Pain and Inflammation as Mediators of Tofacitinib Treatment Effect on Fatigue in Patients with Ankylosing Spondylitis: A Mediation Analysis.

Abstract

Tofacitinib is an oral Janus kinase inhibitor for treatment of ankylosing spondylitis (AS). Using mediation modelling, we describe interrelationships between fatigue, pain, morning stiffness, C-reactive protein (CRP) and tofacitinib treatment in patients with AS. Data from phase2 (NCT01786668)/phase3 (NCT03502616) studies of patients receiving tofacitinib 5mg twice daily (BID) or placebo were used. Initial models included treatment as the independent binary variable (tofacitinib 5mg BID versus placebo); fatigue (Functional Assessment of Chronic Illness Therapy-Fatigue [FACIT-F; modelA] or Bath AS Disease Activity Index [BASDAI] Q1 [modelB]) as the dependent variable; and pain (total back pain/nocturnal spinal pain [modelA] or pain measured by BASDAI Q2/3 [modelB]), morning stiffness (BASDAI Q5/6) and CRP as mediator variables. Pooled data from 370/371 patients were included in modelsA/B. Initial models demonstrated that tofacitinib treatment affects fatigue mainly indirectly via pain and morning stiffness. As a result, initial models were respecified to exclude direct treatment effect and the indirect effect via CRP. For respecified modelA, 44.0% of the indirect effect of tofacitinib treatment on fatigue was mediated via back pain/morning stiffness, 40.0% via morning stiffness alone and 16.0% via back pain alone (all P < 0.05). For respecified modelB, 80.8% of the indirect effect of tofacitinib treatment on fatigue was mediated via pain/morning stiffness and 19.2% via pain alone (both P < 0.05). In tofacitinib-treated patients with AS, improvements in fatigue were collectively mediated through combined treatment effects on morning stiffness and pain.