TNF-α Activating Osteoclasts in Patients with Psoriatic Arthritis Enhances the Recruitment of Osteoclast Precursors: A Plausible Role of WNT5A-MCP-1 in Osteoclast Engagement in Psoriatic Arthritis

Psoriatic arthritis (PsA) results from joint destruction by osteoclasts. The promising efficacy of TNF-α blockage indicates its important role in osteoclastogenesis of PsA. WNT ligands actively regulate osteoclastogenesis. We investigated how WNT ligands activate osteoclasts amid the TNF-α milieu in PsA. We first profiled the expression of WNT ligands in CD14+ monocyte-derived osteoclasts (MDOC) from five PsA patients and five healthy controls (HC) and then validated the candidate WNT ligands in 32 PsA patients and 16 HC. Through RNA interference against WNT ligands in MDOC, we determined the mechanisms by which TNF-α exerts its effects on osteclastogenesis or chemotaxis. WNT5A was selectively upregulated by TNF-α in MDOC from PsA patients. The number of CD68+WNT5A+ osteoclasts increased in PsA joints. CXCL1, CXCL16, and MCP-1 was selectively increased in supernatants of MDOC from PsA patients. RNA interference against WNT5A abolished the increased MCP-1 from MDOC and THP-1-cell-derived osteoclasts. The increased migration of osteoclast precursors (OCP) induced by supernatant from PsA MDOC was abolished by the MCP-1 neutralizing antibody. WNT5A and MCP-1 expressions were decreased in MDOC from PsA patients treated by biologics against TNF-α but not IL-17. We conclude that TNF-α recruits OCP by increased MCP-1 production but does not directly activate osteoclastogenesis in PsA.

Canadian Adalimumab Post-Marketing Observational Epidemiological Study Effectiveness in Psoriatic Arthritis (COMPLETE-PsA): 12-Month Results of Comparative Effectiveness of Adalimumab and nbDMARDs

Objective COMPLETE-PsA was an observational study of biologic-naïve Canadian adults with active psoriatic arthritis (PsA) treated with adalimumab or a non-biologic disease-modifying antirheumatic drug (nbDMARDs) regimen, after inadequate response/intolerance to a current nbDMARD treatment regimen. The aim of this analysis was to assess 12-month effectiveness of adalimumab versus nbDMARDs. Methods Patients enrolled between March 2012 and November 2017 were included. The following clinical parameters and patient-reported outcomes were collected/calculated per routine care: DAPSA28, DAS28, ESR, CRP, MDGA, PtGA, pain, HAQ-DI, SF-12, enthesitis, dactylitis, BSA, and time to achieving ACR50, ACR70 and modified MDA (mMDA). Results Two hundred seventy-seven adalimumab-treated and 148 nbDMARD-treated patients were included. At baseline, adalimumab-treated patients were less likely to be employed; had longer morning stiffness; higher DAPSA28, DAS28, MDGA, PtGA, pain, and HAQ-DI; and lower prevalence of dactylitis (all p<0.05). Adalimumab-treated patients showed lower baseline-adjusted DAPSA28 (16.5 vs. 26.6), DAS28 (2.8 vs. 3.9), MDGA (25.3 vs. 37.1), and ESR (10.2 vs. 15.4 mm/hr) after 3 months compared to nbDMARD-treated patients, with observed improvements maintained to month 12. Time to achievement of ACR50, ACR70, and mMDA was significantly (p<0.01) shorter among adalimumab-treated patients, with the likelihood of having dactylitis [OR: 0.4 (0.2–0.6)] and BSA<3% [2.7 (1.5–5.0)] significantly lower and higher, respectively. Switching to another biologic was less likely in adalimumab-treated vs. nbDMARD -treated patients (HR [95% CI]: 0.3 [0.2-0.5]). Conclusion In a real-world Canadian PsA population, adalimumab was more effective than nbDMARDs at reducing disease activity and the severity of skin involvement and demonstrated higher retention.

Occurrence and risk factors of uveitis in juvenile psoriatic arthritis: Data from a population-based nationwide study in Germany

Objective Data on uveitis in juvenile psoriatic arthritis (JPsA), a category of juvenile idiopathic arthritis (JIA), are scarce. We describe prevalence and risk factors for JPsA-associated uveitis (JPsA-U). Methods Cross-sectional data from the National Pediatric Rheumatological Database (from 2002 to 2014) were used to characterize JPsA-U and assess risk factors for uveitis development. Results Uveitis developed in 6.6% of 1862 JPsA patients. JPsA-U patients were more frequently female (73.0 vs 62.9%, p=0.031), ANA positive (60.3 vs 37.0%, p<0.001), younger at JPsA onset (5.3 ± 4.1 vs 9.3 ± 4.4 years, p<0.001), and received DMARD (disease modifying antirheumatic drug) treatment significantly more frequently than JPsA patients without uveitis. On multivariable analysis of a subgroup of 655 patients, mean cJADAS during study documentation was significantly associated with uveitis development. Children with early onset of JPsA were significantly more frequently ANA positive (48.4% vs 35.7% for those younger than 5 years at JPsA onset versus those aged 5 years and older, p<0.001), less often affected by skin disease (55.3% vs 61.0%, p=0.032), but more frequently by uveitis (17.3% vs 3.8%, p<0.001), and required DMARD treatment more frequently (52.9% vs 43.8%, p<0.001). Conclusion The characteristics of JPsA patients developing uveitis are similar to those of patients with uveitis in other JIA categories, such as oligoarticular JIA. Especially those children with early onset of JPsA seem to be at a higher risk for ocular involvement. Our data support the notion of a major clinical difference between those patients with early versus late onset of JPsA.

High Dimensional Analyses of Circulating Immune Cells in Psoriatic Arthritis Detects Elevated Phosphorylated STAT3

Psoriatic arthritis (PsA) is a chronic inflammatory arthritis, affecting up to 40% of patients with psoriasis. Constitutive expression by CD4+ T cells of an active form of STAT3, a signal transducer and transcription factor, has been shown to induce many of the major features of PsA in an animal model. We used high dimensional mass cytometry (CyTOF) to probe ex-vivo levels of phosphorylated STAT3 (pSTAT3) in circulating immune cell subpopulations from PsA patients during active and inactive states. We evaluated the frequency of 16 immune cell populations and the levels of the activated forms of STAT3 (pSTAT3) and, for comparison, STAT1 (pSTAT1) and Src (pSrc) in whole blood fixed shortly after collection. In addition to PsA patients, we studied active rheumatoid arthritis (RA) patients. Increased levels of pSTAT3 were found in all the CD4+ T cell subsets analyzed, specifically, Th1, Th2, Th17, T follicular helper (Tfh) and T regulatory (Treg) as well as in CD14+CD16- (classical) monocytes from active PsA patients compared to inactive patients. After correcting for body mass index (BMI), smoking and conventional disease modifying antirheumatic drugs (c-DMARDs), levels of pSTAT3 levels remained increased in Th1 and Tfh CD4+ T cells, and in CD14+CD16- monocytes from active patients compared to inactive patients. No differences between the patient groups were observed for pSTAT1 or pSrc. No differences were found between the active PsA and active RA groups after correction for multiple testing. During active PsA, circulating Th1 and Tfh CD4+ T cells, and CD14+CD16- monocytes expressing high levels of pSTAT3 may play a role in PsA pathophysiology, perhaps by migration to inflamed sites.