Identifying and Quantifying the Role of Inflammation in Pain Reduction for Patients With Psoriatic Arthritis Treated With Tofacitinib: A Mediation Analysis

Abstract

Introduction Pain is a multidimensional factor and core domain of psoriatic arthritis (PsA). This analysis aimed to quantify the role of potential inflammation-associated outcomes on pain reduction in patients with PsA receiving tofacitinib, using mediation modeling. Methods Pooled data were from two phase 3 studies (OPAL Broaden and OPAL Beyond) of patients with active PsA treated with tofacitinib 5 mg twice daily or placebo. Mediation modeling was utilized to quantify the indirect effects (via Itch Severity Item [ISI], C-reactive protein [CRP] levels, swollen joint count [SJC], Psoriasis Area and Severity Index [PASI], and enthesitis [using Leeds Enthesitis Index]) and direct effects (representing all other factors) of tofacitinib treatment on pain improvement. Results The initial model showed that tofacitinib treatment affects pain, primarily indirectly, via ISI, CRP, SJC, PASI, and enthesitis (overall 84.0%; P = 0.0009), with 16.0% ( P = 0.5274) attributable to the direct effect. The model was respecified to exclude SJC and PASI. Analysis of the final model revealed that 29.5% ( P = 0.0579) of tofacitinib treatment effect on pain was attributable to the direct effect, and 70.5% ( P < 0.0001) was attributable to the indirect effect. ISI, CRP, and enthesitis mediated 37.4% ( P = 0.0002), 15.3% ( P = 0.0107), and 17.8% ( P = 0.0157) of the tofacitinib treatment effect on pain, respectively. Conclusions The majority of the effect of tofacitinib on pain was collectively mediated by itch, CRP, and enthesitis, with itch being the primary mediator of treatment effect. Trial Registration : NCT01877668, NCT01882439. Graphical PLS Supplementary Information The online version contains supplementary material available at 10.1007/s40744-022-00482-5.

Navigating the complexity of pain in psoriatic arthritis and axial spondyloarthritis

“…In the tofacitinib, a Janus Kinase (JAK) inhibitor, in a phase 3 PsA trial of bio-naïve patients, known as OPAL Broaden. Mediation analysis demonstrated that 70.5% of pain reduction was through improvement of itch, enthesitis and C-reactive protein (CRP) (swollen joint count and skin score did not have weight in the model), leaving 29.5% as a direct effect of this agent [33 ▪ ]. Mediation analysis of the upadacitinib trial in biologic naive PsA patients showed that the majority of pain reduction was a direct effect versus and indirect effect on inflammation, using the surrogate measures of itch, enthesitis, and CRP as the key measures in the model for inflammation reduction [34 ▪ ].…”

Efficacy of tofacitinib in psoriatic arthritis: literature review and case report

“…Лечение ТОФА приводило к стойкому улучшению течения дактилита независимо от его локализации, с единичными случаями возникновения нового дактилита [31]. Изучение этой же когорты больных показало, что наиболее яркий эффект ТОФА отмечен в отношении кожного зуда, уровня СРБ и уменьшения признаков энтезита [32]. Показан также хороший эффект ТОФА остаточной боли [33].…”

Statistical and Scientific Considerations Concerning the Interpretation, Replicability, and Transportability of Research Findings

“…As another example, in studying treatment effects in rheumatoid arthritis, one may aim to study the extent to which biologic therapy reduces the rate of joint damage over 2 years through a reduction of C-reactive protein (CRP). Recently, de Vlam et al 37 studied the mediating role of inflammatory markers (CRP, swollen joint count, Leeds Enthesitis Index, Psoriasis Area and Severity Index, and an itch severity score) on the causal effect of tofacitinib on pain reduction in PsA.…”