Axial spondyloarthritis (axSpA) is a chronic inflammatory disease characterized by complex pain mechanisms that extend beyond inflammation. Although inflammatory nociceptive pain - primarily mediated by pro-inflammatory cytokines - represents the classic pathway and therapeutic target, many patients continue to experience pain despite suppression of inflammation. This residual pain often reflects non-inflammatory processes, including nociplastic and neuropathic pain. Central sensitization, a key mechanism of nociplastic pain, contributes to pain amplification and poor response to treatment. Fibromyalgia, considered the typical phenotype of nociplastic pain, can co-occur with axSpA and is associated with increased symptom burden and reduced efficacy of anti-inflammatory therapies. Neuropathic pain, albeit less common, can result from structural complications and requires targeted therapeutic approaches. In addition, biological sex differences further influence pain perception and treatment outcomes: female patients report more widespread pain, show higher rates of central sensitization and have a worse response to biologic therapies than male patients. Current treatment paradigms are effective for inflammation-driven symptoms but often fail to address the broader spectrum of pain phenotypes in axSpA. Future work should include the development of biomarkers to differentiate pain mechanisms, the refinement of assessment tools and the evaluation of multimodal therapies that target both inflammation and pain processes. This evolving understanding necessitates a shift from an inflammation-centric to a mechanism-informed approach to pain management in axSpA.
{"title":"Inflammation and pain as interconnected targets in axial spondyloarthritis.","authors":"Xenofon Baraliakos,Victoria Navarro-Compán,Nelly Ziade,Denis Poddubnyy","doi":"10.1038/s41584-025-01348-0","DOIUrl":"https://doi.org/10.1038/s41584-025-01348-0","url":null,"abstract":"Axial spondyloarthritis (axSpA) is a chronic inflammatory disease characterized by complex pain mechanisms that extend beyond inflammation. Although inflammatory nociceptive pain - primarily mediated by pro-inflammatory cytokines - represents the classic pathway and therapeutic target, many patients continue to experience pain despite suppression of inflammation. This residual pain often reflects non-inflammatory processes, including nociplastic and neuropathic pain. Central sensitization, a key mechanism of nociplastic pain, contributes to pain amplification and poor response to treatment. Fibromyalgia, considered the typical phenotype of nociplastic pain, can co-occur with axSpA and is associated with increased symptom burden and reduced efficacy of anti-inflammatory therapies. Neuropathic pain, albeit less common, can result from structural complications and requires targeted therapeutic approaches. In addition, biological sex differences further influence pain perception and treatment outcomes: female patients report more widespread pain, show higher rates of central sensitization and have a worse response to biologic therapies than male patients. Current treatment paradigms are effective for inflammation-driven symptoms but often fail to address the broader spectrum of pain phenotypes in axSpA. Future work should include the development of biomarkers to differentiate pain mechanisms, the refinement of assessment tools and the evaluation of multimodal therapies that target both inflammation and pain processes. This evolving understanding necessitates a shift from an inflammation-centric to a mechanism-informed approach to pain management in axSpA.","PeriodicalId":18810,"journal":{"name":"Nature Reviews Rheumatology","volume":"94 1","pages":""},"PeriodicalIF":33.7,"publicationDate":"2026-01-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146015157","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 : 2026-01-07DOI: 10.1038/s41584-025-01350-6
Anthony K. Shum
{"title":"COPA syndrome spans multiple organs but is defined by STING in the lung","authors":"Anthony K. Shum","doi":"10.1038/s41584-025-01350-6","DOIUrl":"https://doi.org/10.1038/s41584-025-01350-6","url":null,"abstract":"","PeriodicalId":18810,"journal":{"name":"Nature Reviews Rheumatology","volume":"43 1","pages":""},"PeriodicalIF":33.7,"publicationDate":"2026-01-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145908215","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 : 2026-01-05DOI: 10.1038/s41584-025-01347-1
Sruthi Vijaya Retnakumar, Jagadeesh Bayry
{"title":"Engineered sialylated IgG1 Fc as a dose-sparing alternative to IVIG","authors":"Sruthi Vijaya Retnakumar, Jagadeesh Bayry","doi":"10.1038/s41584-025-01347-1","DOIUrl":"https://doi.org/10.1038/s41584-025-01347-1","url":null,"abstract":"","PeriodicalId":18810,"journal":{"name":"Nature Reviews Rheumatology","volume":"19 1","pages":""},"PeriodicalIF":33.7,"publicationDate":"2026-01-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145902565","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 : 2025-12-19DOI: 10.1038/s41584-025-01344-4
Hance Clarke, Mary-Ann Fitzcharles
Fibromyalgia remains a challenge for researchers and clinicians. Three studies published in 2025 shed light on mechanisms and management by implicating gut microbiota in symptom perpetuation, demonstrating the potential of home-based neuromodulation, and examining the uncertain role of low-dose naltrexone.
{"title":"Progress in mechanisms and therapy for fibromyalgia","authors":"Hance Clarke, Mary-Ann Fitzcharles","doi":"10.1038/s41584-025-01344-4","DOIUrl":"10.1038/s41584-025-01344-4","url":null,"abstract":"Fibromyalgia remains a challenge for researchers and clinicians. Three studies published in 2025 shed light on mechanisms and management by implicating gut microbiota in symptom perpetuation, demonstrating the potential of home-based neuromodulation, and examining the uncertain role of low-dose naltrexone.","PeriodicalId":18810,"journal":{"name":"Nature Reviews Rheumatology","volume":"22 2","pages":"84-85"},"PeriodicalIF":32.7,"publicationDate":"2025-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145785845","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 : 2025-12-19DOI: 10.1038/s41584-025-01345-3
Adam P. Croft, Annie Hackland
Advances in cellular and spatial profiling technologies have rapidly expanded the understanding of fibroblast heterogeneity within the target tissues of disease. In 2025, there has been a shift towards a consensus definition of shared cross-tissue fibroblast states and a greater understanding of their molecular drivers and disease-relevant effector functions.
{"title":"Fibroblast heterogeneity in 2025","authors":"Adam P. Croft, Annie Hackland","doi":"10.1038/s41584-025-01345-3","DOIUrl":"10.1038/s41584-025-01345-3","url":null,"abstract":"Advances in cellular and spatial profiling technologies have rapidly expanded the understanding of fibroblast heterogeneity within the target tissues of disease. In 2025, there has been a shift towards a consensus definition of shared cross-tissue fibroblast states and a greater understanding of their molecular drivers and disease-relevant effector functions.","PeriodicalId":18810,"journal":{"name":"Nature Reviews Rheumatology","volume":"22 2","pages":"86-88"},"PeriodicalIF":32.7,"publicationDate":"2025-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145794496","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 : 2025-12-18DOI: 10.1038/s41584-025-01346-2
Jessica McHugh
A new study reveals that the Epstein–Barr virus can reprogramme autoreactive B cells into pathogenic antigen-presenting cells in systemic lupus erythematosus, providing a mechanistic link between infection and autoimmunity.
{"title":"Mechanistic link uncovered between EBV infection and SLE","authors":"Jessica McHugh","doi":"10.1038/s41584-025-01346-2","DOIUrl":"10.1038/s41584-025-01346-2","url":null,"abstract":"A new study reveals that the Epstein–Barr virus can reprogramme autoreactive B cells into pathogenic antigen-presenting cells in systemic lupus erythematosus, providing a mechanistic link between infection and autoimmunity.","PeriodicalId":18810,"journal":{"name":"Nature Reviews Rheumatology","volume":"22 2","pages":"73-73"},"PeriodicalIF":32.7,"publicationDate":"2025-12-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145770803","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 : 2025-12-15DOI: 10.1038/s41584-025-01342-6
Carol A. Hitchon, Hani S. El-Gabalawy
New research published in 2025 sheds light on the pre-clinical period that precedes the onset of classifiable rheumatoid arthritis, from risk factors to immunological events and opportunities to prevent the transition to clinical disease.
{"title":"Advances in understanding preclinical rheumatoid arthritis and prospects for prevention","authors":"Carol A. Hitchon, Hani S. El-Gabalawy","doi":"10.1038/s41584-025-01342-6","DOIUrl":"10.1038/s41584-025-01342-6","url":null,"abstract":"New research published in 2025 sheds light on the pre-clinical period that precedes the onset of classifiable rheumatoid arthritis, from risk factors to immunological events and opportunities to prevent the transition to clinical disease.","PeriodicalId":18810,"journal":{"name":"Nature Reviews Rheumatology","volume":"22 2","pages":"82-83"},"PeriodicalIF":32.7,"publicationDate":"2025-12-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145760023","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 : 2025-12-11DOI: 10.1038/s41584-025-01327-5
Najoua Lalaoui, Seth L. Masters
TNF is a central regulator of immune responses, inflammation and programmed cell death, and has an essential role in maintaining tissue and immune homeostasis. Abnormal TNF signalling is implicated in a broad spectrum of physiological and pathological processes, as exemplified by monogenic disorders arising from dysregulation of core components of the TNF pathway. These rare conditions encompass various autoinflammatory syndromes, immunodeficiencies, autoimmune diseases and neurodegenerative conditions, and offer unique insights into the molecular mechanisms driving pathology via TNF-mediated inflammation and cell death. Collectively, these diseases underscore the importance of tightly regulated TNF signalling for immune balance and illustrate how distinct molecular defects can produce overlapping clinical phenotypes. Variability in pathway integration and tissue-specific gene expression further shapes disease presentation, whereas disruption of post-translational modifications and cell-death regulators have emerged as central pathogenic mechanisms. Together, these insights highlight the need for precise genetic and mechanistic understanding to inform diagnosis and therapeutic strategies. Monogenic disorders involving key elements of the TNF pathway now encompass a diverse and expanding group of conditions, spanning autoinflammatory, autoimmune, immunodeficiency and neurodegenerative diseases. This Review discusses the genetic causes, clinical features and current therapeutic strategies for these disorders, emphasizing the value of accurate molecular diagnosis and targeted interventions.
{"title":"Monogenic disorders of the TNF signalling pathway","authors":"Najoua Lalaoui, Seth L. Masters","doi":"10.1038/s41584-025-01327-5","DOIUrl":"10.1038/s41584-025-01327-5","url":null,"abstract":"TNF is a central regulator of immune responses, inflammation and programmed cell death, and has an essential role in maintaining tissue and immune homeostasis. Abnormal TNF signalling is implicated in a broad spectrum of physiological and pathological processes, as exemplified by monogenic disorders arising from dysregulation of core components of the TNF pathway. These rare conditions encompass various autoinflammatory syndromes, immunodeficiencies, autoimmune diseases and neurodegenerative conditions, and offer unique insights into the molecular mechanisms driving pathology via TNF-mediated inflammation and cell death. Collectively, these diseases underscore the importance of tightly regulated TNF signalling for immune balance and illustrate how distinct molecular defects can produce overlapping clinical phenotypes. Variability in pathway integration and tissue-specific gene expression further shapes disease presentation, whereas disruption of post-translational modifications and cell-death regulators have emerged as central pathogenic mechanisms. Together, these insights highlight the need for precise genetic and mechanistic understanding to inform diagnosis and therapeutic strategies. Monogenic disorders involving key elements of the TNF pathway now encompass a diverse and expanding group of conditions, spanning autoinflammatory, autoimmune, immunodeficiency and neurodegenerative diseases. This Review discusses the genetic causes, clinical features and current therapeutic strategies for these disorders, emphasizing the value of accurate molecular diagnosis and targeted interventions.","PeriodicalId":18810,"journal":{"name":"Nature Reviews Rheumatology","volume":"22 1","pages":"8-25"},"PeriodicalIF":32.7,"publicationDate":"2025-12-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145728613","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 : 2025-12-10DOI: 10.1038/s41584-025-01343-5
Huji Xu
In 2025, a new wave of ‘off-the-shelf’ B cell-depleting modalities for the treatment of autoimmune diseases emerged, encompassing allogeneic cellular therapies, in vivo chimeric antigen receptor engineering, and bispecific antibodies.
{"title":"The dawn of ‘off-the-shelf’ B cell-depleting therapies for autoimmune diseases","authors":"Huji Xu","doi":"10.1038/s41584-025-01343-5","DOIUrl":"10.1038/s41584-025-01343-5","url":null,"abstract":"In 2025, a new wave of ‘off-the-shelf’ B cell-depleting modalities for the treatment of autoimmune diseases emerged, encompassing allogeneic cellular therapies, in vivo chimeric antigen receptor engineering, and bispecific antibodies.","PeriodicalId":18810,"journal":{"name":"Nature Reviews Rheumatology","volume":"22 2","pages":"78-79"},"PeriodicalIF":32.7,"publicationDate":"2025-12-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145717633","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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