Pub Date : 2026-02-01Epub Date: 2025-12-31DOI: 10.1016/j.jaut.2025.103520
Dario Roccatello , Alice Barinotti , Massimo Radin , Irene Cecchi , Elena Rubini , Daniele Mancardi , Martina Cozzi , Roberta Fenoglio , Savino Sciascia
Refractory lupus nephritis (LN) poses a significant clinical challenge in the management of systemic lupus erythematosus (SLE) due to its resistance to conventional immunosuppressive therapies. This study evaluates the immunological, anti-inflammatory and anti-fibrotic effects of daratumumab, a CD38-targeting monoclonal antibody, in patients with refractory LN who failed standard treatments. Previous findings demonstrated daratumumab safety and efficacy, improving renal function and reducing proteinuria, anti-dsDNA antibodies, and SLEDAI-2K. In the present study, daratumumab treatment resulted in immunophenotypic remodelling, including increased CD3+ and CD8+ T-cell counts and decreased B-cell populations alongside significant reductions in fibrotic and inflammatory markers (APRIL, TNF-R1, TNF-R2, TWEAK, MMP-1, MMP-2, MMP-3). Additionally, a case study of a patient with antiphospholipid antibodies (aPL) and a history of recurrent thromboses and renal flares, demonstrated an improvement in thrombin generation and endothelial function. These results suggest daratumumab to be a promising and targeted therapeutic option for managing refractory LN by modulating immune and fibrotic responses.
{"title":"Daratumumab monotherapy reverses the immune and pro-fibrotic profiles in refractory lupus nephritis patients: a pilot case study","authors":"Dario Roccatello , Alice Barinotti , Massimo Radin , Irene Cecchi , Elena Rubini , Daniele Mancardi , Martina Cozzi , Roberta Fenoglio , Savino Sciascia","doi":"10.1016/j.jaut.2025.103520","DOIUrl":"10.1016/j.jaut.2025.103520","url":null,"abstract":"<div><div>Refractory lupus nephritis (LN) poses a significant clinical challenge in the management of systemic lupus erythematosus (SLE) due to its resistance to conventional immunosuppressive therapies. This study evaluates the immunological, anti-inflammatory and anti-fibrotic effects of daratumumab, a CD38-targeting monoclonal antibody, in patients with refractory LN who failed standard treatments. Previous findings demonstrated daratumumab safety and efficacy, improving renal function and reducing proteinuria, anti-dsDNA antibodies, and SLEDAI-2K. In the present study, daratumumab treatment resulted in immunophenotypic remodelling, including increased CD3<sup>+</sup> and CD8<sup>+</sup> T-cell counts and decreased B-cell populations alongside significant reductions in fibrotic and inflammatory markers (APRIL, TNF-R1, TNF-R2, TWEAK, MMP-1, MMP-2, MMP-3). Additionally, a case study of a patient with antiphospholipid antibodies (aPL) and a history of recurrent thromboses and renal flares, demonstrated an improvement in thrombin generation and endothelial function. These results suggest daratumumab to be a promising and targeted therapeutic option for managing refractory LN by modulating immune and fibrotic responses.</div></div>","PeriodicalId":15245,"journal":{"name":"Journal of autoimmunity","volume":"158 ","pages":"Article 103520"},"PeriodicalIF":7.0,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145880513","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 : 2026-02-01Epub Date: 2025-11-24DOI: 10.1016/j.jaut.2025.103504
Divyasha Saxena , Kelly Walter , Elizabeth Amona , Maiying Kong , Stanley Perlman , Jian Zheng
Background
Central nervous system (CNS) infections contribute to the development of neuroinflammation and neurodegenerative diseases. However, the mechanisms underlying the correlation between CNS infection and subsequent inflammatory course remain largely unknown.
Methods
Here, we addressed this question by infecting mice with a sublethal dose of a well-studied neurotropic coronavirus, mouse hepatitis virus (MHV), and investigated the effects of infection on the subsequent induction of a mouse multiple sclerosis (MS) model (myelin oligodendrocyte glycoprotein 35-55 (MOG35-55) peptide-induced experimental autoimmune encephalitis (EAE)).
Results
Unexpectedly, C57BL/6J mice that recovered from MHV infection showed alleviated clinical signs of induced EAE. Mechanistically, this protection is mediated by a novel CNS-resident Foxp3+ CD8 T cell population induced by interleukin (IL)-10, which was secreted by myeloid cells that infiltrated the MHV-infected CNS as part of the MHV-specific immune response. These Foxp3+ CD8 T cells ameliorated EAE severity by decreasing the quantity and function of autoreactive CD4 and CD8 T cell infiltrating CNS independent of antigen specificity, as well as by inhibiting the activation of microglia accumulating in the affected spinal cords (SCs). The persistence of these Foxp3+ CD8 T cells in the CNS may contribute to the long-term post-acute sequelae of infection.
Conclusion
This study reveals a novel post-infectious anti-inflammatory milieu that develops in MHV-infected CNS of MHV and leads to the generation of Foxp3+ CD8 regulatory T cells, thereby diminishing the progression of subsequent autoimmune disease.
{"title":"Prior murine neurotropic coronavirus infection ameliorates experimental autoimmune encephalitis","authors":"Divyasha Saxena , Kelly Walter , Elizabeth Amona , Maiying Kong , Stanley Perlman , Jian Zheng","doi":"10.1016/j.jaut.2025.103504","DOIUrl":"10.1016/j.jaut.2025.103504","url":null,"abstract":"<div><h3>Background</h3><div>Central nervous system (CNS) infections contribute to the development of neuroinflammation and neurodegenerative diseases. However, the mechanisms underlying the correlation between CNS infection and subsequent inflammatory course remain largely unknown.</div></div><div><h3>Methods</h3><div>Here, we addressed this question by infecting mice with a sublethal dose of a well-studied neurotropic coronavirus, mouse hepatitis virus (MHV), and investigated the effects of infection on the subsequent induction of a mouse multiple sclerosis (MS) model (myelin oligodendrocyte glycoprotein 35-55 (MOG<sub>35-55</sub>) peptide-induced experimental autoimmune encephalitis (EAE)).</div></div><div><h3>Results</h3><div>Unexpectedly, C57BL/6J mice that recovered from MHV infection showed alleviated clinical signs of induced EAE. Mechanistically, this protection is mediated by a novel CNS-resident Foxp3<sup>+</sup> CD8 T cell population induced by interleukin (IL)-10, which was secreted by myeloid cells that infiltrated the MHV-infected CNS as part of the MHV-specific immune response. These Foxp3<sup>+</sup> CD8 T cells ameliorated EAE severity by decreasing the quantity and function of autoreactive CD4 and CD8 T cell infiltrating CNS independent of antigen specificity, as well as by inhibiting the activation of microglia accumulating in the affected spinal cords (SCs). The persistence of these Foxp3<sup>+</sup> CD8 T cells in the CNS may contribute to the long-term post-acute sequelae of infection.</div></div><div><h3>Conclusion</h3><div>This study reveals a novel post-infectious anti-inflammatory milieu that develops in MHV-infected CNS of MHV and leads to the generation of Foxp3<sup>+</sup> CD8 regulatory T cells, thereby diminishing the progression of subsequent autoimmune disease.</div></div>","PeriodicalId":15245,"journal":{"name":"Journal of autoimmunity","volume":"158 ","pages":"Article 103504"},"PeriodicalIF":7.0,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145584424","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}
Sjögren's disease (SjD), formerly termed Sjögren's syndrome, is a chronic autoimmune exocrinopathy that has seen substantial advances in basic research over the past decade. Classical experimental approaches have revealed immune dysregulation encompassing aberrant activation of the adaptive immune system, activation of humoral autoimmunity against autoantigens, and upstream participation of innate immune mechanisms. In parallel, with the rapid development of sequencing and omics technologies, researchers are able to use these high-throughput methods to gain a more unbiased, sytem-wide view of disease processes and pathegenesis in SjD. Among them, numerous disease-associated traits have been revealed by genomics and epigenomics, while transcriptomics, proteomics, and immunogenomics have also depicted a more detailed landscape of phenotypes and cell states of immune cells, as well as the roles of key molecules such as Toll-like receptors (TLRs) in promoting autoimmune responses, yielding profound insights for the understanding of SjD. Meanwhile, these diverse data analysis methods offer the researchers impotant tools to further invertigate and understand SjD in the future. The convergence of these modalities supports data-driven disease prediction, refined patient stratification, and identification of therapeutic targets, thereby expanding translational opportunities. Collectively, integrating innovative omics with classical methodologies provides a coherent framework for capturing the pathogenesis of SjD, linking system-wide views to experimental validation, and accelerating the path from pathobiology to precision therapeutics. This review summarizes recent advances in the understanding of the pathogenesis of SjD, lymphomagenesis in SjD, patient stratification and promising targeted therapy, and also outlines future perspectives and challenges to be addressed.
{"title":"Deciphering Sjögren's disease: New insights and perspectives extend from advanced omics approaches and immunology","authors":"Hu Chen , Naoki Kaneko , Yukiko Ohyama , Masafumi Moriyama","doi":"10.1016/j.jaut.2025.103521","DOIUrl":"10.1016/j.jaut.2025.103521","url":null,"abstract":"<div><div>Sjögren's disease (SjD), formerly termed Sjögren's syndrome, is a chronic autoimmune exocrinopathy that has seen substantial advances in basic research over the past decade. Classical experimental approaches have revealed immune dysregulation encompassing aberrant activation of the adaptive immune system, activation of humoral autoimmunity against autoantigens, and upstream participation of innate immune mechanisms. In parallel, with the rapid development of sequencing and omics technologies, researchers are able to use these high-throughput methods to gain a more unbiased, sytem-wide view of disease processes and pathegenesis in SjD. Among them, numerous disease-associated traits have been revealed by genomics and epigenomics, while transcriptomics, proteomics, and immunogenomics have also depicted a more detailed landscape of phenotypes and cell states of immune cells, as well as the roles of key molecules such as Toll-like receptors (TLRs) in promoting autoimmune responses, yielding profound insights for the understanding of SjD. Meanwhile, these diverse data analysis methods offer the researchers impotant tools to further invertigate and understand SjD in the future. The convergence of these modalities supports data-driven disease prediction, refined patient stratification, and identification of therapeutic targets, thereby expanding translational opportunities. Collectively, integrating innovative omics with classical methodologies provides a coherent framework for capturing the pathogenesis of SjD, linking system-wide views to experimental validation, and accelerating the path from pathobiology to precision therapeutics. This review summarizes recent advances in the understanding of the pathogenesis of SjD, lymphomagenesis in SjD, patient stratification and promising targeted therapy, and also outlines future perspectives and challenges to be addressed.</div></div>","PeriodicalId":15245,"journal":{"name":"Journal of autoimmunity","volume":"158 ","pages":"Article 103521"},"PeriodicalIF":7.0,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145917686","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 : 2025-12-01Epub Date: 2025-11-19DOI: 10.1016/j.jaut.2025.103500
Alen Zabotti , Lucia Novelli , Michele Maria Luchetti Gentiloni , Giuliana Guggino , Ana Biljan , Ennio Lubrano , Dennis McGonagle
Interleukin-23 (IL-23) plays a pivotal role in the intricate interplay between the skin, gut, and joints, contributing significantly to the pathogenesis of various inflammatory diseases including psoriasis, psoriatic arthritis (PsA), inflammatory bowel disease (IBD) and Behcet's disease. In recent years, several IL-23 inhibitors have been granted approval for the treatment of psoriasis, PsA and IBD. As up to one-third of patients diagnosed with psoriasis may go on to develop PsA and given the strong immunogenetic pathway incrimination of the IL-23 pathway in both psoriasis and PsA, dermatological lead therapy for psoriasis may therefore delay the development of PsA. Furthermore, patients with psoriasis or PsA are associated with increased risk of developing IBD. There is also evidence for psoriasis-directed therapy preventing IBD in keeping with the known pivotal role of IL-23 in both intestinal homeostasis and in the pathogenesis of IBD, including ulcerative colitis and Crohn's disease. This review discusses the multifaceted roles of IL-23 in regulating immune response and maintaining tissue homeostasis within the skin-gut-joint axis. In particular, the use of IL-23 inhibitors in trials in patients with psoriasis, IBD and PsA patients will also be discussed in relation to reverse translational immunology insights around inflammation in these domains.
{"title":"The pivotal role of Interleukin-23 in the skin-gut-joint axis","authors":"Alen Zabotti , Lucia Novelli , Michele Maria Luchetti Gentiloni , Giuliana Guggino , Ana Biljan , Ennio Lubrano , Dennis McGonagle","doi":"10.1016/j.jaut.2025.103500","DOIUrl":"10.1016/j.jaut.2025.103500","url":null,"abstract":"<div><div>Interleukin-23 (IL-23) plays a pivotal role in the intricate interplay between the skin, gut, and joints, contributing significantly to the pathogenesis of various inflammatory diseases including psoriasis, psoriatic arthritis (PsA), inflammatory bowel disease (IBD) and Behcet's disease. In recent years, several IL-23 inhibitors have been granted approval for the treatment of psoriasis, PsA and IBD. As up to one-third of patients diagnosed with psoriasis may go on to develop PsA and given the strong immunogenetic pathway incrimination of the IL-23 pathway in both psoriasis and PsA, dermatological lead therapy for psoriasis may therefore delay the development of PsA. Furthermore, patients with psoriasis or PsA are associated with increased risk of developing IBD. There is also evidence for psoriasis-directed therapy preventing IBD in keeping with the known pivotal role of IL-23 in both intestinal homeostasis and in the pathogenesis of IBD, including ulcerative colitis and Crohn's disease. This review discusses the multifaceted roles of IL-23 in regulating immune response and maintaining tissue homeostasis within the skin-gut-joint axis. In particular, the use of IL-23 inhibitors in trials in patients with psoriasis, IBD and PsA patients will also be discussed in relation to reverse translational immunology insights around inflammation in these domains.</div></div>","PeriodicalId":15245,"journal":{"name":"Journal of autoimmunity","volume":"157 ","pages":"Article 103500"},"PeriodicalIF":7.0,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145563125","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}
Despite treatment advances, some rheumatoid arthritis (RA) patients fail to achieve remission with biological/targeted synthetic DMARDs. We prospectively evaluated 200 patients to determine if interferon profiles and autoantibodies predict treatment outcomes. A significant positive correlation between rheumatoid factor and IFN-γ levels was observed. Patients with high IFN-γ/low IFN-α2 profiles achieved significantly higher remission rates and demonstrated elevated B cell-stimulating cytokines with distinct immunological clustering patterns. This group showed superior responses to IL-6 inhibitors. Anti-carbamylated protein IgM antibodies differed significantly between groups. Interferon profiling offers a practical screening approach for personalized therapy selection in RA.
{"title":"Treatment outcomes stratified by interferon profile and autoantibodies in rheumatoid arthritis","authors":"Shoichi Fukui , Tohru Michitsuji , Yushiro Endo , Ayako Nishino , Kaori Furukawa , Toshimasa Shimizu , Masataka Umeda , Remi Sumiyoshi , Tomohiro Koga , Naoki Iwamoto , Mami Tamai , Tomoki Origuchi , K.A. van Schie , Yukitaka Ueki , Nobutaka Eiraku , Tamami Yoshitama , Naoki Matsuoka , Takahisa Suzuki , Akitomo Okada , Hiroaki Hamada , Shin-ya Kawashiri","doi":"10.1016/j.jaut.2025.103490","DOIUrl":"10.1016/j.jaut.2025.103490","url":null,"abstract":"<div><div>Despite treatment advances, some rheumatoid arthritis (RA) patients fail to achieve remission with biological/targeted synthetic DMARDs. We prospectively evaluated 200 patients to determine if interferon profiles and autoantibodies predict treatment outcomes. A significant positive correlation between rheumatoid factor and IFN-γ levels was observed. Patients with high IFN-γ/low IFN-α2 profiles achieved significantly higher remission rates and demonstrated elevated B cell-stimulating cytokines with distinct immunological clustering patterns. This group showed superior responses to IL-6 inhibitors. Anti-carbamylated protein IgM antibodies differed significantly between groups. Interferon profiling offers a practical screening approach for personalized therapy selection in RA.</div></div>","PeriodicalId":15245,"journal":{"name":"Journal of autoimmunity","volume":"157 ","pages":"Article 103490"},"PeriodicalIF":7.0,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145199594","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 : 2025-12-01Epub Date: 2025-11-07DOI: 10.1016/j.jaut.2025.103498
Manuel Rojas , Luke S. Heuer , Weici Zhang , Nicolle Sweeney , Carolina Ramírez-Santana , Patrick S.C. Leung , Alvin Lam , Shraddha Kamat , Andrew R. Mendelsohn , Manley Huang , Bo Yu , Paulina Ackerman , Qisheng Wei , James W. Larrick , Yi-Guang Chen , William M. Ridgway
Human membrane-bound CD137 (mCD137) is a well-known costimulatory molecule; however, it is alternatively spliced into two transcripts (sCD137-1, 2) whose function is not yet known. Here, we show that sCD137 isoforms lack the CRD4 region and form unique structures compared to mCD137. Human activated Tregs produce both CD137 splice isoforms, which are rapidly upregulated after cell activation, and identify an activated Treg phenotype along with FOXP3, CTLA4, and sCTLA4. We engineered recombinant Fc-Hu-sCD137 variants, which are immunosuppressive, inhibiting IFN-γ secretion and proliferation in purified CD4+ and CD8+ T cells in an APC-independent manner. These effects are mediated by the downregulation of S6 and 4EBP1 of the mTOR complex 1 pathway. Human sCD137 variants, in contrast to the membrane-bound form, are immunosuppressive and may be a novel treatment for inflammation and autoimmunity.
{"title":"Alternate splicing converts human CD137 from costimulatory to immunosuppressive function","authors":"Manuel Rojas , Luke S. Heuer , Weici Zhang , Nicolle Sweeney , Carolina Ramírez-Santana , Patrick S.C. Leung , Alvin Lam , Shraddha Kamat , Andrew R. Mendelsohn , Manley Huang , Bo Yu , Paulina Ackerman , Qisheng Wei , James W. Larrick , Yi-Guang Chen , William M. Ridgway","doi":"10.1016/j.jaut.2025.103498","DOIUrl":"10.1016/j.jaut.2025.103498","url":null,"abstract":"<div><div>Human membrane-bound CD137 (mCD137) is a well-known costimulatory molecule; however, it is alternatively spliced into two transcripts (sCD137-1, 2) whose function is not yet known. Here, we show that sCD137 isoforms lack the CRD4 region and form unique structures compared to mCD137. Human activated Tregs produce both <em>CD137</em> splice isoforms, which are rapidly upregulated after cell activation, and identify an activated Treg phenotype along with <em>FOXP3</em>, <em>CTLA4</em>, and <em>sCTLA4</em>. We engineered recombinant Fc-Hu-sCD137 variants, which are immunosuppressive, inhibiting IFN-γ secretion and proliferation in purified CD4<sup>+</sup> and CD8<sup>+</sup> T cells in an APC-independent manner. These effects are mediated by the downregulation of S6 and 4EBP1 of the mTOR complex 1 pathway. Human sCD137 variants, in contrast to the membrane-bound form, are immunosuppressive and may be a novel treatment for inflammation and autoimmunity.</div></div>","PeriodicalId":15245,"journal":{"name":"Journal of autoimmunity","volume":"157 ","pages":"Article 103498"},"PeriodicalIF":7.0,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145463046","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 : 2025-12-01Epub Date: 2025-09-09DOI: 10.1016/j.jaut.2025.103476
Frauke Stascheit , Daniel Schulze , Sophie Lehnerer , Lea Gerischer , Maike Stein , Paolo Doksani , Meret Herdick , Carla Dusemund , Philipp Mergenthaler , Paul Triller , Jan D. Lünemann , Sarah Hoffmann , Andreas Meisel
Objective
New therapeutic options have recently emerged for patients with highly active, acetylcholine receptor antibody–positive (AChR-Ab+) generalized myasthenia gravis (gMG), including fast-acting, endplate-protective agents such as complement C5 inhibitors (C5-I) and neonatal Fc receptor inhibitors (FcRn-I). However, objective biomarkers beyond clinical scoring systems are lacking to guide individualized treatment decisions.
Methods
In this exploratory, prospective real-world study, we assessed serum calprotectin (sCLP) and serum neurofilament light chain (sNfL) levels in a total of 22 AChR-Ab+ gMG patients, who were treatment-naïve for either C5-I or FcRn-I. Changes in biomarker levels were correlated with clinical response, as measured by the Myasthenia Gravis–Activities of Daily Living (MG-ADL) score.
Results
We observed a correlation of changes in sCLP and sNfl with clinical treatment response to C5-I and FcRn-I therapies. Specifically, rising levels of sNfL and sCLP were associated with a poor treatment response, as measured by the MG-ADL score.
Conclusion
Our preliminary findings suggest that markers of systemic inflammation (such as sCLP) and local destruction of the neuromuscular junction (such as sNfL) may assist in treatment decision-making for gMG patients. Larger, multicenter studies are warranted to validate these results and define their clinical utility.
{"title":"Calprotectin and neurofilament serum levels correlate with treatment response in myasthenia gravis under intensified therapy–A pilot study","authors":"Frauke Stascheit , Daniel Schulze , Sophie Lehnerer , Lea Gerischer , Maike Stein , Paolo Doksani , Meret Herdick , Carla Dusemund , Philipp Mergenthaler , Paul Triller , Jan D. Lünemann , Sarah Hoffmann , Andreas Meisel","doi":"10.1016/j.jaut.2025.103476","DOIUrl":"10.1016/j.jaut.2025.103476","url":null,"abstract":"<div><h3>Objective</h3><div>New therapeutic options have recently emerged for patients with highly active, acetylcholine receptor antibody–positive (AChR-Ab<sup>+</sup>) generalized myasthenia gravis (gMG), including fast-acting, endplate-protective agents such as complement C5 inhibitors (C5-I) and neonatal Fc receptor inhibitors (FcRn-I). However, objective biomarkers beyond clinical scoring systems are lacking to guide individualized treatment decisions.</div></div><div><h3>Methods</h3><div>In this exploratory, prospective <em>real-world</em> study, we assessed serum calprotectin (sCLP) and serum neurofilament light chain (sNfL) levels in a total of 22 AChR-Ab<sup>+</sup> gMG patients, who were treatment-naïve for either C5-I or FcRn-I. Changes in biomarker levels were correlated with clinical response, as measured by the Myasthenia Gravis–Activities of Daily Living (MG-ADL) score.</div></div><div><h3>Results</h3><div>We observed a correlation of changes in sCLP and sNfl with clinical treatment response to C5-I and FcRn-I therapies. Specifically, rising levels of sNfL and sCLP were associated with a poor treatment response, as measured by the MG-ADL score.</div></div><div><h3>Conclusion</h3><div>Our preliminary findings suggest that markers of systemic inflammation (such as sCLP) and local destruction of the neuromuscular junction (such as sNfL) may assist in treatment decision-making for gMG patients. Larger, multicenter studies are warranted to validate these results and define their clinical utility.</div></div>","PeriodicalId":15245,"journal":{"name":"Journal of autoimmunity","volume":"157 ","pages":"Article 103476"},"PeriodicalIF":7.0,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145020299","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 : 2025-12-01Epub Date: 2025-10-15DOI: 10.1016/j.jaut.2025.103492
François Barde , Kevin Chevalier , Paul Decker , Matéo Merin , Amélie Nicolas , Alain Lescoat , Alban Deroux , Vincent Koether , Emmanuel Chatelus , Cyrille Coustal , Alexandre Maria , Martin Michaud , Grégory Pugnet , Anne Murarasu , Sébastien Riviere , Pierre Charles , Claire de Moreuil , Juliette Lodovichetti , François Maillet , Arthur Renaud , Benjamin Chaigne
Objectives
Mycophenolate mofetil (MMF) and rituximab (RTX) are recommended as first-line therapies for skin and interstitial lung disease (ILD) involvement in systemic sclerosis (SSc). However, data on their combined use remain limited. This study evaluated the efficacy and safety of MMF/RTX combination therapy compared to each drug alone.
Methods
We conducted a retrospective multicenter French study including SSc patients treated with MMF, RTX, or MMF/RTX combination for ≥12-months. Primary outcomes were changes in modified Rodnan skin score (mRSS) and predicted forced vital capacity (FVC) at 12 months. Secondary outcomes included factors associated with improvement in skin or ILD and adverse events.
Results
Forty-seven patients received MMF/RTX combination, 30 received RTX, and 50 received MMF. At 12 months, intra-group analyses showed significant mRSS improvement with MMF/RTX combination and MMF (p = 0.002 and p = 0.04, respectively). FVC increased significantly only with combination group (p = 0.003). In multivariate inter-group analysis, MMF/RTX combination was independently associated with greater mRSS improvement versus RTX (OR 0.07, 95 % CI [0.007–0.67], p = 0.02) and greater skin and/or lung improvement compared to RTX (OR 0.27 [0.08–0.89], p = 0.03) or MMF (OR 0.24 [0.07–0.81], p = 0.02). Adverse events were not significantly increased with MMF/RTX combination. In subgroup analyses restricted to MMF/RTX combination group, patients with upfront initiation significantly improved their FVC compared to patients with sequential introduction. Upfront initiation of MMF/RTX was associated with ILD improvement in multivariate analysis.
Conclusion
In SSc, MMF/RTX combination is well-tolerated and improves skin and ILD involvement, particularly when MMF and RTX are introduced simultaneously.
目的：霉酚酸酯（MMF）和利妥昔单抗（RTX）被推荐作为皮肤和间质性肺疾病（ILD）累及系统性硬化症（SSc）的一线治疗药物。然而，关于它们联合使用的数据仍然有限。本研究评估了MMF/RTX联合治疗与单独用药相比的有效性和安全性。方法：我们在法国进行了一项回顾性多中心研究，纳入了MMF、RTX或MMF/RTX联合治疗≥12个月的SSc患者。主要结局是12个月时改良罗德曼皮肤评分（mRSS）和预测用力肺活量（FVC）的变化。次要结局包括与皮肤或ILD改善和不良事件相关的因素。结果：MMF/RTX联合治疗47例，RTX治疗30例，MMF治疗50例。在12个月时，组内分析显示MMF/RTX联合治疗和MMF显著改善mRSS （p = 0.002和p = 0.04分别）。FVC只有联合组显著升高（p = 0.003）。在多变量组间分析中，与RTX相比，MMF/RTX联合治疗与更大的mRSS改善（OR 0.07, 95% CI [0.007-0.67], p = 0.02）以及与RTX （OR 0.27 [0.08-0.89], p = 0.03）或MMF （OR 0.24 [0.07-0.81], p = 0.02）相比，更大的皮肤和/或肺改善独立相关。MMF/RTX联合治疗的不良事件没有显著增加。在仅限于MMF/RTX联合组的亚组分析中，与顺序引入患者相比，预先引入患者的FVC显著改善。在多变量分析中，MMF/RTX的前期治疗与ILD的改善相关。结论：在SSc中，MMF/RTX联合使用耐受性良好，可改善皮肤和ILD受损伤，特别是当MMF和RTX同时使用时。
{"title":"Evaluation of the mycophenolate mofetil–rituximab combination in systemic sclerosis: a French retrospective multicenter study (MycRiSSc)","authors":"François Barde , Kevin Chevalier , Paul Decker , Matéo Merin , Amélie Nicolas , Alain Lescoat , Alban Deroux , Vincent Koether , Emmanuel Chatelus , Cyrille Coustal , Alexandre Maria , Martin Michaud , Grégory Pugnet , Anne Murarasu , Sébastien Riviere , Pierre Charles , Claire de Moreuil , Juliette Lodovichetti , François Maillet , Arthur Renaud , Benjamin Chaigne","doi":"10.1016/j.jaut.2025.103492","DOIUrl":"10.1016/j.jaut.2025.103492","url":null,"abstract":"<div><h3>Objectives</h3><div>Mycophenolate mofetil (MMF) and rituximab (RTX) are recommended as first-line therapies for skin and interstitial lung disease (ILD) involvement in systemic sclerosis (SSc). However, data on their combined use remain limited. This study evaluated the efficacy and safety of MMF/RTX combination therapy compared to each drug alone.</div></div><div><h3>Methods</h3><div>We conducted a retrospective multicenter French study including SSc patients treated with MMF, RTX, or MMF/RTX combination for ≥12-months. Primary outcomes were changes in modified Rodnan skin score (mRSS) and predicted forced vital capacity (FVC) at 12 months. Secondary outcomes included factors associated with improvement in skin or ILD and adverse events.</div></div><div><h3>Results</h3><div>Forty-seven patients received MMF/RTX combination, 30 received RTX, and 50 received MMF. At 12 months, intra-group analyses showed significant mRSS improvement with MMF/RTX combination and MMF (p = 0.002 and p = 0.04, respectively). FVC increased significantly only with combination group (p = 0.003). In multivariate inter-group analysis, MMF/RTX combination was independently associated with greater mRSS improvement versus RTX (OR 0.07, 95 % CI [0.007–0.67], p = 0.02) and greater skin and/or lung improvement compared to RTX (OR 0.27 [0.08–0.89], p = 0.03) or MMF (OR 0.24 [0.07–0.81], p = 0.02). Adverse events were not significantly increased with MMF/RTX combination. In subgroup analyses restricted to MMF/RTX combination group, patients with upfront initiation significantly improved their FVC compared to patients with sequential introduction. Upfront initiation of MMF/RTX was associated with ILD improvement in multivariate analysis.</div></div><div><h3>Conclusion</h3><div>In SSc, MMF/RTX combination is well-tolerated and improves skin and ILD involvement, particularly when MMF and RTX are introduced simultaneously.</div></div>","PeriodicalId":15245,"journal":{"name":"Journal of autoimmunity","volume":"157 ","pages":"Article 103492"},"PeriodicalIF":7.0,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145308154","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 : 2025-12-01Epub Date: 2025-09-17DOI: 10.1016/j.jaut.2025.103484
Xiao Guan , Zhiyi Huang , Jingrong Chen , Xiaoli Fan , Song Guo Zheng
Rheumatoid arthritis (RA) is a chronic systemic autoimmune disease with an unclear etiology, in which abnormal copper homeostasis has been shown in the blood and synovial fluid of the joints of patients. As an essential trace element in the human body, copper plays a critical role in various biological processes, including antioxidant defense, angiogenesis, and bone maintenance. However, the accumulation of excessive copper ions has been shown to be positively correlated with disease activity and the degree of inflammation in RA. While copper-bound ceruloplasmin may exert anti-inflammatory effects, excess "free" copper acts as a potent pro-oxidant, driving oxidative stress, cartilage and bone destruction, inflammatory responses, as well as pannus formation. The recently discovered copper-dependent cell death pathway, named cuproptosis, further adds to the complexity of its role in RA. This review integrates current research advances on the double-edged role of copper in the pathogenesis of RA, systematically examines copper-related therapeutic strategies, and finally analyzes their potential applications and challenges. The aim is to harness the physiological functions of copper while mitigating its pathological effects, thereby opening new avenues for the diagnosis and precision treatment of RA.
{"title":"The double-edged sword role of copper in rheumatoid arthritis: Mechanisms, therapeutics, and challenges","authors":"Xiao Guan , Zhiyi Huang , Jingrong Chen , Xiaoli Fan , Song Guo Zheng","doi":"10.1016/j.jaut.2025.103484","DOIUrl":"10.1016/j.jaut.2025.103484","url":null,"abstract":"<div><div>Rheumatoid arthritis (RA) is a chronic systemic autoimmune disease with an unclear etiology, in which abnormal copper homeostasis has been shown in the blood and synovial fluid of the joints of patients. As an essential trace element in the human body, copper plays a critical role in various biological processes, including antioxidant defense, angiogenesis, and bone maintenance. However, the accumulation of excessive copper ions has been shown to be positively correlated with disease activity and the degree of inflammation in RA. While copper-bound ceruloplasmin may exert anti-inflammatory effects, excess \"free\" copper acts as a potent pro-oxidant, driving oxidative stress, cartilage and bone destruction, inflammatory responses, as well as pannus formation. The recently discovered copper-dependent cell death pathway, named cuproptosis, further adds to the complexity of its role in RA. This review integrates current research advances on the double-edged role of copper in the pathogenesis of RA, systematically examines copper-related therapeutic strategies, and finally analyzes their potential applications and challenges. The aim is to harness the physiological functions of copper while mitigating its pathological effects, thereby opening new avenues for the diagnosis and precision treatment of RA.</div></div>","PeriodicalId":15245,"journal":{"name":"Journal of autoimmunity","volume":"157 ","pages":"Article 103484"},"PeriodicalIF":7.0,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145086284","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 : 2025-12-01Epub Date: 2025-11-11DOI: 10.1016/j.jaut.2025.103499
Wenfeng Xi, Yunlu Feng, Wen Shi, Jianing Li, Tao Guo, Xiaoyin Bai , Aiming Yang
Background
Type 1 autoimmune pancreatitis (AIP) is a rare, immune-mediated pancreatic disease prone to relapse. The influence of age on relapse risk remains unclear. This study aimed to determine whether age at diagnosis is associated with disease relapse.
Methods
We retrospectively analyzed 413 patients with type 1 AIP with over 2 years of follow-up. Patients were divided into two groups based on age at diagnosis: <60 years (n = 221) and ≥60 years (n = 192). Relapse rates were compared between groups. Logistic regression was used to assess the association between age group and relapse risk. Subgroup analyses by sex, diabetes, smoking, and heavy drinking were performed to test the stability of this association.
Results
The median age was 58.0 years, with 79.4 % male patients and a median follow-up of 4.6 years. The overall relapse rate was 41.9 %, being higher in the <60 years group (46.2 %) than in the ≥60 years group (37.0 %). Age <60 years was significantly associated with increased relapse risk (OR = 1.7; 95 % CI: 1.1–2.7, P = 0.022) in multivariate logistic analysis. This effect was consistent across all subgroups examined.
Conclusions
In type 1 AIP, age<60 years increases the risk of disease relapse. Age should be considered in long-term disease management.
{"title":"Association between age groups and relapse of type 1 autoimmune pancreatitis: a large-scale retrospective cohort study","authors":"Wenfeng Xi, Yunlu Feng, Wen Shi, Jianing Li, Tao Guo, Xiaoyin Bai , Aiming Yang","doi":"10.1016/j.jaut.2025.103499","DOIUrl":"10.1016/j.jaut.2025.103499","url":null,"abstract":"<div><h3>Background</h3><div>Type 1 autoimmune pancreatitis (AIP) is a rare, immune-mediated pancreatic disease prone to relapse. The influence of age on relapse risk remains unclear. This study aimed to determine whether age at diagnosis is associated with disease relapse.</div></div><div><h3>Methods</h3><div>We retrospectively analyzed 413 patients with type 1 AIP with over 2 years of follow-up. Patients were divided into two groups based on age at diagnosis: <60 years (n = 221) and ≥60 years (n = 192). Relapse rates were compared between groups. Logistic regression was used to assess the association between age group and relapse risk. Subgroup analyses by sex, diabetes, smoking, and heavy drinking were performed to test the stability of this association.</div></div><div><h3>Results</h3><div>The median age was 58.0 years, with 79.4 % male patients and a median follow-up of 4.6 years. The overall relapse rate was 41.9 %, being higher in the <60 years group (46.2 %) than in the ≥60 years group (37.0 %). Age <60 years was significantly associated with increased relapse risk (OR = 1.7; 95 % CI: 1.1–2.7, <em>P</em> = 0.022) in multivariate logistic analysis. This effect was consistent across all subgroups examined.</div></div><div><h3>Conclusions</h3><div>In type 1 AIP, age<60 years increases the risk of disease relapse. Age should be considered in long-term disease management.</div></div>","PeriodicalId":15245,"journal":{"name":"Journal of autoimmunity","volume":"157 ","pages":"Article 103499"},"PeriodicalIF":7.0,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145504531","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}
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