Pub Date : 2025-12-05DOI: 10.1038/s41584-025-01340-8
Jessica McHugh
A new study uncovers how UBA1 mutations in VEXAS syndrome simultaneously promote myeloid inflammatory cell death and skew haematopoietic stem cells towards a myeloid lineage.
{"title":"Unravelling the cellular mechanisms of VEXAS syndrome","authors":"Jessica McHugh","doi":"10.1038/s41584-025-01340-8","DOIUrl":"10.1038/s41584-025-01340-8","url":null,"abstract":"A new study uncovers how UBA1 mutations in VEXAS syndrome simultaneously promote myeloid inflammatory cell death and skew haematopoietic stem cells towards a myeloid lineage.","PeriodicalId":18810,"journal":{"name":"Nature Reviews Rheumatology","volume":"22 1","pages":"5-5"},"PeriodicalIF":32.7,"publicationDate":"2025-12-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145680162","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 : 2025-12-03DOI: 10.1038/s41584-025-01337-3
Rachel Knevel
Advances in artificial intelligence (AI) are transforming patient stratification in rheumatology. In 2025, three landmark studies demonstrated how multimodal AI approaches spanning clinical, molecular and longitudinal data can uncover distinct disease subtypes and predict therapeutic response, advancing the field towards precision rheumatology.
{"title":"Advances in AI-based patient stratification for rheumatic diseases","authors":"Rachel Knevel","doi":"10.1038/s41584-025-01337-3","DOIUrl":"10.1038/s41584-025-01337-3","url":null,"abstract":"Advances in artificial intelligence (AI) are transforming patient stratification in rheumatology. In 2025, three landmark studies demonstrated how multimodal AI approaches spanning clinical, molecular and longitudinal data can uncover distinct disease subtypes and predict therapeutic response, advancing the field towards precision rheumatology.","PeriodicalId":18810,"journal":{"name":"Nature Reviews Rheumatology","volume":"22 2","pages":"75-77"},"PeriodicalIF":32.7,"publicationDate":"2025-12-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145664281","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 : 2025-12-03DOI: 10.1038/s41584-025-01332-8
Kelsey H. Collins, Ida K. Haugen, Tuhina Neogi, Farshid Guilak
Osteoarthritis (OA) is a painful disorder of the synovial joints characterized by dysfunctional cellular metabolism and extracellular matrix degradation that activates maladaptive repair responses, including pro-inflammatory pathways of innate immunity. OA has historically been viewed as an unavoidable consequence of ageing owing to wear-and-tear of the joint. Most strategies to mitigate OA have primarily focused on the articular cartilage and, more recently, other specific joint tissues, which limits understanding of OA as a systemic disease beyond the joint. Preclinical and clinical data support a paradigm shift in understanding OA as a disease of the whole person, focusing on changes throughout the body that both promote and are caused by OA. This shift provides novel insights into why preclinical research findings have not been successfully translated into clinical therapies. Moreover, a viable strategy for OA drug development could be to treat pain separately from OA structural damage. Challenging classically held views that lack evidence or have been disproven is required for progress. We explore some key emerging questions that should be carefully considered in future OA studies. Adapting and integrating new technologies, techniques, and tools into the rapidly evolving understanding of OA could lead to the development of drugs that might not only treat OA but also provide mechanistic insight into other conditions that result from the dysregulation of systemic factors or from the communication breakdown in inter-organ crosstalk. Such developments would reposition OA researchers from adapting approaches from other fields of science and medicine to leaders in the fight against chronic disease. Emerging evidence suggests a paradigm shift in viewing osteoarthritis (OA) as a systemic, bidirectional disease. This Review examines the current data supporting this concept, outlines key challenges in research approaches, and proposes strategies to improve preclinical studies and clinical trial design.
{"title":"Osteoarthritis as a systemic disease","authors":"Kelsey H. Collins, Ida K. Haugen, Tuhina Neogi, Farshid Guilak","doi":"10.1038/s41584-025-01332-8","DOIUrl":"10.1038/s41584-025-01332-8","url":null,"abstract":"Osteoarthritis (OA) is a painful disorder of the synovial joints characterized by dysfunctional cellular metabolism and extracellular matrix degradation that activates maladaptive repair responses, including pro-inflammatory pathways of innate immunity. OA has historically been viewed as an unavoidable consequence of ageing owing to wear-and-tear of the joint. Most strategies to mitigate OA have primarily focused on the articular cartilage and, more recently, other specific joint tissues, which limits understanding of OA as a systemic disease beyond the joint. Preclinical and clinical data support a paradigm shift in understanding OA as a disease of the whole person, focusing on changes throughout the body that both promote and are caused by OA. This shift provides novel insights into why preclinical research findings have not been successfully translated into clinical therapies. Moreover, a viable strategy for OA drug development could be to treat pain separately from OA structural damage. Challenging classically held views that lack evidence or have been disproven is required for progress. We explore some key emerging questions that should be carefully considered in future OA studies. Adapting and integrating new technologies, techniques, and tools into the rapidly evolving understanding of OA could lead to the development of drugs that might not only treat OA but also provide mechanistic insight into other conditions that result from the dysregulation of systemic factors or from the communication breakdown in inter-organ crosstalk. Such developments would reposition OA researchers from adapting approaches from other fields of science and medicine to leaders in the fight against chronic disease. Emerging evidence suggests a paradigm shift in viewing osteoarthritis (OA) as a systemic, bidirectional disease. This Review examines the current data supporting this concept, outlines key challenges in research approaches, and proposes strategies to improve preclinical studies and clinical trial design.","PeriodicalId":18810,"journal":{"name":"Nature Reviews Rheumatology","volume":"22 2","pages":"105-117"},"PeriodicalIF":32.7,"publicationDate":"2025-12-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145664532","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 : 2025-12-02DOI: 10.1038/s41584-025-01296-9
Juhi R. Kuchroo, Naomi Goldman, Arlene H. Sharpe
Immune-checkpoint molecules have essential roles in regulating immune responses, which maintain the delicate balance between physiological immune reactions and autoimmunity. The clinical success of immune checkpoint blockade for cancer therapy, and the occurrence of immune-related adverse events during cancer immunotherapy, highlight the profound effect of modulating these receptors on both tumour-specific and ‘self’-specific responses. As a result, interest in exploring how these molecules can be targeted to treat autoimmune and rheumatological diseases is expanding. Targeting of the immune-checkpoint molecules PD-1, B and T lymphocyte attenuator (BTLA) and T cell immunoreceptor with Ig and ITIM domains (TIGIT) to induce immune tolerance has shown therapeutic promise in pre-clinical models and, in some instances, clinical trials. A comprehensive understanding of how these receptors function in various immune cell populations, particularly T cells, and across different diseases is crucial for the successful translation of these findings to clinical applications. Immune-checkpoint agonists are a promising therapeutic approach for autoimmune disease. This Review discusses the immune-checkpoint receptors PD-1, BTLA and TIGIT as well as the preclinical and clinical evidence for therapeutically targeting these receptors for the treatment of rheumatic diseases.
{"title":"PD-1, BTLA and TIGIT as therapeutic targets for rheumatic disease","authors":"Juhi R. Kuchroo, Naomi Goldman, Arlene H. Sharpe","doi":"10.1038/s41584-025-01296-9","DOIUrl":"10.1038/s41584-025-01296-9","url":null,"abstract":"Immune-checkpoint molecules have essential roles in regulating immune responses, which maintain the delicate balance between physiological immune reactions and autoimmunity. The clinical success of immune checkpoint blockade for cancer therapy, and the occurrence of immune-related adverse events during cancer immunotherapy, highlight the profound effect of modulating these receptors on both tumour-specific and ‘self’-specific responses. As a result, interest in exploring how these molecules can be targeted to treat autoimmune and rheumatological diseases is expanding. Targeting of the immune-checkpoint molecules PD-1, B and T lymphocyte attenuator (BTLA) and T cell immunoreceptor with Ig and ITIM domains (TIGIT) to induce immune tolerance has shown therapeutic promise in pre-clinical models and, in some instances, clinical trials. A comprehensive understanding of how these receptors function in various immune cell populations, particularly T cells, and across different diseases is crucial for the successful translation of these findings to clinical applications. Immune-checkpoint agonists are a promising therapeutic approach for autoimmune disease. This Review discusses the immune-checkpoint receptors PD-1, BTLA and TIGIT as well as the preclinical and clinical evidence for therapeutically targeting these receptors for the treatment of rheumatic diseases.","PeriodicalId":18810,"journal":{"name":"Nature Reviews Rheumatology","volume":"22 2","pages":"89-104"},"PeriodicalIF":32.7,"publicationDate":"2025-12-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145656837","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 : 2025-12-01DOI: 10.1038/s41584-025-01339-1
Christine T. N. Pham, Farshid Guilak
Many of the current therapies for arthritis lack a targeted approach, limiting clinical benefits. Nanoparticle-based delivery systems have enabled more precise and efficient delivery of therapeutic agents, particularly nucleic acids. Studies in 2025 emphasize the promise of these strategies for the treatment of various forms of arthritis.
{"title":"Advances in RNA-based nanotherapies for arthritis","authors":"Christine T. N. Pham, Farshid Guilak","doi":"10.1038/s41584-025-01339-1","DOIUrl":"10.1038/s41584-025-01339-1","url":null,"abstract":"Many of the current therapies for arthritis lack a targeted approach, limiting clinical benefits. Nanoparticle-based delivery systems have enabled more precise and efficient delivery of therapeutic agents, particularly nucleic acids. Studies in 2025 emphasize the promise of these strategies for the treatment of various forms of arthritis.","PeriodicalId":18810,"journal":{"name":"Nature Reviews Rheumatology","volume":"22 2","pages":"80-81"},"PeriodicalIF":32.7,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145645158","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 : 2025-11-28DOI: 10.1038/s41584-025-01338-2
Maria Papatriantafyllou
T helper 17 cells that lose IL-17 expression drive inflammation in a mouse model of chronic rheumatoid arthritis.
在慢性类风湿关节炎小鼠模型中，失去IL-17表达的T辅助17细胞驱动炎症。
{"title":"ExTH17 cells maintain chronic inflammation in RA","authors":"Maria Papatriantafyllou","doi":"10.1038/s41584-025-01338-2","DOIUrl":"10.1038/s41584-025-01338-2","url":null,"abstract":"T helper 17 cells that lose IL-17 expression drive inflammation in a mouse model of chronic rheumatoid arthritis.","PeriodicalId":18810,"journal":{"name":"Nature Reviews Rheumatology","volume":"22 2","pages":"74-74"},"PeriodicalIF":32.7,"publicationDate":"2025-11-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145611241","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 : 2025-11-27DOI: 10.1038/s41584-025-01329-3
Fabian Proft, Andre L. Ribeiro, Shikha Singla, Vinod Chandran, Wilson Liao, Christine Lindsay, Enrique R. Soriano, Tina Bhutani, Atul Deodhar, Kurt de Vlam, Lihi Eder, Mitsumasa Kishimoto, Ying Ying Leung, Ennio Lubrano, Dennis McGonagle, Denis Poddubnyy, Laura Savage, Filip Van den Bosch, Philip Mease
Despite advances in the treatment of psoriatic arthritis (PsA), a substantial proportion of patients continue to report persistent symptoms and impaired quality of life. However, terminology remains inconsistent for patients who fail to achieve disease control despite treatment, which limits research comparability and contributes to therapeutic inertia. To address this gap, a Group for Research and Assessment of Psoriasis and Psoriatic Arthritis (GRAPPA) task force developed consensus definitions for two distinct states: complex-to-manage PsA (C2M-PsA) and treatment-refractory PsA (TR-PsA). C2M-PsA is defined as a state of persistent symptoms despite treatment with at least one biologic or targeted synthetic DMARD (b/tsDMARD), extending beyond biological non-response to include factors such as comorbidities, overlapping conditions, psychosocial burden and treatment-related challenges (for example, non-adherence). TR-PsA, a more specific subset of C2M-PsA, is characterized by failure of at least three therapies with distinct mechanisms of action (including at least two biologic/targeted synthetic DMARDs), persistent symptoms considered problematic by both patient and clinician, and objective evidence of ongoing inflammation — after ruling out alternative explanations for treatment refractoriness. These consensus-derived GRAPPA definitions provide a shared framework to standardize terminology, support individualized care, and improve patient stratification in research and practice. Prospective validation across diverse settings and phenotypes is needed to confirm their reliability, responsiveness and clinical utility. In this Consensus Statement, a Group for Research and Assessment of Psoriasis and Psoriatic Arthritis task force presents consensus definitions for two distinct states, complex-to-manage PsA and treatment-refractory PsA, with the aim of standardizing terminology, improving patient stratification and guiding clinical decision-making and future research.
{"title":"Consensus definitions of complex-to-manage and treatment-refractory psoriatic arthritis: a GRAPPA initiative","authors":"Fabian Proft, Andre L. Ribeiro, Shikha Singla, Vinod Chandran, Wilson Liao, Christine Lindsay, Enrique R. Soriano, Tina Bhutani, Atul Deodhar, Kurt de Vlam, Lihi Eder, Mitsumasa Kishimoto, Ying Ying Leung, Ennio Lubrano, Dennis McGonagle, Denis Poddubnyy, Laura Savage, Filip Van den Bosch, Philip Mease","doi":"10.1038/s41584-025-01329-3","DOIUrl":"10.1038/s41584-025-01329-3","url":null,"abstract":"Despite advances in the treatment of psoriatic arthritis (PsA), a substantial proportion of patients continue to report persistent symptoms and impaired quality of life. However, terminology remains inconsistent for patients who fail to achieve disease control despite treatment, which limits research comparability and contributes to therapeutic inertia. To address this gap, a Group for Research and Assessment of Psoriasis and Psoriatic Arthritis (GRAPPA) task force developed consensus definitions for two distinct states: complex-to-manage PsA (C2M-PsA) and treatment-refractory PsA (TR-PsA). C2M-PsA is defined as a state of persistent symptoms despite treatment with at least one biologic or targeted synthetic DMARD (b/tsDMARD), extending beyond biological non-response to include factors such as comorbidities, overlapping conditions, psychosocial burden and treatment-related challenges (for example, non-adherence). TR-PsA, a more specific subset of C2M-PsA, is characterized by failure of at least three therapies with distinct mechanisms of action (including at least two biologic/targeted synthetic DMARDs), persistent symptoms considered problematic by both patient and clinician, and objective evidence of ongoing inflammation — after ruling out alternative explanations for treatment refractoriness. These consensus-derived GRAPPA definitions provide a shared framework to standardize terminology, support individualized care, and improve patient stratification in research and practice. Prospective validation across diverse settings and phenotypes is needed to confirm their reliability, responsiveness and clinical utility. In this Consensus Statement, a Group for Research and Assessment of Psoriasis and Psoriatic Arthritis task force presents consensus definitions for two distinct states, complex-to-manage PsA and treatment-refractory PsA, with the aim of standardizing terminology, improving patient stratification and guiding clinical decision-making and future research.","PeriodicalId":18810,"journal":{"name":"Nature Reviews Rheumatology","volume":"22 2","pages":"132-144"},"PeriodicalIF":32.7,"publicationDate":"2025-11-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41584-025-01329-3.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145608735","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 : 2025-11-26DOI: 10.1038/s41584-025-01328-4
Joshua Heerey, Joanne Kemp, Pim van Klij, Vasco Mascarenhas, Mark Scholes, Fleur Boel, Paul Dijkstra, Kay Crossley, Sita Bierma-Zeinstra, Rintje Agricola
{"title":"Cam morphology and the development of femoroacetabular impingement syndrome and hip osteoarthritis","authors":"Joshua Heerey, Joanne Kemp, Pim van Klij, Vasco Mascarenhas, Mark Scholes, Fleur Boel, Paul Dijkstra, Kay Crossley, Sita Bierma-Zeinstra, Rintje Agricola","doi":"10.1038/s41584-025-01328-4","DOIUrl":"https://doi.org/10.1038/s41584-025-01328-4","url":null,"abstract":"","PeriodicalId":18810,"journal":{"name":"Nature Reviews Rheumatology","volume":"13 1","pages":""},"PeriodicalIF":33.7,"publicationDate":"2025-11-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145599896","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}
{"title":"Positive phase II trial of IL-17A–IL-17F-targeting nanobody sonelokimab for PsA","authors":"Holly Webster","doi":"10.1038/s41584-025-01335-5","DOIUrl":"10.1038/s41584-025-01335-5","url":null,"abstract":"A nanobody that targets IL-17A and IL-17F has shown promise in a phase II study of patients with active psoriatic arthritis.","PeriodicalId":18810,"journal":{"name":"Nature Reviews Rheumatology","volume":"22 1","pages":"4-4"},"PeriodicalIF":32.7,"publicationDate":"2025-11-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145599341","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 : 2025-11-24DOI: 10.1038/s41584-025-01326-6
Rebecca H. Haberman, Alexis Ogdie, Joseph F. Merola, Jose U. Scher, Lihi Eder
{"title":"The obesity–inflammation axis in psoriatic disease: mechanisms and therapeutic strategies","authors":"Rebecca H. Haberman, Alexis Ogdie, Joseph F. Merola, Jose U. Scher, Lihi Eder","doi":"10.1038/s41584-025-01326-6","DOIUrl":"https://doi.org/10.1038/s41584-025-01326-6","url":null,"abstract":"","PeriodicalId":18810,"journal":{"name":"Nature Reviews Rheumatology","volume":"100 1","pages":""},"PeriodicalIF":33.7,"publicationDate":"2025-11-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145583189","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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