Kurt de Vlam1, Philip J Mease2, Andrew G Bushmakin3, Roy Fleischmann4, Alexis Ogdie5, Valderilio F Azevedo6, Joseph F Merola7, John Woolcott8, Joseph C Cappelleri3, Lara Fallon9, Peter C Taylor10. 1. Department of Rheumatology, University Hospitals Leuven, Leuven, Belgium. 2. Swedish Medical Center, University of Washington, Seattle, WA, USA. 3. Pfizer Inc, Groton, CT, USA. 4. Metroplex Clinical Research Center, University of Texas Southwestern Medical Center, Dallas, TX, USA. 5. Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. 6. Universidade Federal do Paraná, Curitiba, Brazil. 7. Division of Rheumatology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA. 8. Pfizer Inc, Collegeville, PA, USA. 9. Pfizer Inc, Kirkland, Montreal, QC, Canada. lara.fallon@pfizer.com. 10. University of Oxford, Oxford, UK.
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.
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.
Authors: Eva Kosek; Milton Cohen; Ralf Baron; Gerald F Gebhart; Juan-Antonio Mico; Andrew S C Rice; Winfried Rief; A Kathleen Sluka Journal: Pain Date: 2016-07 Impact factor: 6.961
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Authors: S Rifbjerg-Madsen; A W Christensen; R Christensen; M L Hetland; H Bliddal; L E Kristensen; B Danneskiold-Samsøe; K Amris Journal: PLoS One Date: 2017-07-07 Impact factor: 3.240