Arthritis & Rheumatology最新文献

Objective: Glucagon-like peptide 1 receptor agonists (GLP-1RAs) and sodium-glucose cotransporter 2 inhibitors (SGLT2i) facilitate weight loss and exhibit immunomodulatory effects, but their impact on the risk of developing autoimmune rheumatic diseases (ARDs) is unclear. We compared ARD incidence following initiation of GLP-1RAs or SGLT2i versus a weight-neutral comparator (dipeptidyl peptidase 4 inhibitors [DPP4i]).

Methods: We performed a population-based cohort study using administrative health data from a Canadian province with universal health care. We included adults with type 2 diabetes (T2D) and no prior ARD initiating a GLP-1RA, SGLT2i, or DPP4i between January 1, 2014, and December 31, 2022. Incident ARD cases, including rheumatoid arthritis, psoriatic disease, axial spondyloarthritis, and systemic ARDs (SARDs; systemic lupus erythematosus, systemic sclerosis, Sjögren disease, idiopathic inflammatory myopathies, and systemic vasculitides), were identified using validated algorithms. Propensity score (PS) weighting was used to balance cohorts at treatment initiation. Then hazard ratios (HRs) were estimated using Cox regression.

Results: Among 229,300 adults, 49,514 initiated GLP-1RAs, 101,925 initiated SGLT2i, and 77,861 initiated DPP4i. After PS weighting, ARD incidence per 10,000 person-years was 29.1 (95% confidence interval [CI] 23.5-35.5) with GLP-1RAs, 24.4 (95% CI 19.8-29.7) with SGLT2i, and 27.3 (95% CI 22.1-33.4) with DPP4i. Mean follow-up was 1.3 to 1.6 years. Relative to DPP4i, adjusted HRs (aHRs) of ARD were 1.04 (95% CI 0.81-1.33) with GLP-1RAs and 0.93 (95% CI 0.75-1.16) with SGLT2i. Risk of SARDs, but not other diseases, was lower with SGLT2i versus DPP4i (aHR 0.51 [95% CI 0.31-0.84]).

Conclusion: Neither GLP-1RA nor SGLT2i treatment was associated with increased or decreased ARD risk versus DPP4i in adults with T2D; however, SGLT2i use was associated with significantly lower risk of SARDs, warranting further study.

Objective: Cardiac involvement is a major cause of morbidity in systemic lupus erythematosus (SLE). Tumor necrosis factor-like weak inducer of apoptosis (TWEAK) is elevated in SLE, but its contribution to lupus-associated cardiac injury is unclear. We investigated the role of TWEAK/Fn14 signaling in SLE-related cardiomyopathy and its potential as a biomarker and therapeutic target.

Methods: Serum TWEAK, inflammatory cytokines, autoantibodies, and oxidative stress markers were measured in 242 SLE patients and 66 age- and sex- matched controls, with correlation to echocardiographic, electrocardiographic, and myocardial enzyme findings. Cardiac pathology and redox signaling were assessed in pristane-induced lupus models using wild-type and Fn14-deficient mice by histopathology, immunoblotting, immunofluorescence, and quantitative proteomics. Direct effects of TWEAK on mitochondrial oxidative stress, antioxidant signaling, and apoptosis were examined in primary cardiomyocytes isolated from lupus-prone MRL/lpr mice.

Results: Serum TWEAK levels were significantly elevated in patients with SLE and were highest in those with cardiac abnormalities compared with healthy controls. TWEAK correlated positively with malondialdehyde, 8-hydroxy-2' -deoxyguanosine, disease activity, and inflammatory cytokines, and inversely with superoxide dismutase. Elevated baseline TWEAK predicted new cardiac abnormalities during follow-up and declined with clinical improvement. In lupus mice, Fn14 deficiency reduced cardiac reactive oxygen species accumulation, restored Nrf2/HO-1 antioxidant signaling, attenuated histopathological injury, and preserved cardiac function. In vitro, TWEAK induced mitochondrial superoxide production, suppressed Nrf2 signaling, and promoted apoptosis in lupus-prone cardiomyocytes.

Conclusion: TWEAK/Fn14 signaling drives oxidative stress- mediated cardiomyocyte injury in SLE and represents a promising biomarker and therapeutic target for lupus-associated cardiac damage.

Objective: Predictive biomarkers for patients with early rheumatoid arthritis (RA) are needed. This exploratory post hoc analysis investigated inflammatory biomarkers associated with baseline disease activity and biomarkers predictive of treatment response in seropositive patients with early RA from a phase 3 study.

Methods: AVERT-2 (NCT02504268) included disease-modifying antirheumatic drug-naive, anticitrullinated protein antibody-positive patients randomized to abatacept+methotrexate (MTX) or placebo+MTX for 56 weeks. Correlations were assessed between biomarkers and disease activity, pharmacodynamic (PD) changes on disease-associated biomarkers in response to treatment, and baseline biomarkers to predict treatment response at week 52.

Results: In the analysis, 446 patients received abatacept+MTX and 300 received placebo+MTX. Of 103 biomarkers, 47 demonstrated a significant reduction in PD changes with abatacept+MTX versus placebo+MTX, with 18 out of 47 biomarkers showing correlations with baseline disease activity. High baseline interleukin-10 (IL-10) levels were associated with greater probability of achieving efficacy measures by week 52 in patients receiving abatacept+MTX versus placebo+MTX, consistent with a significant reduction in disease activity with abatacept+MTX (P <0.03 to P <0.0007). Higher baseline IL-10 levels were associated with lower bone erosive development with abatacept+MTX compared with placebo+MTX.

Conclusion: Treatment with abatacept+MTX resulted in significantly greater reduction of biomarkers relevant to RA, and high baseline IL-10 levels predicted better treatment response with abatacept+MTX versus placebo+MTX across clinical outcomes. Findings suggest a well-suited mechanism of action for abatacept+MTX in patients with early RA and high baseline IL-10 levels.

Objectives: We employed global genetic deletion of CD14 and intra-articular CD14 blockade across multiple murine OA models that vary in severity of pathology and rate of progression, to test the hypothesis that CD14 inhibition attenuates synovial inflammation and associated pain during disease progression.

Methods: Human OA synovial fluid samples were evaluated for associations between sCD14 levels with knee hyperalgesia and inflammation. Next, the effect of CD14-deficiency on OA progression was assessed across mild to severe murine surgical models of PTOA, where pain behavior and a high-dimensional transcriptomic and proteomic analysis of CD14-dependent synovial inflammation were performed. In a therapeutic approach, local delivery of a CD14 blocking antibody was administered, and the effects on OA histopathology and pain were evaluated across surgical and nonsurgical murine models of PTOA.

Results: Increased sCD14 within human synovial fluid correlates with joint effusion volume and knee hyperalgesia. Further, targeting CD14 protects from increased evoked pain behaviors and OA-driven mobility impairments across murine models that differ in severity, and across male and female cohorts. Using flow cytometry, single-cell transcriptomics, and spatial proteomics, we further show that CD14-deficiency modulates the synovial and fat pad inflammatory landscape post-injury, reducing myeloid populations and modulating local fibroblast populations. Lastly, across surgical and nonsurgical PTOA models, which incorporated risk factors of sex and obesity, we reveal that local delivery of a CD14 blockade protects against OA-associated pain and mobility loss.

Conclusions: Our results strongly support that targeting synovial and fat pad inflammation through blockade of CD14 can safely ameliorate OA pain and disability after a pre-disposing injury.