Residual disease activity and treatment adjustments in psoriatic arthritis in current clinical practice

Abstract Background With expanding therapeutic possibilities for treatment of psoriatic arthritis (PsA) it will be increasingly important to determine residual disease and define when to adjust treatment. The rationale behind treatment decisions in current daily clinical practice and the relationship with residual disease activity has not been investigated. The aim of this study was to assess current clinical practice on defining residual disease and subsequent treatment decisions made in PsA patients. Methods This cross-sectional study scored disease activity and treatment decisions prospectively in 142 consecutive PsA patients visiting the outpatient clinic for routine follow up. Disease activity parameters were scored by patient and the treating rheumatologist; the rheumatologist additionally registered his opinion on the presence of remaining disease activity despite current treatment (further mentioned as remaining disease) and subsequent treatment decisions. Results Two thirds (90/142) of patients had remaining disease activity according to the treating rheumatologist. Almost half (46%) of these patients had moderate to high disease activity according to the clinical Disease Activity Index for Psoriatic Arthritis (cDAPSA). Residual disease activity was determined by joint disease and pain rather than by active psoriasis. Demographic and clinical features were similar between groups with or without residual disease. Among patients with remaining disease activity, 74% were treated with either a conventional synthetic disease-modifying anti-rheumatic drug (csDMARD) only or a first TNF-inhibiting biological agent, suggesting opportunities for treatment modification. However, treatment adjustment was initiated in only 21 (23%) of the 90 patients with residual disease. When comparing patients with remaining disease activity with and without treatment adjustment, we found no differences in objective disease activity measures, such as joint counts and patient scores. These data suggest that treatment is not adjusted in a large majority of patients with residual disease activity, although options for treatment changes are available. Conclusions Remaining disease activity is present in almost two thirds of patients with PsA when scored by the treating rheumatologist, but triggers treatment adjustment in only a minority. Further research to understand why disease activity does not lead to treatment adjustment is required to enable implementation of treatment strategies in clinical practice

IL-12p40/IL-23p40 Blockade With Ustekinumab Decreases the Synovial Inflammatory Infiltrate Through Modulation of Multiple Signaling Pathways Including MAPK-ERK and Wnt

Background: Psoriatic arthritis (PsA) is a chronic inflammatory joint disease within the spondyloarthritis spectrum. IL-12p40/IL-23p40 blockade reduces PsA disease activity, but its impact on synovial inflammation remains unclear. Objectives: To investigate the cellular and molecular pathways affected by IL-12p40/IL-23p40 blockade with ustekinumab in the synovium of PsA patients. Methods: Eleven PsA patients with at least one inflamed knee or ankle joint were included in a 24-week single-center open-label study and received ustekinumab 45 mg/sc according to standard care at week 0, 4, and 16. Besides clinical outcomes, synovial tissue (ST) samples were obtained by needle arthroscopy from an inflamed knee or ankle joint at baseline, week 12 and 24 and analyzed by immunohistochemistry, RNA-sequencing and real-time quantitative polymerase chain reaction (qPCR). Results: We obtained paired baseline and week 12, and paired baseline, week 12 and 24 ST samples from nine and six patients, respectively. Eight patients completed 24 weeks of clinical follow-up. At 12 weeks 6/11 patients met ACR20, 2/11 met ACR50 and 1/11 met ACR70 improvement criteria, at 24 weeks this was 3/8, 2/8 and 1/8 patients, respectively. Clinical and serological markers improved significantly. No serious adverse events occurred. We observed numerical decreases of all infiltrating cell subtypes at week 12, reaching statistical significance for CD68+ sublining macrophages. For some cell types this was even more pronounced at week 24, but clearly synovial inflammation was incompletely resolved. IL-17A and F, TNF, IL-6, IL-8, and IL-12p40 were not significantly downregulated in qPCR analysis of W12 total biopsies, only MMP3 and IL-23p19 were significantly decreased. RNA-seq analysis revealed 178 significantly differentially expressed genes between baseline and 12 weeks (FDR 0.1). Gene Ontology and KEGG terms enrichment analyses identified overrepresentation of biological processes as response to reactive oxygen species, chemotaxis, migration and angiogenesis as well as MAPK-ERK and PI3K-Akt signaling pathways among the downregulated genes and of Wnt signaling pathway among the upregulated genes. Furthermore, ACR20 responders and non-responders differed strikingly in gene expression profiles in a post-hoc exploratory analysis. Conclusions: Ustekinumab suppresses PsA synovial inflammation through modulation of multiple signal transduction pathways, including MAPK-ERK, Wnt and potentially PI3K-Akt signaling rather than by directly impacting the IL-17 pathway