Back pain and morning stiffness as mediators of tofacitinib treatment effect on fatigue in patients with ankylosing spondylitis: a mediation analysis

Background: Fatigue is a prevalent symptom of ankylosing spondylitis (AS) and can contribute to higher levels of disease, disability and poor health-related quality of life. Back pain and morning stiffness are also commonly reported symptoms. Tofacitinib is an oral Janus kinase inhibitor for the treatment of adult patients (pts) with AS. In randomised studies, pts with active AS treated with tofacitinib experienced greater improvements in fatigue, back pain and morning stiffness at Week 12 and 16 of treatment compared with placebo (PBO). Treatment of these symptoms is a priority for pts with AS and their healthcare providers, however, the mechanisms underlying the interrelationships between fatigue, back pain, morning stiffness and treatment are unclear. Objectives: To describe the interrelationships between fatigue, back pain, morning stiffness and tofacitinib treatment in pts with AS, using mediation modelling. Methods: Data from Phase 2 (NCT01786668) and Phase 3 (NCT03502616) studies of pts with active AS treated with tofacitinib 5 mg twice daily (BID) or PBO were used. Mediation modelling, a statistical method to assess the extent to which the effect of an independent variable on a dependent variable is indirect, via identified mediators, or direct, capturing all other (unmeasured) effects, was applied. The initial model included: treatment as the independent binary variable (tofacitinib 5 mg BID vs PBO); fatigue (measured by Functional Assessment of Chronic Illness Therapy-Fatigue) as the dependent variable; mediators included back pain (measured by total back pain/nocturnal spinal pain [numerical rating scale, 0–10]) and morning stiffness (represented by the mean of Bath Ankylosing Spondylitis Disease Activity Index questions 5 and 6). Results: Pooled data from 370 pts were included in the analysis. The initial model showed that 57.5% (p<0.001) of the tofacitinib treatment effect on fatigue was mediated via back pain and morning stiffness (indirect effect); mediation via morning stiffness alone was 49.7% (p<0.01), and 21.2% (p=0.02) via back pain alone. The effect of treatment attributable to factors other than back pain and morning stiffness (ie, direct effect) was not statistically significant (-28.4%; p=0.33). As a result, the initial model was re-specified to exclude the direct treatment effect on fatigue. In the re-specified model ( Figure 1 ), 44.0% (p<0.0001) of the indirect effect of tofacitinib on fatigue was mediated via back pain and morning stiffness; mediation via morning stiffness alone was 40.0% (p<0.001), and 16.0% (p<0.01) via back pain alone. Analyses of the individual study data gave results generally consistent with those from the pooled data. Conclusion: Overall, indirect pathways via morning stiffness accounted for ~84% of the effect of tofacitinib treatment on fatigue: (1) treatment affects morning stiffness, which impacts fatigue; and (2) treatment affects morning stiffness, which affects back pain and, ultimately, back pain affects fatigue. The indirect pathway via back pain alone accounted for ~16% of treatment effect on fatigue. These results suggest that in tofacitinib-treated pts with AS, improvements in fatigue are fully mediated through combined treatment effects on morning stiffness and back pain. REFERENCES: [1]Schneeberger EE et al. Clin Rheumatol 2015; 34: 497-501. [2]Connolly D et al. Occup Ther Int 2019; 2019: 3027280. [3]Braun J. Rheumatology (Oxford) 2018; 57: vi1-vi3. [4]van der Heijde D et al. Ann Rheum Dis 2017; 76: 1340-1347. [5]Deodhar A et al. Ann Rheum Dis 2021; 80: 1004-1013. [6]Richiardi L et al. Int J Epidemiol 2013; 42: 1511-1519. [7]Cappelleri JC et al. Boca Raton, FL: CRC Press, 2013. Acknowledgements: Study sponsored by Pfizer Inc. Medical writing support was provided by Robyn Wilson, CMC Connect, and funded by Pfizer Inc. Disclosure of Interests: Lars Erik Kristensen Speakers bureau: AbbVie, Biogen, Eli Lilly, Galapagos NV, Gilead Sciences, Janssen, Pfizer Inc, Sanofi, UCB, Consultant of: AbbVie, Biogen, Eli Lilly, Galapagos NV, Gilead Sciences, Janssen, Pfizer Inc, Sanofi, UCB, Grant/research support from: AbbVie, Eli Lilly, Pfizer Inc, UCB, Peter C. Taylor Consultant of: AbbVie, BMS, Biogen, Celltrion, Eli Lilly, Fresenius, Galapagos NV, Gilead Sciences, GSK, Janssen, Nordic Pharma, Pfizer Inc, Sanofi, UCB, Grant/research support from: Celgene, Galapagos, Victoria Navarro-Compán Speakers bureau: AbbVie, Janssen, Lilly, MSD, Pfizer Inc, UCB, Consultant of: AbbVie, Janssen, Lilly, Moonlake, MSD, Pfizer Inc, UCB, Grant/research support from: AbbVie, Novartis, Marina Magrey Consultant of: AbbVie, Eli Lilly, Janssen, Novartis, Pfizer Inc, UCB, Grant/research support from: AbbVie, UCB, Joseph C Cappelleri Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, Andrew G Bushmakin Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, Arne Yndestad Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, Oluwaseyi Dina Shareholder of: Pfizer Inc, Employee of: Pfizer Inc. Citation: , volume 81, supplement 1, year 2022, page 1500Session: Spondyloarthritis - treatment (Publication Only)