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.

Keywords: Inflammation; Pain; Psoriatic arthritis; Tofacitinib.

© 2022. The Author(s).

Figures

Fig. 1

Initial mediation model. Treatment (variable “Treatment”) is represented by a binary variable (tofacitinib 5 mg BID versus placebo). Pain (variable “Pain”) was measured by Patient’s Assessment of Arthritis Pain (VAS). Inflammation was measured by ISI (variable “ISI”), CRP (variable “CRP”), SJC (variable “SJC”), PASI (variable “PASI”), and enthesitis (measured by LEI [variable “LEI”]). Variables e_pain, e_crp, e_sjc, e_lei, e_pasi, and e_isi represent error terms. Curved two-headed arrows between error terms represent covariances. Curved two-headed arrows pointing to the same variable represent variance. BID twice daily, CRP C-reactive protein, ISI Itch Severity Item, LEI Leeds Enthesitis Index, PASI Psoriasis Area and Severity Index, SJC swollen joint count (out of 66 joints), VAS Visual Analog Scale

Fig. 2

Mediation effects in the initial model: indirect and direct effects of tofacitinib treatment on pain in patients pooled from OPAL Broaden and OPAL Beyond. Treatment (variable “Treatment”) is represented by a binary variable (tofacitinib 5 mg BID versus placebo). Pain (variable “Pain”) was measured by Patient’s Assessment of Arthritis Pain (VAS). Inflammation was measured by ISI (variable “ISI”), CRP (variable “CRP”), SJC (variable “SJC”), PASI (variable “PASI”), and enthesitis (measured by LEI [variable “LEI”]) at months 1 and 3. BID twice daily, CRP C-reactive protein, ISI Itch Severity Item, LEI Leeds Enthesitis Index, PASI Psoriasis Area and Severity Index, SJC swollen joint count (out of 66 joints), VAS Visual Analog Scale

Fig. 3

Respecified mediation model. Treatment (variable “Treatment”) is represented by a binary variable (tofacitinib 5 mg BID versus placebo). Pain (variable “Pain”) was measured by Patient’s Assessment of Arthritis Pain (VAS). Inflammation was measured by ISI (variable “ISI”), CRP (variable “CRP”), and enthesitis (measured by LEI [variable “LEI”]). Variables e_pain, e_isi e_crp, and e_lei represent error terms. Curved two-headed arrows between error terms represent covariances. Curved two-headed arrows pointing to the same variable represent variance. ID twice daily, CRP C-reactive protein, ISI Itch Severity Item, LEI Leeds Enthesitis Index, VAS Visual Analog Scale

Fig. 4

Mediation effects in the respecified model: indirect and direct effects of tofacitinib treatment on pain in patients pooled from OPAL Broaden and OPAL Beyond. Treatment (variable “Treatment”) is represented by a binary variable (tofacitinib 5 mg BID versus placebo). Pain (variable “Pain”) was measured by Patient’s Assessment of Arthritis Pain (VAS). Inflammation was measured by ISI (variable “ISI”), CRP (variable “CRP”), and enthesitis (measured by LEI [variable “LEI”]) at months 1 and 3. BID twice daily, CRP C-reactive protein, ISI Itch Severity Item, LEI Leeds Enthesitis Index, VAS Visual Analog Scale