OBJECTIVE:To investigate whether residual activated T helper 17 (Th17) cells during inactive disease or low disease activity (LDA) in radiographic axial spondyloarthritis (r-axSpA) are associated with subsequent disease instability. METHODS:Patients with r-axSpA in inactive disease or LDA (Axial Spondyloarthritis Disease Activity Score [ASDAS]<2.1) were included. Peripheral blood mononuclear cells obtained at baseline were analyzed using multicolor flow cytometry. Activated Th17 cells were defined as CD3+CD4+CXCR3-CCR6+CD38+HLA-DR+ cells. Patients were categorized into activated Th17-high and activated Th17-low groups according to the receiver operating characteristics-derived cut-off value of activated Th17 cells among CD4+ T cells. ASDAS was assessed at baseline, 3 months, and 6 months. ASDAS trajectories were analyzed using linear mixed-effects models, and the proportion of patients experiencing loss of LDA (ASDAS≥2.1) was compared between groups. RESULTS:Twenty-one patients with r-axSpA were included (activated Th17-high, n=9; activated Th17-low, n=12). The activated Th17-high group showed a significantly worse ASDAS trajectory during follow-up than the activated Th17-low group (P for interaction<0.05). Loss of LDA occurred in 4 patients (44.4%) in the activated Th17-high group and in none in the activated Th17-low group (P<0.05). Baseline disease activity status (inactive disease [ASDAS<1.3] vs. LDA [1.3≤ASDAS<2.1]) was not associated with differences in ASDAS trajectories (P for interaction=non-significant) or loss of LDA (P=non-significant). CONCLUSION:Residual activated Th17 cells during inactive disease or LDA are associated with subsequent disease worsening in r-axSpA. Cellular immune profiling may help identify patients at risk of disease instability despite apparent clinical control.
OBJECTIVE:Recent guidelines suggest risk-stratified screening for rheumatoid arthritis-associated interstitial lung disease (RA-ILD). However, the diagnostic gap between current routine care and this screening approach remains unquantified. We assessed currently detected RA-ILD in Norway, benchmarking findings against recent screening-based estimates of the true disease burden. METHODS:This 10-year quality assurance audit across six centers covered 43% of the Norwegian population. RA-ILD cases identified via ICD-10 codes were confirmed by manual chart review. Prevalence was calculated relative to a registry-derived total RA background population and benchmarked against a 10% expected target derived from recent prospective studies. Mortality was compared to a 3:1 frequency-matched RA control group using Cox proportional hazards regression. RESULTS:Among 17,305 RA patients, 188 (1.1%) had verified ILD; when benchmarked against an expected 10% prevalence, this indicates an 89% diagnostic gap in routine clinical care. Mean age at ILD detection was 67.5 years. Most cases (93.6%) possessed ≥2 established risk factors for RA-ILD: 93.6% were seropositive, 76.1% had smoking histories, while RA onset age ≥60 and persistently increased inflammatory laboratory markers were present in over half of patients. RA-ILD was associated with significantly increased mortality; 66 (4.1/100 person-years) deaths occurred in the RA-ILD group vs. 120 (2.3/100 person-years) among RA controls (HR 1.77; 95% CI: 1.31-2.39, p<0.001). CONCLUSION:When comparing to prevalence expectations, current routine care may leave a substantial proportion of cases undetected, primarily capturing a high-risk phenotype with excess mortality. Systematic, risk-stratified screening is needed to bridge this diagnostic gap, aiming to enable earlier intervention.
OBJECTIVES:The associations between ambient air pollution mixtures, related metabolic and proteomic signatures, and arthritis subtypes, including rheumatoid arthritis (RA), osteoarthritis (OA), gout, and psoriatic arthritis (PsA), remain unclear. METHODS:This prospective cohort study included 401,676 UK Biobank participants free of arthritis at baseline. Air pollution mixture exposure was quantified using Weighted Quantile Sum (WQS) regression. Metabolic and proteomic signatures were derived using multivariable linear and elastic net regression. Associations with incident arthritis were evaluated using Cox proportional hazards models and generalized propensity score approaches. Causal mediation analysis was performed to assess mediating effects. RESULTS:Over a median follow-up of 13 years, 78,188 any type of arthritis cases were identified. The primary contributors to the WQS mixture index were NOx and NO₂ for RA, PM2.5 for OA, NOx and PM2.5 for gout, and PM2.5 and PM10 for PsA. Higher WQS index scores and their associated metabolic and proteomic signatures were associated with increased risks of arthritis subtypes. These signatures mediated the associations between air pollution mixtures and arthritis risk, with mediation proportions ranging from 4.92% to 35.05%. Top 10 mediating metabolites and proteins showed partial overlap, alongside disease-specific profiles across arthritis subtypes. CONCLUSION:Air pollution mixtures were associated with increased risks of arthritis subtypes, potentially through both shared and disease-specific metabolic and proteomic pathways, highlighting the importance of considering pollutant mixtures and disease heterogeneity in arthritis research and prevention.
Objectives: To evaluate the proportion of patients with giant cell arteritis (GCA)-related large-vessel involvement (LVI) with a complete metabolic remission on PET/CT after treatment with glucocorticoids (GC) only.Methods: This retrospective multicenter cohort enrolled GCA patients with LVI diagnosed on PET/CT. Each patient underwent at least a second PET/CT >3 months after the first procedure and was treated only with GC. Our primary endpoint was the proportion of patients with complete metabolic remission on the second PET/CT.Results: Among the 75 enrolled patients, 32 (43%) showed a complete metabolic remission at last follow-up. The second PET/CT was performed 8 [5-11] months after the initial PET/CT. Among the 32 patients, 16 were weaned off GC with a follow-up >12 months after the negative PET/CT. Among the 43 patients without metabolic remission, 19 showed stable or increased vascular uptake at follow-up, and 24 had persistent PET/CT positivity with fewer involved vascular territories. At last follow-up (median: 51 [27-93] months), 66 and 56% of patients with and without metabolic remission, respectively, had discontinued GC. Two patients showed LVI relapse on a third PET/CT. Of the 34 patients with available data regarding aorta morphology during follow-up, 8 developed an aortic dilation, and all of them had persistent positive PET/CT (log-rank: p < 0.05).Conclusion: A complete metabolic remission on PET/CT was observed in 43% of GCA patients with LVI treated with GC alone. Aortic dilation exclusively occurred in patients with persistent positive PET/CT.
Objective: To assess temporal changes in the direct and indirect economic burden of spondyloarthritis (SpA), including psoriatic arthritis (PsA), in France between 2015 and 2023 using nationwide healthcare data.Methods: We conducted a retrospective population-based study using the French National Health Data System (SNDS). Patients with SpA/PsA were identified through validated administrative algorithms based on ICD-10 codes, long-term disease status, and hospitalization records. Direct medical costs included all reimbursed expenditures related to hospitalizations and outpatient care. Indirect costs were estimated using reimbursed daily allowances for sick leave and work-related injuries, disability benefits, and annuities. Costs were aggregated annually and changes analyzed over time.Results: In 2023, 270,290 individuals with SpA/PsA were identified, accounting for euro1.19 billion in total reimbursed expenditures (euro4,418 per patient). Outpatient care represented the largest share (66.1%), largely driven by medications (euro633.6 million), while hospital-based care accounted for 12.9%. Indirect costs reached euro250.6 million (21.0%). Between 2015 and 2023, the number of patients increased by 45.1%, and total expenditures rose by 52.2%. Medication costs showed the most pronounced growth (+60.7%), alongside a marked increase in outpatient care (+61.3%), reflecting a shift toward ambulatory management. In contrast, the relative contribution of hospital-based care declined, with a substantial decrease in high-cost inpatient drug expenditures. Indirect costs increased by 78.5%, despite stable proportions of beneficiaries receiving sick leave (16.4% to 16.8%) and disability benefits (9.6% to 10.6%), suggesting increased duration or severity of work impairment.Conclusion: Despite major therapeutic advances, the economic burden of SpA in France increased substantially between 2015 and 2023, driven by rising outpatient, medication-related, and indirect costs. These findings highlight the persistent societal impact of SpA and underscore the importance of integrating both healthcare utilization and work-related outcomes when informing healthcare policies and evaluating long-term disease burden.
Exposure to heavy metals is regarded as a potential contributor to the development of hyperuricemia (HU). However, related research findings are inconsistent. This systematic review and meta-analysis aimed to explore the association between blood concentrations of heavy metals (such as lead, cadmium, manganese, mercury) and HU. PubMed, EMBASE, Web of Science, and Cochrane Library databases were searched to collect related studies up to June 2024. The pooled odds ratio (OR) and 95% confidence interval (CI) were calculated utilizing a random-effects model or a fixed-effects model. Sensitivity analysis was conducted, while publication bias was assessed using funnel plots and Egger's test. A total of 19 eligible studies were included. The meta-analysis indicated a significant association between blood lead levels and the risk of HU (OR: 1.88; 95% CI: 1.22-2.92; P<0.005). Blood levels of cadmium (OR: 1.31; 95% CI: 0.68-2.52; non-significant), manganese (OR: 1.04; 95% CI: 0.88-1.22; non-significant), and mercury (OR: 1.55; 95% CI: 0.70-3.44; non-significant) were not significantly associated with the risk of HU. In conclusion, this study demonstrates a significant positive association between blood lead levels and the risk of HU. No significant association is found between blood levels of cadmium, manganese, and mercury and the risk of HU.
OBJECTIVES:In patients with psoriatic arthritis, articular responses vary by joint location with both tumour necrosis factor inhibitors (TNFi). It remains unknown whether this also applies to patients with axial spondyloarthritis (axSpA). METHODS:We included patients with axSpA from the European spondyloarthritis research collaboration network (EuroSpA RCN) who initiated a TNFi between 2001-2022. Joint tenderness was used as a proxy for peripheral articular involvement. Among patients with at least one tender joint at treatment start (baseline) based on a 26-joint count (28-joint count excluding the shoulders), resolution of joint tenderness during a two-year follow-up was assessed with a mixed-effects model for interval-censored data, including random effects for country and patient. RESULTS:A total of 1113 patients (43.4% male, mean (SD) age 44.7 (11.7) years) with 5886 tender joints (median (IQR) 3 (2,7) tender joint count) from eight European countries initiating treatment with a TNFi (n=1113) were included. The knee and wrist were most commonly affected at baseline. Compared with the wrist, the rate of joint tenderness resolution was similar in the elbow (HR=1.06, 95%CI 0.88 to 1.28), lower in the knee (HR=0.76, 95%CI 0.64 to 0.90), while higher in all finger joints, particularly in the first interphalangeal joint (HR=2.64, 95%CI 2.05 to 3.40) and in digits four and five (metacarpophalangeal joint (MCP)4 HR=2.19, 95%CI 1.77 to 2.71) and MCP5 (HR=3.16, 95%CI 2.50 to 4.00). CONCLUSION:The peripheral joint response to TNFi in axSpA appears to be location-dependent, indicating that the joint site should be considered when interpreting treatment response.
OBJECTIVES:To assess whether symptom duration modifies flare risk after biologic/targeted synthetic DMARD (b/ts DMARDs) withdrawal in axial spondyloarthritis (axSpA) following remission/inactive disease. METHODS:We systematically identified randomized placebo-controlled trials evaluating withdrawal or tapering of b/tsDMARDs in axSpA through a previous systematic literature review. Eligible studies included adults with axSpA who achieved inactive disease or remission by ASDAS and were randomized to continuation or withdrawal/tapering, with available flare data. Patient-level data were obtained from Vivli and stratified by symptom duration thresholds of≤2, 3, 4, or 5years. Relative risks (RRs) of flare for continuation versus withdrawal were calculated within each subgroup, and relative risk ratios (RRRs) were estimated. Random-effects meta-analysis was performed. A subgroup analysis included only patients with nr-axSpA. RESULTS:Three RCTs involving 773 patients were included, evaluating adalimumab, certolizumab pegol, and ixekizumab versus placebo; no tsDMARD or tapering studies were eligible. Continuation of bDMARDs was consistently associated with fewer flares than withdrawal. Symptom duration did not significantly modify flare risk overall. In the overall axSpA population, pooled RRRs showed no statistically significant effect modification: 0.61 (95% CI: 0.29-1.28) for≤2years, 0.77 (0.54-1.12) for≤3years, 0.83 (0.45-1.54) for≤4years and 0.82 (0.49-1.37) for≤5years. In nr-axSpA (n=508), pooled RRRs favoured shorter symptom duration at≤4years (0.25 [0.07-0.96]) but not at≤2,≤3 or≤5years. CONCLUSION:Symptom duration did not consistently modify flare risk after bDMARD withdrawal in axSpA overall, although exploratory findings suggest a potential effect in early nr-axSpA.
OBJECTIVES:Interleukin (IL)-33 has been shown to be abnormally expressed in patients diagnosed with ankylosing spondylitis (AS). However, the source of IL-33 and the mechanism(s) through which IL-33 affects bone metabolism in AS remains unclear. METHODS:Serum IL-33 levels were measured in patients diagnosed with AS and healthy controls (HCs). Primary human enthesis cells were isolated from surgically harvested human enthesis tissues to evaluate IL-33 expression under tumor necrosis factor (TNF) and IL-17A stimulation using bulk RNA sequencing and Western blotting. The therapeutic potential of IL-33 in curdlan-treated SKG mice to mimic AS was assessed using anti-IL-33 neutralizing antibodies. The effects of IL-33 on bone remodeling were further explored using osteoblast and osteoclast differentiation assays. RESULTS:Serum IL-33 levels were significantly elevated in patients with AS with a high inflammatory burden and were positively correlated with TNF, IL-17A, and radiographic progression. In AS enthesis tissues and primary cells, IL-33 expression was markedly higher than that in HCs. Notably, synergistic stimulation by TNF and IL-17A significantly upregulated IL-33 at both the transcriptomic and protein levels, particularly in ASenthesis cells. In vivo, anti-IL-33 treatment significantly attenuated clinical arthritis severity, enthesitis scores, and enthesophyte formation in a mouse model of AS. Mechanistically, IL-33 significantly inhibited osteoclastogenesis by suppressing the p38 MAPK-NFATc1 signaling pathway in osteoclast precursors. CONCLUSION:These findings demonstrate that IL-33 is a key mediator that links systemic inflammation to local enthesopathy and pathological bone formation in patients with AS. Accordingly, the IL-33/p38/NFATc1 axis may offer a crucial mechanistic link between osteoclasts and osteoblasts for understanding the pathological bone remodeling characteristics of AS.
