Arthritis & Rheumatology最新文献

Objective: The cystathionine γ-lyase (CSE)/H₂S axis has emerged as a key regulator in tissue fibrogenesis. This study aimed to explore the role of the CSE/H₂S axis in systemic sclerosis (SSc) and to investigate its underlying mechanisms to identify promising therapeutic targets.

Methods: CSE/H₂S levels were assessed in serum samples from 25 patients with SSc and 28 healthy controls. Human dermal fibroblasts from SSc patients and healthy controls were used for functional studies, including PAG (CSE inhibitor) treatment, Gyy4137 (H₂S agent), CSE silencing, and CSE overexpression, combined with LC-MS/MS-based S-sulfhydration proteomics. Molecular dynamics simulations were performed to study the effects of S-sulfhydration on protein structure, and a Smad3 C121S (Cys121 mutated to Ser) mutant was generated to verify the function targets of S-Sulfhydration. In vivo, bleomycin-induced mouse models of skin and lung fibrosis were constructed to evaluate the effects of CSE overexpression.

Results: In human samples, CSE/H₂S levels were reduced in SSc. CSE inhibition promoted extracellular matrix deposition. S-sulfhydration proteomics showed that S-sulfhydration levels were globally reduced in SSc compared to controls. CSE overexpression increased S-sulfhydration on Smad3, suppressed TGF-β1/Smad3 signaling, mitigating skin fibrosis. Notably, cysteine 121 on Smad3, identified as a pivotal target for S-sulfhydration by proteomics, was shown to fine-tune its MH1 domain, with its mutation impairing the antifibrotic effects. In mice, CSE overexpression attenuated bleomycin-induced skin and lung fibrosis.

Conclusion: Smad3 S-sulfhydration mediates the antifibrotic effect of CSE in SSc, highlighting it as a critical mechanism and promising therapeutic target.

Objective: To assess the association between early antimalarial adherence and future acute care utilization and cost in a population-based cohort of incident rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE).

Methods: All patients with incident RA/SLE and new antimalarial use in British Columbia, Canada, between 01/1997 and 03/2022 with at least one year follow-up period were identified using provincial administrative databases. Each antimalarial adherent (proportion of days covered, PDC≥0.90) was propensity score (PS)-matched up to two antimalarial non-adherents (0

Results: We identified 8,768 antimalarial adherent and 16,479 antimalarial non-adherent PS-matched RA/SLE individuals. The adjusted rate ratios (RRs) of hospital admissions and hospitalized days obtained for antimalarial adherent vs. non-adherent patients were 0.89 (95% CI: 0.84-0.94) and 0.79 (95% CI: 0.71-0.88), respectively. The adjusted average hospitalization costs were lower (Est: -$549.6 CAD, 95% CI: -896.1, -203.2, p-value: <0.01) for antimalarial adherent patients than non-adherent patients. Falsification tests and sensitivity analyses confirmed the robustness of the results.

Conclusion: Adherence to antimalarial in RA and SLE patients was associated with a lower risk of hospital admission (11% reduction) and hospitalized days (21% reduction) and lower hospitalization costs ($549.6 CAD lower) compared to patients with non-adherence.

Objective: Evaluate performance of the Predicting Risk of Cardiovascular Disease EVENTs (PREVENT) calculator in rheumatoid arthritis (RA).

Methods: Patients with RA were matched up to 10 controls on age, sex, and enrollment year using national Veterans Health Administration (VHA), Medicare, and National Death Index data (2006-2020). Ten-year estimated cardiovascular disease (CVD) risk was calculated using PREVENT. Calibration (standardized incidence ratio [SIR]; observed:predicted events) and discrimination (sensitivity, Harrel's C-statistics) were compared between RA cases and controls. PREVENT performance was compared with the Pooled Cohorts Equations (PCE) for atherosclerotic CVD (ASCVD) prediction in RA, including net reclassification index (NRI) calculation.

Results: Among 30,687 RA and 231,752 non-RA patients, 28,061 ASCVD and 13,851 heart failure (HF) outcomes were identified over >2 million person-years. PREVENT underestimated overall CVD (SIR 1.83 [1.79-1.88]), ASCVD (SIR 2.25 [2.19-2.32]) and HF risk (SIR 1.41 [1.36-1.46]) to a greater degree in RA compared to controls and exhibited poor sensitivity for ASCVD (61.9%) and HF (63.2%) development. PREVENT performance was poorer for ASCVD prediction compared to the PCE (SIR 1.38 [1.34-1.41]; sensitivity 76.0%). NRI for PREVENT was modest (5.3%). Among 657 reclassified patients who experienced ASCVD, 626 were inappropriately reclassified as low/borderline risk. PREVENT performance significantly improved when including hemoglobin A1c (SIR Overall CVD 1.21 [1.18-1.24], ASCVD 1.45 [1.41-1.50], HF 0.79 [0.76-0.82]; sensitivity ASCVD 80.3%).

Conclusion: PREVENT underestimates CVD risk in RA, consistent with suboptimal performance of existing risk calculators. Preferential use of PREVENT including hemoglobin A1c should be considered. Improving CVD risk stratification in RA remains a high priority.

Objective: To identify serum protein signatures associated with progression to rheumatoid arthritis (RA) and response to abatacept in at-risk individuals.

Methods: A total of 440 serum samples from 118 APIPPRA study participants were selected from baseline to RA onset for 46 RA progressors or to study end for 72 participants who did not develop RA. Samples were analysed using the SomaScan® 7k assay platform. Differential expression analysis was assessed by progression to RA (three pre-RA time intervals to RA, RA progressors versus non-progressors, baseline to RA), and by treatment allocation (abatacept versus placebo). Risk and response signatures were identified in the full 7k panel and two pre-specified subpanels defined as Inflammatory Mediators and Adaptive Immune Cell panel.

Results: We observed significant changes in 80 proteins (68 downregulated and 12 upregulated) occurring between RA onset and 6-24 months before developing disease. Progression to RA was associated with increased levels of acute phase reactants SAA1 and SAA2 and reductions in CTLA4, when compared to non-progressors at the end of treatment. Two upregulated proteins (CTLA4 and CD86), and seven downregulated proteins (CXCL13, FCRL4, FCER2, CCL21, LTA|LTB, FDCSP and IL22RA2) were observed in participants receiving abatacept compared to placebo regardless of RA outcome.

Conclusion: Protein signatures dominated by acute phase proteins define progression to RA, while changes associated with abatacept therapy highlight potential mechanisms of treatment response. Such signatures provide a better understanding of the immune landscape of the at-risk phase opening up the possibility of new treatment modalities for RA prevention.

Background: Eosinophilic granulomatosis with polyangiitis (EGPA) is a small vessel vasculitis characterized by eosinophilia, asthma, and ear, nose, throat (ENT) involvement. Although glucocorticoids (GCs) are effective in controlling symptoms, relapses and GC dependence are common. The aim of this study was to develop predictive models for vasculitis relapse and GC-dependent asthma and/or ENT symptoms.

Methods: This multicenter European retrospective cohort study included EGPA patients fulfilling the 2022 ACR/EULAR criteria. Using the PMSAMPSIZE algorithm, we developed two multivariable prediction models: one for vasculitis relapse and another for GC-dependent asthma and/or ENT symptoms at 2 years. Internal validation was performed using bootstrapping.

Results: A total of 809 patients were followed for a median of 72 months (interquartile range, IQR 37-115). Vasculitis relapse occurred in 228 patients with a 12-year cumulative incidence of 41.2% (95% CI 36.3-46.8). GC-dependent asthma and/or ENT symptoms were observed in 66.4% at 2 years. Predictors of vasculitis relapse included age (nonlinear), GC-dependent asthma before EGPA diagnosis (hazard ratio, HR 1.57), arthralgia (HR 1.27), myocarditis (HR 1.74), peripheral neuropathy (HR 1.39), MPO-ANCA (HR 1.56), and baseline eosinophil count (nonlinear). Predictors of GC-dependent asthma and/or ENT symptoms included older age (odds ratio, OR 0.98 per year), GC-dependent asthma at diagnosis (OR 1.50), chronic sinusitis (OR 1.78), and baseline eosinophil count (OR 0.70 per 10⁹/L).

Conclusion: Using a large EGPA cohort, we developed predictive models for vasculitis relapse and GC-dependent asthma and/or ENT symptoms. These tools may help guide treatment decisions. Prospective external validation in the current therapeutic era is warranted.

Background: Interstitial Lung Disease (ILD) can occur in association with ANCA-associated Vasculitis (AAV-ILD) or as an isolated entity with positive ANCA (ANCA-ILD). However, data on the epidemiology and outcomes of these conditions remain limited.

Methods: A European multicentre retrospective study encompassed patients with AAV-ILD or ANCA-ILD. Baseline and subsequent chest CT studies were centrally reviewed. Primary outcomes included forced vital capacity (FVC) decline, respiratory failure, and mortality.

Results: 162 patients (MPO-ANCA 85%); 123 (76%) had AAV-ILD and 39 (24%) ANCA-ILD. At baseline, Usual Interstitial Pneumonia (UIP) was the most frequent radiologic pattern (57%), while half had a radiological fibrosis grade >10%. Kidney involvement was present in 73%, most commonly Berden focal class. UIP and Non-specific interstitial pneumonia (NSIP) patterns showed greater annual FVC decline than other patterns (UIP: -1.99%, NSIP: -3.76%, [p=0.35] others: +0.36%). An adjusted mixed-effects model indicated that rituximab was associated with mean FVC % improvement at 12 months (+6.02%; p=0.07). Radiologic progression occurred in ~50%, mainly in younger patients with higher fibrosis severity grade. Respiratory failure (19%) was associated with fibrosis severity (grade 4: HR 4.7; p=0.029) and baseline FVC% (HR 0.95; p=0.002). Over a median 4.2-year follow-up, 48% died. Age (HR 1.08; p=0.04) and baseline FVC% (HR 0.97; p=0.05) were independent predictors of mortality.

Conclusion: At baseline, higher fibrosis severity, UIP, and lower FVC% were associated with worse outcomes. Immunosuppressives, such as rituximab, may help preserve lung function. The need for early identification and individualized treatment in ILD associated with AAV or ANCA is underscored.

Objective: Ear, nose and throat (ENT) manifestations are common in ANCA-associated vasculitis (AAV). There is unmet need for drugs to target these manifestations. Granuloma formation is characteristic of proteinase 3 (PR3)-AAV. In a zebrafish model, niclosamide inhibits PR3-induced granuloma formation. We hypothesised that intranasal niclosamide would reduce AAV-associated ENT symptoms.

Methods: PROTECT-V was a randomised, double-blind, placebo-controlled platform trial evaluating pre-exposure prophylaxis agents against COVID-19 infection. This sub-analysis includes patients from a single centre, with AAV, enrolled into the intranasal niclosamide arm. Clinical data were retrospectively collected for nine months before, during, and nine months after treatment. Researchers were blinded to treatment allocation.

Results: Of thirty-two (14 niclosamide; 18 placebo) patients, 11 (34%) were female; median age was 69 years (IQR 59-75). Median prior AAV disease duration was 5.4 years (IQR 1.9-13.1); 19 (59%) had active disease in the year prior to treatment. Median treatment exposure was 200 days (IQR 109-251). During treatment, ENT symptoms were identified in 1/14 (7%) of the niclosamide group compared with 7/18 (39%) of the placebo group (p = 0.04). No significant difference between groups was found in the nine months before or after treatment. Among PR3-ANCA-positive patients, 0/10 in the niclosamide group compared to 5/9 (56%) in the placebo group had ENT symptoms during treatment.

Conclusion: These data are a signal of potential clinical effect on ENT manifestations in AAV. They support a role for the IL6/STAT3 pathway in AAV; intranasal niclosamide or other drug candidates in this pathway warrant further evaluation.