Arthritis & Rheumatology最新文献

Objective: Lupus nephritis (LN) is one of the most severe manifestations of systemic lupus erythematosus (SLE) and is partially driven by type I interferon signaling. Anifrolumab, an approved treatment for patients with SLE, has been investigated in a phase 2 trial in patients with LN receiving standard therapy (TULIP-LN, ClinicalTrials.gov identifier NCT02547922). We studied the impact of anifrolumab treatment on urinary biomarker expression in patients with LN through proteomic analysis of samples from TULIP-LN.

Methods: Urine samples were collected at weeks 0, 12, and 48 from patients treated with the anifrolumab basic regimen (n = 35), intensified regimen (n = 42), or placebo (n = 35), in addition to standard therapy, and analyzed for the presence of 197 proteins. The impact of anifrolumab relative to placebo on prespecified biomarkers linked to histologic activity was assessed, and a comparison of responders versus nonresponders was conducted on proteins detected in ≥75% of samples.

Results: Anifrolumab treatment significantly reduced urinary CD163 and monocyte chemoattractant protein 1 expression at week 12 versus placebo, including in patients classified as proteinuric nonresponders across all regimens. By week 48, biomarker levels declined in all groups, indicating that standard therapy alone can eventually suppress intrarenal inflammation but with slower kinetics. Proteomic analyses further revealed that anifrolumab was superior to placebo in reducing the proteomic inflammatory signature, regardless of responder status.

Conclusion: Compared with placebo, anifrolumab treatment significantly reduced urinary biomarkers of renal histologic activity in patients with LN, which may accelerate the resolution of intrarenal inflammation, potentially preventing damage accrual.

Objective: The cystathionine γ-lyase (CSE)/hydrogen sulfide (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 patients with SSc and healthy controls were used for functional studies, including propargylglycine (CSE inhibitor) treatment, Gyy4137, a slow-releasing hydrogen sulfide donor, CSE silencing, and CSE overexpression, combined with liquid chromatography-tandem mass spectrometry (LC-MS/MS)-based S-sulfhydration proteomics. Molecular dynamics simulations were performed to study the effects of S-sulfhydration on protein structure, and an Smad3 C121S (cysteine [Cys] 121 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 transforming growth factor β 1 (TGFβ1)/Smad3 signaling, mitigating skin fibrosis. Notably, Cys121 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 January 1997 and March 2022 with at least one year of follow-up were identified using provincial administrative databases. Each antimalarial adherent patient (proportion of days covered [PDC] ≥ 0.90) was propensity score (PS) matched up to two antimalarial nonadherent patients (0 < PDC < 0.90). The outcomes hospital admissions, hospitalized days, and hospitalization cost were assessed in the following year. We estimated the impact of early antimalarial adherence on these outcomes, accounting for potential confounders, using quasi-Poisson and linear models with robust SEs. We conducted falsification tests and sensitivity analyses to examine robustness to healthy adherer effect and unmeasured confounders.

Results: We identified 8,768 antimalarial adherent and 16,479 antimalarial nonadherent PS-matched individuals with RA/SLE. The adjusted rate ratios of hospital admissions and hospitalized days obtained for antimalarial adherent versus nonadherent patients were 0.89 (95% confidence interval [CI] 0.84-0.94) and 0.79 (95% CI 0.71-0.88), respectively. The adjusted average hospitalization costs were lower (estimate: CAD -$549.64, 95% CI -$896.05 to -$203.22, P < 0.01) for antimalarial adherent patients than nonadherent patients. Falsification tests and sensitivity analyses confirmed the robustness of the results.

Conclusion: Adherence to antimalarials in patients with RA and SLE was associated with a lower risk of hospital admission (11% reduction) and hospitalized days (21% reduction) and lower hospitalization costs (CAD $549.64 lower) compared to nonadherence.

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, Medicare, and National Death Index data (2006-2020). Ten-year estimated cardiovascular disease (CVD) risk was calculated using PREVENT. Calibration (standardized incidence ratio [SIR] and observed/predicted events) and discrimination (sensitivity and Harrel's C-statistics) were compared between RA cases and controls. PREVENT performance was compared with the Pooled Cohort Equations (PCE) for atherosclerotic CVD (ASCVD) prediction in RA, including net reclassification index (NRI) calculation.

Results: Among 30,687 patients with RA and 231,752 patients without RA, 28,061 ASCVD and 13,851 heart failure (HF) outcomes were identified over >2 million person-years. PREVENT underestimated overall CVD (SIR 1.83, 95% confidence interval [CI] 1.79-1.88), ASCVD (SIR 2.25, 95% CI 2.19-2.32) and HF risk (SIR 1.41, 95% CI 1.36-1.46) to a greater degree in RA compared with controls and exhibited poor sensitivity for ASCVD (61.9%) and HF (63.2%) development. PREVENT performance was poorer for ASCVD prediction compared with the PCE (SIR 1.38, 95% CI 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 or borderline risk. PREVENT performance significantly improved when including hemoglobin A1c (overall CVD: SIR 1.21, 95% CI 1.18-1.24; ASCVD: SIR 1.45, 95% CI 1.41-1.50; HF: SIR 0.79, 95% CI 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: Our study objective was 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 (Arthritis Prevention In the Preclinical Phase of RA with Abatacept) study participants were selected from baseline to RA onset for 46 progressors of RA or to study end for 72 participants who did not develop RA. Samples were analyzed using the SomaScan 7k assay platform. Differential expression analysis was assessed by progression to RA (three pre-RA time intervals to RA, progressors of RA vs nonprogressors, baseline to RA), and by treatment allocation (abatacept vs placebo). Risk and response signatures were identified in the full 7k panel and two prespecified subpanels defined as Inflammatory Mediators and Adaptive Immune Cell panel.

Results: We observed significant changes in 80 proteins (68 down-regulated and 12 up-regulated) occurring between RA onset and 6 to 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 nonprogressors at the end of treatment. Two up-regulated proteins (CTLA4 and CD86) and seven down-regulated 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, whereas 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.

Objective: Eosinophilic granulomatosis with polyangiitis (EGPA) is a small vessel vasculitis characterized by eosinophilia, asthma, and ear, nose, and 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 patients with EGPA fulfilling the 2022 American College of Rheumatology/EULAR criteria. Using Fine-Gray and logistic regression, we developed two multivariable prediction models, one for vasculitis relapse and another for GC-dependent asthma and/or ENT symptoms at 2 Internal validation was performed using bootstrapping.

Results: A total of 809 patients were observed for a median of 72 months (interquartile range 37-115). Vasculitis relapse occurred in 228 patients with a 12-year cumulative incidence of 41.2% (95% confidence interval 36.3-46.8). GC-dependent asthma and/or ENT symptoms were observed in 66.4% at two 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), myeloperoxidase-antineutrophil cytoplasmic antibody (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 cohort with EGPA, 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.

Objective: Interstitial lung disease (ILD) can occur in association with antineutrophil cytoplasmic antibody (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 multicenter retrospective study encompassed patients with AAV-ILD or ANCA-ILD. Baseline and subsequent chest computed tomography studies were centrally reviewed. Primary outcomes included forced vital capacity % (FVC%) decline, respiratory failure, and mortality.

Results: Of 162 patients (myeloperoxidase [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%), whereas half had a radiologic fibrosis grade >10%. Kidney involvement was present in 73%, most commonly Berden focal class. UIP and nonspecific 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 a higher fibrosis severity grade. Respiratory failure (19%) was associated with fibrosis severity (grade 4 hazard ratio [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.