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

Rheumatol Ther. 2022 Oct;9(5):1451-1464. doi: 10.1007/s40744-022-00482-5. Epub 2022 Sep 8.


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.

Keywords: Inflammation; Pain; Psoriatic arthritis; Tofacitinib.

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