Yang,Zhu Chen","doi":"10.1002/art.70124","DOIUrl":"https://doi.org/10.1002/art.70124","url":null,"abstract":"OBJECTIVEAggressive fibroblast-like synoviocytes (FLS) drive synovial hyperplasia, extracellular matrix (ECM) remodeling, and pannus formation in rheumatoid arthritis (RA). However, the pathogenic FLS subpopulations and their upstream regulators remain incompletely defined. This study aimed to (i) identify FLS subpopulation(s) responsible for synovial hyperplasia, ECM remodeling and pannus development; (ii) elucidate the molecular mechanisms regulating their pathogenic activation, and (iii) explore therapeutic strategies targeting FLS activation and pannus-associated neovascularization in RA.METHODSWe integrated bulk RNA-sequencing, proteomics, and single-cell transcriptomics to identify pathogenic FLS subpopulation(s) in RA synovium. Functional assays were conducted to assess the effects of AEBP1 and POSTN expression on FLS activation, ECM remodeling, and angiogenesis. Bioinformatic analyses and cell biological experiments were adopted to identify the upstream regulator responsible for AEBP1 expression in FLS. We subsequently investigated the pathological impact of TWIST1-AEBP1-POSTN axis in CIA mice model.RESULTSWe identified a pathogenic POSTN+ FLS subgroup selectively enriched within the sublining layer of synovium that exhibited robust ECM remodeling and fibrogenic features. Mechanistically, we showed that AEBP1 was selectively elevated in these cells, where it activated TGF-β signaling to drive fibroblast activation, migration and proliferation. Besides, AEBP1 also induced POSTN expression, which was responsible for neovascularization. Further, inflammatory signalings induced TWIST1 expression, which directly regulated AEBP1 transcription in FLS. Intra-articular modulation of AEBP1 in CIA mice had opposite effects on synovial hyperplasia, bone erosion, and pannus formation. Moreover, the pharmacological inhibition of TWIST1 by harmine reduced AEBP1 and POSTN expression, limited the expansion of pathogenic THY1+ FLS, and alleviated joint pathology.CONCLUSIONOur study suggests that POSTN+ FLS located in the synovial sublining contribute to RA progression through the TWIST1-AEBP1-POSTN axis. Accordingly, targeting of this axis may offer a novel and effective approach for RA treatment.","PeriodicalId":129,"journal":{"name":"Arthritis & Rheumatology","volume":"5 1","pages":""},"PeriodicalIF":13.3,"publicationDate":"2026-03-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147359215","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-03-01Epub Date: 2026-02-24DOI: 10.1002/art.70044
Derin Karacabeyli, Diane Lacaille, Na Lu, Hui Xie, J Antonio Aviña-Zubieta
Objective: Glucagon-like peptide 1 receptor agonists (GLP-1RAs) and sodium-glucose cotransporter 2 inhibitors (SGLT2i) facilitate weight loss and exhibit immunomodulatory effects, but their impact on the risk of developing autoimmune rheumatic diseases (ARDs) is unclear. We compared ARD incidence following initiation of GLP-1RAs or SGLT2i versus a weight-neutral comparator (dipeptidyl peptidase 4 inhibitors [DPP4i]).
Methods: We performed a population-based cohort study using administrative health data from a Canadian province with universal health care. We included adults with type 2 diabetes (T2D) and no prior ARD initiating a GLP-1RA, SGLT2i, or DPP4i between January 1, 2014, and December 31, 2022. Incident ARD cases, including rheumatoid arthritis, psoriatic disease, axial spondyloarthritis, and systemic ARDs (SARDs; systemic lupus erythematosus, systemic sclerosis, Sjögren disease, idiopathic inflammatory myopathies, and systemic vasculitides), were identified using validated algorithms. Propensity score (PS) weighting was used to balance cohorts at treatment initiation. Then hazard ratios (HRs) were estimated using Cox regression.
Results: Among 229,300 adults, 49,514 initiated GLP-1RAs, 101,925 initiated SGLT2i, and 77,861 initiated DPP4i. After PS weighting, ARD incidence per 10,000 person-years was 29.1 (95% confidence interval [CI] 23.5-35.5) with GLP-1RAs, 24.4 (95% CI 19.8-29.7) with SGLT2i, and 27.3 (95% CI 22.1-33.4) with DPP4i. Mean follow-up was 1.3 to 1.6 years. Relative to DPP4i, adjusted HRs (aHRs) of ARD were 1.04 (95% CI 0.81-1.33) with GLP-1RAs and 0.93 (95% CI 0.75-1.16) with SGLT2i. Risk of SARDs, but not other diseases, was lower with SGLT2i versus DPP4i (aHR 0.51 [95% CI 0.31-0.84]).
Conclusion: Neither GLP-1RA nor SGLT2i treatment was associated with increased or decreased ARD risk versus DPP4i in adults with T2D; however, SGLT2i use was associated with significantly lower risk of SARDs, warranting further study.
{"title":"Glucagon-Like Peptide 1 Receptor Agonists, Sodium-Glucose Cotransporter 2 Inhibitors, and Risk of Autoimmune Rheumatic Diseases.","authors":"Derin Karacabeyli, Diane Lacaille, Na Lu, Hui Xie, J Antonio Aviña-Zubieta","doi":"10.1002/art.70044","DOIUrl":"10.1002/art.70044","url":null,"abstract":"<p><strong>Objective: </strong>Glucagon-like peptide 1 receptor agonists (GLP-1RAs) and sodium-glucose cotransporter 2 inhibitors (SGLT2i) facilitate weight loss and exhibit immunomodulatory effects, but their impact on the risk of developing autoimmune rheumatic diseases (ARDs) is unclear. We compared ARD incidence following initiation of GLP-1RAs or SGLT2i versus a weight-neutral comparator (dipeptidyl peptidase 4 inhibitors [DPP4i]).</p><p><strong>Methods: </strong>We performed a population-based cohort study using administrative health data from a Canadian province with universal health care. We included adults with type 2 diabetes (T2D) and no prior ARD initiating a GLP-1RA, SGLT2i, or DPP4i between January 1, 2014, and December 31, 2022. Incident ARD cases, including rheumatoid arthritis, psoriatic disease, axial spondyloarthritis, and systemic ARDs (SARDs; systemic lupus erythematosus, systemic sclerosis, Sjögren disease, idiopathic inflammatory myopathies, and systemic vasculitides), were identified using validated algorithms. Propensity score (PS) weighting was used to balance cohorts at treatment initiation. Then hazard ratios (HRs) were estimated using Cox regression.</p><p><strong>Results: </strong>Among 229,300 adults, 49,514 initiated GLP-1RAs, 101,925 initiated SGLT2i, and 77,861 initiated DPP4i. After PS weighting, ARD incidence per 10,000 person-years was 29.1 (95% confidence interval [CI] 23.5-35.5) with GLP-1RAs, 24.4 (95% CI 19.8-29.7) with SGLT2i, and 27.3 (95% CI 22.1-33.4) with DPP4i. Mean follow-up was 1.3 to 1.6 years. Relative to DPP4i, adjusted HRs (aHRs) of ARD were 1.04 (95% CI 0.81-1.33) with GLP-1RAs and 0.93 (95% CI 0.75-1.16) with SGLT2i. Risk of SARDs, but not other diseases, was lower with SGLT2i versus DPP4i (aHR 0.51 [95% CI 0.31-0.84]).</p><p><strong>Conclusion: </strong>Neither GLP-1RA nor SGLT2i treatment was associated with increased or decreased ARD risk versus DPP4i in adults with T2D; however, SGLT2i use was associated with significantly lower risk of SARDs, warranting further study.</p>","PeriodicalId":129,"journal":{"name":"Arthritis & Rheumatology","volume":" ","pages":"654-664"},"PeriodicalIF":10.9,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12991922/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145852797","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-03-01Epub Date: 2025-11-14DOI: 10.1002/art.43373
Ivana Capuano, Eleonora Riccio, Antonio Pisani, Pasquale Buonanno
{"title":"Trimethoprim-sulfamethoxazole prophylaxis in antineutrophil cytoplasmic antibody-associated vasculitis: watch out for pseudoacute kidney injury. Comment on the article by Kim et al.","authors":"Ivana Capuano, Eleonora Riccio, Antonio Pisani, Pasquale Buonanno","doi":"10.1002/art.43373","DOIUrl":"10.1002/art.43373","url":null,"abstract":"","PeriodicalId":129,"journal":{"name":"Arthritis & Rheumatology","volume":" ","pages":"769-770"},"PeriodicalIF":10.9,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145032342","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-03-01Epub Date: 2025-11-24DOI: 10.1002/art.43385
Ronald van Vollenhoven
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