Arthritis Research & Therapy最新文献

Objectives: Citrullination is a post-translational modification that serves as an autoantigen in Rheumatoid Arthritis (RA). It remains unclear whether there is an excess production of specific citrullinated proteins in RA patients that is driving the autoantibody response. The aim of this study was to undertake an unsupervised proteomic analysis of the circulating RA citrullinome, and determine the consequences of citrullination in RA.

Methods: Citrullinated serum proteins were isolated and measured by mass spectrometry from 10 anti-citrullinated protein antibody (ACPA) positive RA patients and 10 controls. Cit-proteins and cit-immune complexes (IC) were measured in a larger cohort of unaffected first-degree relatives (FDR, ACPA- n = 31, ACPA+ n = 26) and RA (n = 31). Autoantibodies to citrullinated C9, and linear peptides of citrullinated C9 were measured. Structural changes imparted by citrullination were studied in-silico using Alphafold 3.0.

Results: Differential analysis of the RA citrullinome revealed a higher expression of complement proteins. Validation studies revealed that the levels of cit-C9 (p = 0.02) and cit-CFI (Complement Factor I, p = 0.019) were higher in RA than controls. Cit-C9 IgG, but not cit-CFI, immune complexes were elevated in ACPA+ FDR (p < 0.0001) and RA (p < 0.0001) compared to ACPA- FDR. Autoantibodies to cit-C9 were also higher in ACPA+ FDR (p = 0.01) and RA (p = 0.002). Reactivity to linear peptides of cit/homocit C9 were enriched in RA patients compared to controls. In-silico modelling revealed structural changes to the monomeric and multimeric structure of cit-C9.

Conclusion: This analysis of the circulating citrullinome in RA reveals the generation of citrullinated complement proteins that serve as autoantigens.

Background: To evaluate synovial fluid biomarkers of cartilage degradation, inflammation, and pain in participants with knee osteoarthritis pain treated with subcutaneous injectable pentosan polysulfate sodium (iPPS).

Methods: In an exploratory phase 2, double-blind trial, 61 participants were randomized 1:1:1 to twice-weekly iPPS, once-weekly iPPS, or placebo for 39 days, with a 365-day follow-up. The primary endpoint was change from baseline in synovial fluid biomarkers at Day 56. Secondary endpoints included serum and urinary biomarker analysis at Days 56 and 168, and synovial fluid biomarkers at Day 168. Further secondary endpoints evaluated clinical responses through to Day 365. Adverse events were assessed for safety.

Results: Subcutaneous iPPS treatment was associated with altered synovial fluid biomarkers at Day 56. In iPPS-treated versus placebo-treated participants at Day 56, the adjusted change from baseline least squares mean difference of cartilage metabolism markers COMP and ARGS decreased -23.60% (-62.60, 15.40) and -56.60% (-106.59, -6.62; p = 0.028), respectively. Endogenous inhibitor of cartilage degradation, TIMP-1, increased 10.55% (-35.35, 56.45) in iPPS versus placebo. Inflammation biomarker TNF-α decreased - 110.15% (-270.57, 50.27) and pain modulator βNGF decreased - 36.05% (-97.86, 25.77). Serum biomarkers COMP and C2C decreased -10.64% (-21.82, 0.55) and -7.30% (-17.48, 2.88) respectively, and serum CTX-I increased 35.74% (5.46, 66.01; p = 0.022). Synovial fluid ARGS remained significantly decreased at Day 168 -74.01% (-137.57, -10.45; p = 0.024), and serum CTX-I remained significantly increased 65.52% (8.73, 122.31; p = 0.025) at Day 168. At Day 168, synovial and serum COMP remained decreased - 24.40% (-68.99, 20.20) and - 10.85% (-26.03, 4.33), respectively; and serum ARGS decreased - 7.79% (-16.22, 0.63). Serum C2C further decreased - 29.25% (-54.45, -4.04; p = 0.024), and serum CTX-I further increased 65.52% (8.73, 122.31; p = 0.025) versus placebo, suggesting ongoing iPPS effects on osteoarthritis biomarkers. Urinary CTX-II decreased at both timepoints - 53.27% (-157.40, 50.86) and - 8.03% (-38.00, 21.94) respectively. iPPS was well tolerated with no serious related AEs or AEs of special interest.

Conclusion: This study provides insight into local and systemic activity of subcutaneous iPPS via anti-inflammatory, pain, and cartilage degradation pathways. Changes in synovial fluid ARGS, serum CTX-I, and serum C2C suggest potential mechanisms for iPPS in knee osteoarthritis.

Trial registration: Prospectively registered on the Australian New Zealand Clinical Trials Registry at anzctr.org.au (ACTRN12621000136808) on February 10, 2021.

Background: Although the quality of care related to rheumatoid arthritis (RA) has improved, ensuring high-quality care globally remains a significant challenge. To address this issue, we have introduced a modified Quality of Care Index (QCI) to evaluate variations in RA care services worldwide and analyze the influencing factors.

Methods: The QCI was derived from a principal component analysis of global incidence, mortality, and prognostic indicators of RA. Joinpoint regression and linear mixed models were employed to analyze the temporal trends of the QCI and its influencing factors.

Result: In 2021, the global QCI for RA was 72.09. Among this, the QCI for males was 77.25, while for females it was 71.12. Based on Joinpoint regression, the AAPC of the global RA QCI from 1990 to 2021 was 0.30(0.29-0.31), with 0.22(0.20-0.23) for males and 0.29(0.28-0.30) for females. Based on the LMM model, it was found that age, gender, year, and SDI were all statistically significantly associated with QCI (p < 0.05). Specifically, positive correlations with QCI were observed in the following groups: under 14 years, 20-24 years, 40-54 years, 70-74 years, males, and high-SDI regions. Conversely, negative correlations with QCI were identified in the age groups 15-19 years, 25-39 years, 55-69 years, and 75 years and above.

Conclusion: Disparities in RA-related care exist across gender, age, and geographic regions. Further emphasis should be placed on improving care for female RA patients and those in low-SDI regions.

Background: Rheumatoid arthritis (RA) and gout are traditionally considered distinct diseases with differing pathogenic mechanisms, making their coexistence controversial. Emerging evidence suggests this overlap may be underestimated. This study aimed to evaluate their epidemiological association, genetic causality, and intersecting molecular features.

Methods: Epidemiological analyses used National Health and Nutrition Examination Survey (NHANES; 2007 ~ 2018, n = 19,705) data. Propensity score matching and weighted multivariate logistic regression assessed gout prevalence, temporal trends, and risk factors in RA. Restricted cubic spline (RCS) analysis examined nonlinear serum urate (SUA)-gout associations within RA. Mendelian randomization (MR) analyses based on genome-wide association study (GWAS) data evaluated causal effects of overall RA, Seronegative RA (SNRA), and Seropositive RA (SPRA) on gout and SUA, with multiple testing controlled by Bonferroni correction. Transcriptomic analyses from the Gene Expression Omnibus (GEO) used differential expression and weighted gene co-expression network analysis (WGCNA). Results were integrated with disease-related genes from the Comparative Toxicogenomics Database (CTD), Online Mendelian Inheritance in Man (OMIM), and GeneCards databases for enrichment and pathway analyses.

Results: NHANES data indicated higher gout prevalence among RA patients compared to matched controls (10.3% vs. 4.8%, P < 0.001), with an increasing trend over time (P = 0.006). Weighted logistic regression supported RA as an independent risk factor for gout (OR: 2.67; 95% CI: 1.95 to 3.67; P < 0.001). RCS analysis revealed a nonlinear SUA-gout association in RA (P < 0.05). MR supported a causal effect of RA on gout, strongest for SNRA (OR = 1.132; 95% CI: 1.044 to 1.227; P = 0.003) after Bonferroni correction, whereas no effect was found for SPRA on gout or for RA, SNRA, and SPRA on SUA. Bioinformatics analysis identified 207 shared RA-gout genes enriched in interferon signaling, immune activation, and antiviral defense pathways, highlighting five hub genes (RSAD2, DDX60, IFIT1, IFIT3, XAF1) central to a convergent interferon-driven mechanism.

Conclusions: RA and gout may overlap more than previously recognized, with stronger genetic evidence in SNRA. No causal effect on SUA suggests the link may not primarily involve urate pathways. Transcriptomic overlap in interferon signaling indicates potential molecular intersections, warranting further investigation.