OBJECTIVE:To explore the association between Mettl3-modified Piezo1 in CD4+ T cells and the inflammatory response in ankylosing spondylitis (AS). METHODS:Peripheral venous blood and epidemiological datas were collected from 53 AS patients and 53 healthy controls. Enzyme-linked immunosorbent assay (ELISA) was employed to measure the levels of inflammatory cytokines. Real-time quantitative PCR (qRT-PCR) was utilized to detect the transcriptional levels of Mettl3 and Piezo1. A Mettl3-knockdown human Jurkat T cell model was established using siRNA technology. Western blot was performed to detect the protein levels of genes. MeRIP-PCR was used to validate the modification effect of Mettl3 on Piezo1. RESULTS:The transcriptional level of Mettl3 was downregulated, while that of Piezo1 was upregulated in CD4+ T cells from AS patients, showing a negative correlation between them. ROC curve analysis indicated that both Mettl3 and Piezo1 possessed diagnostic capabilities, with the AUC for Mettl3 being 0.661 (95% CI: 0.555-0.767) and for Piezo1 being 0.938 (95% CI: 0.890-0.987). Subgroup analysis revealed that the Piezo1 mRNA level was significantly lower in the group using biologic agents compared to the group not using them. Cellular experimental results demonstrated that si-Mettl3 could elevate the protein level of Piezo1 in Jurkat T cells, accompanied by the increase of TNF-α. MeRIP-PCR further confirmed the role of Mettl3 in the m6A methylation modification of Piezo1. CONCLUSIONS:The inhibition of Mett13 in CD4+ T cells in ankylosing spondylitis enhances the expression level of Piezo1 protein through m6A methylation modification, promoting the development of inflammatory responses in ankylosing spondylitis.

SLE is a highly heterogeneous autoimmune disease, and its diagnosis and assessment depend on the detection of specific autoantibodies. Electrochemical sensors have shown significant potential in the field of medical testing, especially in the detection of autoantibodies, due to their high sensitivity, fast response, miniaturization, and low cost advantages. Compared with traditional immunological methods, electrochemical sensors have lower detection limits, wider linear ranges, and multi index synchronous analysis capabilities by converting antigen antibody recognition events into quantifiable electrical signals, providing a new technological path for dynamic monitoring of SLE biomarkers. The study adopted a retrospective cohort design, including diagnosed SLE patients who were divided into double positive, single positive, and double negative groups based on antibody expression. Clinical data were collected and renal outcomes were followed up. Research has shown that patients with double positive anti dsDNA antibodies and anti Sm antibodies have significantly increased 24-h urinary protein and more severe kidney damage; The levels of complement C3 and C4 decrease, and immune activation intensifies, which may be related to disease activity. The risk of end-stage renal disease is significantly increased, highlighting the clinical hazards of double positive status. Through multiple regression analysis, it was further confirmed that dual positivity of anti dsDNA and anti Sm antibodies is an independent risk factor for predicting poor renal prognosis. Even after adjusting for potential confounding factors such as age, gender, and underlying diseases, this combination of serological markers is still closely associated with poor renal function, and special attention should be paid to these patients in clinical management. Therefore, co expression of anti dsDNA and anti Sm antibodies can serve as important predictive indicators for renal prognosis in SLE patients.

Background:This study estimated the status of youth-onset rheumatoid arthritis (RA) and gout among adolescents and young adults (AYAs, aged 15-39 years) in East Asian five countries from 1990 to 2021, and analyzed disparities among these countries. Method:The numbers and age-standardized rates (ASRs) of prevalence, incidence, and disability-adjusted life years (DALYs) were calculated. Age-period-cohort (APC) analysis was employed to assess disease burden trends. Frontier analysis was applied to examine differences in health potential among countries. Eight machine learning time series models were employed to forecast the future burden trends. Results:China had the highest disease burden numbers among five countries in 2021 (e.g., gout prevalence cases: 1,434,359.2; incidence cases: 363,759.3; DALYs: 48,394.2). From 1990 to 2021, the Democratic People's Republic of Korea had the highest ASRs for gout (e.g., ASPR of 283.1 per 100,000 in 2021) and China had the highest ASRs for RA (e.g., ASDR of 20.9 per 100,000 in 2021). Male ASRs consistently exceeded female ASRs in gout, whereas the opposite pattern was observed in RA. APC analysis revealed that ASRs of both diseases increased with age and later birth cohorts. Machine learning forecasts indicated fluctuating upward trends by 2050. For instance, the Prophet model predicted that China's gout ASDR would rise to 9.3 per 100,000 (95% UI: 8.8-9.7) by 2050, while the ARIMA model suggested that China's RA ASPR would peak at 131.9 per 100,000 (95% UI: 128.1-135.8). The ARIMA model performed best for predicting ASPR in China and ASIR in Japan, whereas the Prophet was more appropriate for the remaining indicators. Conclusion:The burden of youth-onset RA and gout has become a major public health concern in East Asia. Therefore, East Asian countries should implement targeted screening strategies (such as early serum uric acid monitoring in young men) and formulate disease-specific interventions.

OBJECTIVES:To identify and validate novel urinary protein biomarkers associated with disease activity in RA, and to investigate their potential biological roles. METHODS:We employed a multi-phase strategy integrating proteomic discovery, biomarker validation, population-based analysis and mechanistic studies. Differentially expressed proteins (DEPs) were first identified using data-independent acquisition-based proteomic profiling in a discovery set comprising RA patients and healthy controls (HCs). Candidate proteins were subsequently validated by ELISA in two independent validation cohorts. Population-based associations were assessed in two RA cohorts (n = 301 cross-sectional; n = 214 longitudinal), with disease activity evaluated using VAS and DAS28 scores. Functional relevance was further examined in synovial tissues, fibroblast-like synoviocytes (FLS) and cytokine assays. RESULTS:A total of 209 DEPs were identified between RA patients and HCs, with enrichment analyses highlighting immune-related pathways. Among these, IGLV3-1 demonstrated high diagnostic potential (AUC = 0.99) and was consistently validated in two independent cohorts. In population-based analyses, IGLV3-1 levels were positively associated with both VAS (β = 1.070, 95% CI: 0.264-1.875) and DAS28 scores (β = 0.672, 95% CI: 0.029-1.315) and predicted a reduced likelihood of VAS pain improvement (OR = 0.188, 95% CI: 0.047-0.746). Mechanistically, IGLV3-1 was upregulated in RA synovial tissues and FLS, and positively correlated with IL-6, IL-8 and IL-12p70 levels. Its knockdown via siRNA in FLS led to reduced expression of these pro-inflammatory cytokines at both mRNA and protein levels. CONCLUSION:IGLV3-1 is a novel urinary protein biomarker that reflects RA disease activity and predicts clinical outcomes.

Background:Rheumatoid arthritis (RA) is a chronic autoimmune synovitis characterized by progressive joint destruction. Vitamin D exerts immunomodulatory and anti-inflammatory effects, and its insufficiency is highly prevalent in RA and closely related to exacerbated inflammatory status. Synovial succinate acts as a pro-inflammatory metabolic mediator that aggravates intra-articular inflammation. However, the interactive associations among vitamin D, synovial succinate, and RA disease activity remain poorly defined. This cross-sectional study aimed to elucidate their correlations in RA patients. Methods:A total of 120 RA patients were enrolled and stratified according to serum 25-hydroxyvitamin D [25(OH)D] levels (deficiency: < 20 µg/L). Demographic parameters, 28-joint Disease Activity Score (DAS-28), serum C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), and synovial succinate levels were compared between groups. Pearson correlation and multiple linear regression analyses were performed to evaluate correlations and independent determinants of disease activity. Results:RA patients with vitamin D deficiency presented a significantly lower BMI, higher serum CRP and elevated synovial succinic acid levels compared with those without vitamin D deficiency, whereas no inter-group differences in DAS-28 scores and ESR were observed. Correlation analysis revealed that serum vitamin D levels were negatively correlated with CRP (P = 0.012), ESR (P = 0.049) and synovial succinic acid levels (P = 0.030), while no significant correlation was found between vitamin D and DAS-28 scores. Additionally, synovial succinic acid levels were positively correlated with DAS-28 scores (P = 0.002), CRP (P = 0.035) and ESR (P = 0.031), respectively. Multiple linear regression analysis validated that age, ESR and synovial succinic acid were independent positive influencing factors for increased DAS-28 scores in RA patients. Conclusion:This study demonstrates a high prevalence of vitamin D deficiency in RA patients, which is associated with elevated synovial succinate. Synovial succinate is significantly correlated with disease activity and serves as an independent influencing factor for DAS-28, together with age and ESR. Given the cross-sectional design, these findings confirm associative rather than causal relationships.

Abstract Objective To detect anti-drug antibody (ADA), Neutralizing Antibody (NAb) and Adalimumab (ADL) concentration in Rheumatoid arthritis (RA) and Ankylosing spondylitis (AS) and investigate correlations with clinical efficacy. Methods 78 active RA patients, 59 active AS patients and 30 age, sex matched healthy individuals were recruited. The treatment course was 24 weeks with assessments every 12 weeks. ADL concentration, ADA and NAb were measured by enzyme-linked immunosorbent assay (ELISA). SPSS 26.0 was applied for statistical analysis. Results The ADA incidence in AS group was higher than that in RA group after 24 weeks of treatment. The ADL concentration in AS/RA group with ADA was lower than that without ADA after 12/24 weeks of treatment. At 24 weeks of treatment: In RA group, the Remission-Low activity group’s ADL concentration was higher than that of the Moderate-Severe activity group, and the ADA positive rate was lower (χ²=4.481, P = 0.034). In AS group, the Remission-Low activity group’s ADL concentration was higher than that of the High-Extreme high activity group, and the ADA positive rate was lower (χ²=5.184, P = 0.023). Logistic regression analysis showed that ADA at 12/24 weeks and disease course were risk factors for Moderate-Severe activity status in RA group and High-Extreme high activity status in AS group. In contrast, log₁₀(ADL concentration) at 24 weeks was a protective factor in RA, and log₁₀(ADL concentration) at 12 and 24 weeks were protective factors in AS. Conclusion The total incidence of ADA, which is almost entirely NAb in RA and AS patients at 24 weeks after ADL treatment, is approximately 20%. AS patients show higher ADA incidence than RA patients. ADA correlates with lower ADL concentration and is closely related to disease activity.

Rheumatoid arthritis (RA) is a chronic autoimmune inflammatory disorder with a high prevalence among postmenopausal women (PMW), and it is associated with substantial functional impairment and reduced quality of life. To inform targeted prevention strategies for high-risk populations in the U.S., a comprehensive and up-to-date assessment of disease burden in this population is needed. We conducted a quantitative analysis of the prevalence, years lived with disability (YLDs), and disability-adjusted life years (DALYs) of RA among PMW (PMWRA) in the U.S. from 1990 to 2021. In addition, disease trends were projected for 2022–2035 using data from the Global Burden of Disease Study (GBD) 2021. We extracted state-level estimates of prevalence, YLDs, and DALYs for PMWRA across 51 U.S. states from 1990 to 2021. Temporal trends were summarized using the average annual percent change (AAPC), and geographic and age-specific differences were assessed. Major risk factors contributing to state- and age-specific YLDs and DALYs were analyzed. Future projections were forecast using autoregressive integrated moving average (ARIMA) and exponential smoothing state-space (ETS) models. All analyses were conducted using R version 4.4.2 and the Joinpoint Regression Program. From 1990 to 2021, prevalence, YLD, and DALY rates among U.S. PMWRA showed upward trends, with AAPCs of 0.55, 0.50, and 0.04, respectively; the corresponding total percent changes in numbers were 1.13, 1.10, and 0.82. In 2021, Montana exhibited the highest prevalence (2,235.76), YLD (277.29), and DALY rates (362.62) among all states nationwide. The disease burden increased with the rising sociodemographic index up to a threshold and then declined. Age-stratified analyses indicated increasing prevalence, YLD, and DALY rates across nearly all age groups. Smoking emerged as the principal risk factor for PMWRA-related YLDs and DALYs across ages and regions. Forecasts based on ARIMA and ETS models indicated continued increases in prevalence and YLDs, whereas DALY rates were projected to decline. The burden of PMWRA among U.S. women is projected to continue rising, with concentration in specific states and age groups, which emphasizes the need for targeted public-health interventions to mitigate the burden in this population.

Background This research aimed to investigate the associations of multiple adipose-muscle indices with secondary osteoporosis (OP) and sarcopenia in rheumatoid arthritis (RA) patients. Objectives To develop a comprehensive early diagnostic model for musculoskeletal loss in RA patients based on non-invasive adipose-muscle indices. Design A cross-sectional and Mendelian randomization (MR) study. Methods Fourteen machine learning (ML) algorithms were applied to select features from 33 candidate variables and were incorporated to construct clinical predictive models for OP, sarcopenia, and osteo-sarcopenia (OS). Restricted cubic spline (RCS) analysis explored dose-response relationships. MR methods were used to analyze potential causal effects. Results Six key features were identified, of which the fat-to-muscle ratio (FMR) and the skeletal muscle mass-to-visceral fat area ratio (SVR) were the most prominent. FMR was a risk factor for OP, whereas SVR was a protective factor against sarcopenia. The LightGBM model demonstrated superior performance in predicting OS (AUC = 0.988). MR analysis further indicated that body fat mass fully mediated the causal pathway from RA to OP and sarcopenia. Conclusion ML models based on hybrid adipose-muscle indices demonstrated exceptional predictive value for subclinical musculoskeletal loss in RA patients.

OBJECTIVE:Despite growing interest in the gut microbiota and blood metabolome in patients with ankylosing spondylitis (AS), its role remains poorly understood. Here, we investigate how microbial and metabolic alterations contribute to AS. METHODS:Fecal microbiome data from 40 AS patients were compared with those from 40 healthy controls (HCs) using 16S ribosomal RNA (rRNA) gene sequencing. The plasma metabolic profiles were analyzed and integrated with the microbiota data to identify biological characteristics specific to AS. RESULTS:AS patients showed significant enrichment of specific genera, including Megamonas, Elusimicrobium, Dysgonomonas, Ruminococcus_gauvreauii_group, and unclassified_Prevotellaceae. Pathways with the most differentially expressed metabolites included bile secretion; neomycin, kanamycin, and gentamicin biosynthesis; and arachidonic acid metabolism. Positive correlations between Megamonas and Elusimicrobium and metabolites such as piribedil, l-cystathionine, and crocetin dialdehyde suggested microbial enrichment in AS patients. CONCLUSIONS:A disrupted gut microbiota and altered metabolites are present in AS patients. Integrating microbiome and metabolomic data reveals significant disruptions in AS patients, improving our understanding of its pathogenesis.

BACKGROUND:Adults aged 50 and over are particularly vulnerable to musculoskeletal (MSK) disorders, with their impact expected to intensify as the global population ages. This study aims to comprehensively assess the global burden of MSK disorders among adults aged 50 and over from 1990 to 2021, as well as temporal trends, risk factors and sociodemographic inequalities. METHODS:Data were sourced from the Global Burden of Disease 2021 study. Temporal trends in age-standardized rates were evaluated by calculating average annual percent changes (AAPC). Absolute and relative inequalities were assessed using the slope index of inequality and concentration index, respectively. RESULTS:From 1990 to 2021, MSK disorders remained the largest contributor to total years lived with disability (YLDs) among adults aged 50 and over globally. The global age-standardized incidence rate significantly decreased (AAPC = -0.181, 95% CI: -0.190 to -0.172), whereas the global prevalence and disability-adjusted life-year (DALY) rates significantly increased (AAPC = 0.126, 95% CI: 0.118-0.134, and AAPC = 0.057, 95% CI: 0.042-0.072, respectively). High sociodemographic index (SDI) countries exhibited the highest age-standardized incidence, prevalence and DALY rates (11 236.6, 56 308.1 and 5277.1 per 100 000 population, respectively), whereas low-middle SDI countries showed the most rapid increases in prevalence and DALY rates (AAPC = 0.229, 95% CI: 0.218-0.240, and AAPC = 0.230, 95% CI: 0.204-0.256, respectively). Significantly positive associations were identified between SDI and age-standardized incidence, prevalence and DALY rates (all p < 0.001). High body mass index (BMI) was the largest contributor to global DALYs of MSK disorders, accounting for 10.3% of the total in this population, whereas occupational ergonomic factors, smoking and kidney dysfunction contributed 7.3%, 6.0% and 0.2%, respectively. Although the proportions of DALYs due to occupational ergonomic factors and smoking declined globally (from 9.2% to 7.3% and from 8.9% to 6.0%, respectively), those due to high BMI and kidney dysfunction increased (from 7.7% to 10.3% and from 0.19% to 0.22%, respectively). Both absolute and relative SDI-related inequalities persisted across 204 countries and territories, with no significant changes observed. CONCLUSIONS:MSK disorders have remained the largest contributor to disability among adults aged 50 and over. Despite significant progress in reducing the incidence rate, both the prevalence and DALY rates have significantly increased. With the expanding global ageing population, there is an urgent need for improved prevention strategies to mitigate the long-term impacts of MSK disorders in this vulnerable population.

Rheumatoid arthritis (RA) is an autoimmune disease with destructive arthritis as its main clinical manifestation, which is a major cause of disability. It is very important to formulate and update a guideline for the diagnosis and treatment of RA that adhere to international guideline development standards and can be applied to clinical practice in China. This guideline is endorsed and developed by the National Clinical Research Center for Dermatologic and Immunologic Diseases, collaborated with Rheumatologists Branch of Chinese Medical Doctor Association, Rheumatology Rehabilitation Branch of Chinese Association of Rehabilitation Medicine, Rheumatology Branch of Chinese Research Hospital Association, and Rheumatology Branch of Beijing Association of Holistic Integrative Medicine, based on grading of recommendations assessment, development and evaluation (GRADE) and reporting items for practice guidelines in healthcare (RIGHT). Evidence-based recommendation were developed for 10 clinical scenario that are most relevant to Chinese rheumatologists, aiming to improve and standardize the diagnosis and treatment of RA in China, which may finally improve the quality of life and prognosis of patients.

This randomized, double-blind, adaptive phase 2/3 trial aimed to evaluate the efficacy and safety of ivarmacitinib, a novel selective JAK1 inhibitor, in patients with active ankylosing spondylitis (AS). In phase 2, patients were randomized (1:1:1:1) to receive ivarmacitinib at a dose of 2, 4, or 8 mg or placebo once daily for 12 weeks. Based on interim analysis, ivarmacitinib 4 mg was selected as the recommended dose. In phase 3, patients were randomized (1:1) to receive ivarmacitinib 4 mg or placebo for 12 weeks; from week 12 onward, all patients received ivarmacitinib 4 mg once daily through week 24. The primary end point was the proportion of patients achieving a ≥20% improvement in the Assessment of SpondyloArthritis international Society (ASAS20) response criteria at week 12. During the entire study, 504 patients were randomized (ivarmacitinib 4 mg, n = 187; placebo, n = 186). At week 12, the ASAS20 response rate was significantly higher in the ivarmacitinib 4 mg group compared to the placebo group (48.7% vs 29.0%; one-sided P = 0.0001). The ASAS40 response rate (32.1% vs 18.3%) and all other secondary end points also favored ivarmacitinib 4 mg. Efficacy was sustained through 24 weeks. During the placebo-controlled period, treatment-emergent adverse events occurred in 79.7% of the ivarmacitinib group and 65.6% of the placebo group. Ivarmacitinib 4 mg significantly improved the signs and symptoms of AS at week 12 compared to placebo, with sustained efficacy through 24 weeks and a tolerable safety profile. These findings support ivarmacitinib 4 mg as a new treatment option for active AS.

Gout rarely affects the axial joints, and sacroiliac joint involvement is exceptionally uncommon.1 This report describes the case of a 30-year-old female with a family history of gout who had recurrent knee swelling and low back pain for 2 years, initially misdiagnosed with ankylosing spondylitis. Laboratory findings showed episodic hyperuricemia and elevated inflammatory markers, while MRI revealed bilateral sacroiliitis and bone island in the right sacroiliac joint. HLA-B27 was negative, and no family history of psoriasis or ankylosing spondylitis was noted. The atypical presentation of inflammatory low back pain, along with episodic joint redness, swelling, and pain, prompted further investigation. Dual-energy computed tomography confirmed urate crystal deposition in the sacroiliac joint and knees, accompanied by bone erosion, leading to a final diagnosis of primary sacroiliac joint gout. The patient's symptoms improved significantly after being treated with diclofenac and benzbromarone. This case emphasizes dual-energy computed tomography's diagnostic utility in differentiating gouty arthritis from inflammatory sacroiliitis, especially in patients with atypical presentations, family history of gout, or hyperuricemia. Although rare, axial joint gout should be considered a differential diagnosis for axial and large joint pain. Dual-energy computed tomography provides critical insights, allowing the accurate localization of urate deposits and preventing misdiagnosis or delayed treatment. This case highlights the need for increased clinical awareness and appropriate imaging for rare presentations of gout.

OBJECTIVE:This study aimed to investigate the clinical efficacy and pharmacoeconomics of tofacitinib versus adalimumab in treating patients with rheumatoid arthritis (RA). METHODS:Propensity score matching was used to obtain matched cohorts of 116 RA patients treated with tofacitinib or adalimumab. Clinical and laboratory indicators were compared before and after treatment between the two groups. A Markov model was used to assess cost-effectiveness, incorporating direct and indirect costs. Sensitivity analyses validated model stability, with a 6-month cycle simulating lifelong disease progression (27 years). RESULTS:Both the tofacitinib-treated group and the adalimumab-treated group showed significant improvements in terms of swollen and tender joint counts, duration of morning stiffness, VAS and HAQ scores, and ESR, CRP, and DAS28 levels (P < 0.05). Adalimumab treatment resulted in reductions in rheumatoid factor levels (P < 0.05). ACR20 (χ2 = 0.240, P = 0.624), ACR50 (χ2 = 0.321, P = 0.571), and ACR70 (χ2 = 0.222, P = 0.637) response rates did not differ significantly between groups. Adverse events included tuberculosis, leukopenia, mild liver dysfunction in the adalimumab group, and herpes zoster and mild liver dysfunction in the tofacitinib group, with gastrointestinal reactions observed in both groups (P > 0.05). Cost-effectiveness analysis indicated that tofacitinib was more cost-effective than adalimumab. Univariate sensitivity analysis identified ACR50 and ACR70 response rates as key influencing factors, while probabilistic sensitivity analysis showed a 99.38% probability of tofacitinib being cost-effective relative to adalimumab. CONCLUSION:Tofacitinib combined with methotrexate demonstrated comparable clinical efficacy and safety to adalimumab combined with methotrexate, with better cost-effectiveness, supporting its use as a favorable treatment strategy. Key Points • Our research indicates that tofacitinib exhibits a more favorable pharmacoeconomic profile for treating rheumatoid arthritis, characterized by reduced treatment costs and increased quality-adjusted life years. • Tofacitinib consistently demonstrated its cost-effectiveness superiority over adalimumab across various sensitivity analyses, exhibiting a 99.38% likelihood of being more cost-effective.

To explore the role of gut microbiota and plasma metabolites in the therapeutic mechanism of tofacitinib in ankylosing spondylitis (AS). Ten AS patients and ten matched healthy controls (HC) were enrolled in this study. 16S rRNA sequencing and LC–MS profiling was conducted to investigate the gut microbiota and plasma metabolite before and after tofacitinib therapy. An AS mouse model was established to validate the effect of tofacitinib in vivo via H E staining, western blot, and ELISA. Tofacitinib improved clinical symptoms in AS patients. Microbiota analysis revealed Microbiota analysis revealed reduced α-diversity (ACE, Chao1) and altered community structure in AS patients compared to HC, which partially normalized post-treatment. LEfSe identified 84 taxa biomarkers; Barnesiella, Coprobacter, Lachnospira, and Lactobacillus tended to return to normal after tofacitinib treatment. Plasma metabolomics uncovered 3 key metabolies, including choline metabolism, glycerophospholipid metabolism, and phenylalanine metabolism. Spearman analysis revealed that the gut microbiota were closely related to the changes in differential plasma metabolites. Combinated tofacitinib and trichostatin therapy attenuated inflammation, restored metabolism caused by AS in mice in vivo. AS patients suffer from dysbiosis of gut microbiota, and the mechanism of tofacitinib treatment of AS may be related to the modulation of gut microbiota and alteration of plasma metabolites.

OBJECTIVE:This randomized, double-blind, adaptive phase 2/3 trial aimed to evaluate the efficacy and safety of ivarmacitinib, a novel selective JAK1 inhibitor, in patients with active ankylosing spondylitis (AS). METHODS:In phase 2, patients were randomized (1:1:1:1) to receive ivarmacitinib at a dose of 2, 4, or 8 mg or placebo once daily for 12 weeks. Based on interim analysis, ivarmacitinib 4 mg was selected as the recommended dose. In phase 3, patients were randomized (1:1) to receive ivarmacitinib 4 mg or placebo for 12 weeks; from week 12 onward, all patients received ivarmacitinib 4 mg once daily through week 24. The primary end point was the proportion of patients achieving a ≥20% improvement in the Assessment of SpondyloArthritis international Society (ASAS20) response criteria at week 12. RESULTS:During the entire study, 504 patients were randomized (ivarmacitinib 4 mg, n = 187; placebo, n = 186). At week 12, the ASAS20 response rate was significantly higher in the ivarmacitinib 4 mg group compared to the placebo group (48.7% vs 29.0%; one-sided P = 0.0001). The ASAS40 response rate (32.1% vs 18.3%) and all other secondary end points also favored ivarmacitinib 4 mg. Efficacy was sustained through 24 weeks. During the placebo-controlled period, treatment-emergent adverse events occurred in 79.7% of the ivarmacitinib group and 65.6% of the placebo group. CONCLUSION:Ivarmacitinib 4 mg significantly improved the signs and symptoms of AS at week 12 compared to placebo, with sustained efficacy through 24 weeks and a tolerable safety profile. These findings support ivarmacitinib 4 mg as a new treatment option for active AS.

Our study identifies several novel circRNAs with high diagnostic utility for RA, highlighting their potential as promising biomarkers and therapeutic targets.

Objective To assess the efficacy/safety of ivarmacitinib, a selective Janus kinase (JAK) 1 inhibitor, in patients with moderate-to-severe active rheumatoid arthritis (RA) who had an inadequate response to conventional synthetic disease-modifying antirheumatic drugs (csDMARDs). Methods Patients were randomised (1:1:1) to receive either placebo (n=188), ivarmacitinib 4 mg (n=189) or ivarmacitinib 8 mg (n=189) once daily, with background csDMARDs allowed. After 24 weeks, patients on placebo switched to ivarmacitinib 4 mg for an additional 28 weeks, while those on ivarmacitinib continued their initial dosage. The primary endpoint was the proportion of patients achieving a 20% improvement in the American College of Rheumatology response criteria (ACR20) at week 24. Results At week 24, ACR20 response rates were significantly higher in the ivarmacitinib 4 mg (70.4%) and 8 mg (75.1%) groups compared with the placebo group (40.4%; both p<0.0001). Both ivarmacitinib doses achieved numerically higher Disease Activity Score 28-joint count C reactive protein of <2.6/≤3.2 response rates compared with placebo. Improvements in efficacy and patient-reported outcomes were sustained through 52 weeks and were noted in patients who switched from placebo after week 24. During the placebo-controlled period, treatment-emergent adverse events (TEAEs) occurred in 81.5% and 90.5% of patients in the ivarmacitinib 4 mg and 8 mg groups, versus 79.3% in the placebo group. Infection-related TEAEs were slightly higher in the ivarmacitinib groups. Conclusions Ivarmacitinib may offer a potential therapeutic option for patients with RA who have an inadequate response to csDMARDs, with a safety profile that was generally manageable over 1 year of treatment and similar to other JAK inhibitors. Trial registration number NCT04333771.

OBJECTIVES:To investigate the correlation between fat-to-muscle ratio (FMR) or other body composition and secondary osteoporosis (OP) in patients with rheumatoid arthritis (RA) and to develop a predictive model using FMR and related clinical factors. DESIGN:Cross-sectional observational study with machine learning-based risk modelling. SETTING:Tertiary hospital in eastern China, secondary care level. PARTICIPANTS:A total of 670 hospitalised RA patients (135 males and 535 females; aged 58.00 (50.00-67.00) years; disease duration 8.00 (2.00-16.00) years) and 126 healthy controls were recruited between October 2019 and October 2022. There were no differences in basic indicators such as gender, age distribution and body mass index between the two groups. RA diagnosis followed American College of Rheumatology (ACR) 1987 or ACR/European League Against Rheumatism 2010 criteria. Exclusion criteria included major organ dysfunction, endocrine disease, infection or long-term hormone or psychotropic drug use. PRIMARY AND SECONDARY OUTCOME MEASURES:Primary outcomes included total skeletal muscle mass, fat mass, FMR measured by bioelectrical impedance analysis and bone mineral density measured by dual-energy X-ray absorptiometry. Secondary outcomes included RA disease activity scores (clinical disease activity index (CDAI), simplified disease activity index, disease activity score in 28 joints (DAS28)) and glucocorticoid use. Logistic regression and four additional machine learning algorithms were used to build predictive models for OP. RESULTS:The RA group (age, 58.00; duration, 8.00; DAS28, 5.03; rheumatoid factor, 104.75; C-reactive protein, 25.65; erythrocyte sedimentation rate (ESR), 59.00) exhibited reduced total skeletal muscle mass (19.49 vs 25.38, p<0.001), hip bone mineral density (0.90 vs 1.15, p<0.001) and L1-4 bone mineral density (0.86 vs 1.08, p<0.001), alongside increased total fat mass (18.33 vs 16.37, p=0.020) and FMR (0.98 vs 0.68, p<0.001). Total fat mass was positively correlated with simplified and CDAI (p<0.001). Total skeletal muscle mass was negatively correlated with ESR (p=0.001) and positively correlated with both L1-4 and hip bone mineral density (p<0.001). FMR showed a positive correlation with clinical disease activity index (p<0.001). There were significant differences in total fat mass and FMR among RA patients with varying disease activity levels (p<0.001). RA patients with concomitant OP or using glucocorticoids had a higher total fat mass and FMR than their respective control groups, with only total skeletal muscle mass levels being lower (p<0.01). We developed predictive models using multiple machine learning algorithms, which identified that both age and FMR were key factors associated with secondary OP in RA patients. Subgroup analysis identified an interaction effect between FMR and gender and restricted cubic spline fitted the dose-response relationship between FMR and OP. CONCLUSION:FMR may serve as a useful clinical indicator of secondary OP in RA patients. A model based on FMR and associated risk factors can predict the possibility of secondary OP.