Faculty Bibliography

OBJECTIVE:To assess guselkumab + golimumab combination therapy versus guselkumab monotherapy in participants with active psoriatic arthritis (PsA) and inadequate response to tumor necrosis factor inhibitors (TNFi-IR). METHODS:Adults with active TNFi-IR PsA (three or more tender/swollen joints) were randomized (2:1) to subcutaneous guselkumab (100 mg) + golimumab (50 mg) combination therapy (n = 59) or guselkumab monotherapy (n = 32) every 4 weeks through week 20. The primary endpoint was week 24 minimal disease activity (MDA) achievement. Additional endpoints included ≥20%/50%/70% improvement in American College of Rheumatology response criteria (ACR20/50/70): improvements in psoriasis, dactylitis, and enthesitis; changes in patient-reported physical function; and impact of screening C-reactive protein (CRP) on MDA/ACR50 response. RESULTS:At baseline, participants had a median of 13 tender and 8 swollen joints and psoriatic body surface area of 3%; 23% had dactylitis. At week 24, 29% and 22% of participants achieved MDA with guselkumab + golimumab combination therapy and guselkumab monotherapy, respectively (odds ratio [OR] 1.4 [90% confidence interval 0.6-3.3]; P = 0.557); 44% and 22% achieved ACR50 (nominal P = 0.034). Participants with CRP levels ≥0.3mg/dL (intended enrollment population) receiving combination therapy (n = 40; monotherapy n = 22) had greater odds of achieving MDA (OR 12.3; nominal P = 0.025; 32% vs 5%) and ACR50 (OR 9.6; nominal P = 0.003; 55% vs 14%) at week 24. Combination therapy was associated with higher ACR20 (66% vs 44%) and ACR70 (27% vs 16%) responses and greater physical function improvements than monotherapy. Improvements in psoriasis, dactylitis, and enthesitis were similar across groups. No new safety signals and no tuberculosis/opportunistic infections occurred through week 36. CONCLUSION/CONCLUSIONS:Although the primary endpoint was not achieved, secondary endpoints and exploratory analyses suggest that participants with TNFi-IR PsA, particularly those with elevated CRP levels, could derive clinically meaningful benefits with guselkumab + golimumab combination therapy, with no new safety concerns, warranting further investigation.

OBJECTIVES/OBJECTIVE:The randomised, double-blind, placebo-controlled, phase 3 Program fOr Evaluation of TYK2 inhibitor Psoriatic Arthritis-1 (POETYK PsA-1) trial evaluated the efficacy, safety, and tolerability of deucravacitinib, an oral, selective tyrosine kinase 2 inhibitor, in patients with PsA naïve to biologic disease-modifying antirheumatic drugs. METHODS:Adults with active PsA, high-sensitivity C-reactive protein concentration ≥ 3 mg/L, and ≥ 1 PsA-related hand and/or foot erosion detectable via radiograph were randomised 1:1 to oral deucravacitinib 6 mg once daily or placebo through week (W) 16. At W16, patients continued receiving deucravacitinib or switched from placebo to deucravacitinib through W52. The primary endpoint was American College of Rheumatology 20% improvement in response (ACR20) at W16. Nonresponder imputation was used for missing data. Efficacy and safety were evaluated through W52. Post hoc rank analysis of covariance was used to evaluate structural damage with no missing data imputation. RESULTS:In 670 patients, a significantly greater proportion of those receiving deucravacitinib vs placebo achieved ACR20 at W16 (54.2% vs 34.1%, P < .001). Responses with deucravacitinib were increased at W52. Patients who switched from placebo to deucravacitinib achieved improvements similar to those in patients who received continuous deucravacitinib. Inhibition of structural damage was observed at W16 and W52. At W16, incidences of serious adverse events (AEs) (deucravacitinib, 1.8%; placebo, 2.4%) and discontinuations due to AEs (2.4%; 1.8%) were low and remained low through W52, without imbalances in cardiovascular events, malignancies, or opportunistic infections. No new safety signals were detected; no deaths occurred. CONCLUSIONS:Deucravacitinib demonstrated superiority vs placebo for clinical responses, patient-reported outcomes, and structural damage inhibition in patients with PsA, with favourable tolerability and safety.

OBJECTIVE:The relationship between physical activity and sleep with inflammatory arthritis (IA) is understudied, and existing research has relied largely on self-report or short-term assessments. The NIH All of Us database provides long-term accelerometry data, enabling more precise estimation of the association between lifestyle behaviors and IA. METHODS:Participants from the All of Us database who shared electronic health record and Fitbit data were included. Daily activity and sleep metrics were compared between individuals with and without IA using multiple linear regression. Cox proportional hazards regression was used to examine the association of activity and sleep patterns with incident IA in a 10-year follow-up period. RESULTS:A total of 23,855 participants were included, 200 of whom had IA. Participants with IA took fewer daily steps (P < 0.001) and had greater sleep variability (P < 0.001) compared to those without IA. 122 individuals had incident IA. Every 1,000 extra daily steps were associated with a 7% lower risk of IA (hazard ratio [HR] 0.93 [95% confidence interval (CI) 0.87-0.99], P = 0.02). Compared to those who walked <5,000 steps daily, those who walked 5,000 to 10,000 steps and 10,000+ steps had a 41% (HR 0.59 [95% CI 0.39-0.91], P = 0.02) and 50% (HR 0.50 [95% CI 0.29-0.86], P = 0.01) reduction in risk of IA. CONCLUSION/CONCLUSIONS:Individuals with IA had reduced step counts and more sleep variability compared to those without IA, highlighting how physical activity and sleep contribute to IA. Additionally, increased daily step count was associated with decreased risk of incident IA, suggesting a possible research intervention for those at high risk of IA.

Shifting human subjects research from research sites to participants' homes removes barriers to participation. Previously, we developed homeRNA, a kit for stabilization of RNA in self-collected blood using a custom-engineered tube containing RNA stabilizer fluid. The stabilized RNA is extracted and used for downstream gene expression analysis. Here, we introduce homeRNAmax, which improves our original design by interfacing with a commercially available blood collection tube (BD Microtainer), allowing homeRNAmax to be used with any blood collection method that uses this tube and doubling the possible sample volume that can be collected and stabilized compared to the original homeRNA. Through a pilot study (n = 19 participants), we show that homeRNAmax (with the Tasso+ blood collection device) produces RNA samples of sufficient quality (mean RIN = 7.8) and yield (mean yield = 1.93 μg) for downstream analysis and can reach participants across the United States, who generally (n = 17/19) found the homeRNAmax kit easy to use. We also present RNA integrity data from an ongoing longitudinal clinical study using homeRNAmax in rheumatology (mean RIN = 7.1). A key aspect of the homeRNA and homeRNAmax platforms is a fluidic feature that prevents the RNA stabilizer from spilling, for which we developed a theoretical model. In brief, fluid in the tube is suspended due to a balance of pressures; an increase in air volume within the tube reduces the air pressure above the fluid, creating a small vacuum, and preventing fluid leakage. Overall, we show that homeRNAmax is a user-friendly, effective tool for remote blood RNA stabilization.

OBJECTIVES/OBJECTIVE:Obesity is highly prevalent in psoriatic arthritis (PsA) and associates with worse disease outcomes. Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are increasingly being used for weight loss and diabetes, but their impact on PsA outcomes remains unclear. We aimed to characterize patients with PsA initiating GLP-1RAs and assess longitudinal changes in weight, PsA activity and cardiometabolic parameters. METHODS:We conducted a retrospective analysis of patients with PsA who initiated GLP-1RAs. PsA disease activity data and cardiometabolic parameters from clinical visits within 1 year before and after GLP-1RA initiation along with demographics and comorbidities were collected. RESULTS:48 patients with a median BMI 34.9 were included. Significant weight loss was observed post-treatment (-6.43 kg (95% CI -9.5, -2.0), p< 0.0001), with 60% losing ≥5 % of their baseline bodyweight. CRP levels (-1.1 mg/L, p=0.002), pain scores (-1.0, p=0.01), and triglyceride levels (-0.35 mmol/L, p=0.02) decreased significantly. Each 1% reduction in body weight was associated with significant improvements in DAPSA [β=-0.49 (95% CI: -0.94, -0.03)], tender joint count [β=-0.18 (95% CI: -0.32, -0.05)], EQ-5D [β=0.0016 (95% CI: 0.008, 0.023)], LDL [β=-0.05 (95% CI: -0.10, -0.003)], and systolic blood pressure [β=-0.67 (95% CI: -1.18, -0.15)]. CONCLUSION/CONCLUSIONS:In this real-world study, GLP-1RA therapy in PsA was associated with clinically meaningful weight loss and improvements in systemic inflammation, pain, and cardiometabolic markers. Improvements in psoriatic outcomes were proportional to the degree of weight loss. These findings warrant further investigation in prospective controlled studies to evaluate the role of GLP-1RAs in PsA management and comorbidities.

Rheumatoid arthritis, psoriatic arthritis, and axial spondyloarthritis are types of inflammatory arthritis (IA) characterized by joint pain and stiffness that, despite therapeutic advances, remain difficult to treat. Changes in physical activity (PA) and sleep patterns may provide insights into IA disease course and activity. Wearable accelerometers have been validated as reliable, objective measures of PA and have provided insight into IA disease activity and progression through both PA and sleep metrics. Furthermore, the granular nature of accelerometry data may provide the opportunity to identify early signals of treatment response or disease flares, leading to more effective and personalized therapeutic regimens in patients with IA. In this review, we summarize the current state of wearable technology in IA and explore the potential of wearables to bridge gaps in care.

OBJECTIVES/OBJECTIVE:There is growing evidence of microbial involvement in immune-mediated inflammatory diseases, including psoriatic arthritis (PsA) and inflammatory bowel disease (IBD). However, it remains unclear whether different PsA phenotypes exhibit distinct microbial profiles. Furthermore, up to 4% of patients with PsA have comorbid IBD, which often remains undiagnosed. We hypothesised that the gut microbiome distinguishes PsA subphenotypes and serves as a biomarker of IBD in patients with PsA independent of faecal calprotectin (fCAL). METHODS:We obtained samples from 192 patients with axial or peripheral PsA and no prior diagnosis of IBD enrolled in the EISER study. Patients with elevated fCAL and subclinical IBD symptoms underwent colonoscopy with intestinal biopsy. Stool samples were used to measure fCAL, and gut microbiome was characterised using shotgun metagenomics. Serum samples were used for cytokine profiling. RESULTS:Axial PsA had lower alpha diversity and loss of several commensals compared with peripheral PsA, as well as a depletion of microbial biotin and arginine metabolism and higher levels of IL-23, IL-17F, and IL-8. Five subjects had newly diagnosed IBD which was characterised by a depletion of tryptophan and vitamin B6 metabolism. They also showed significant enrichment of several taxa compared to non-IBD and with a larger effect size than fCAL. CONCLUSIONS:Our results identify a distinct microbiome and immune profile in axial PsA, with lower microbiome diversity, a depletion of commensals and protective microbial mechanisms, and higher levels of some proinflammatory cytokines. In patients with newly diagnosed IBD, we identified microbial taxa associated with the condition yet independent of fCAL, the current clinical standard.