Pain and Inflammation as Mediators of Tofacitinib Treatment Effect on Fatigue in Patients with Ankylosing Spondylitis: A Mediation Analysis
Abstract Introduction 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. Methods Data f...
| Main Authors: | , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Adis, Springer Healthcare
2023-06-01
|
| Series: | Rheumatology and Therapy |
| Subjects: | |
| Online Access: | https://doi.org/10.1007/s40744-023-00570-0 |
| _version_ | 1797784409698467840 |
|---|---|
| author | Lars Erik Kristensen Victoria Navarro-Compán Marina Magrey Andrew G. Bushmakin Joseph C. Cappelleri Arne Yndestad Oluwaseyi Dina Peter C. Taylor |
| author_facet | Lars Erik Kristensen Victoria Navarro-Compán Marina Magrey Andrew G. Bushmakin Joseph C. Cappelleri Arne Yndestad Oluwaseyi Dina Peter C. Taylor |
| author_sort | Lars Erik Kristensen |
| collection | DOAJ |
| description | Abstract Introduction 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. Methods Data from phase 2 (NCT01786668)/phase 3 (NCT03502616) studies of patients receiving tofacitinib 5 mg twice daily (BID) or placebo were used. Initial models included treatment as the independent binary variable (tofacitinib 5 mg BID versus placebo); fatigue (Functional Assessment of Chronic Illness Therapy-Fatigue [FACIT-F; model A] or Bath AS Disease Activity Index [BASDAI] Q1 [model B]) as the dependent variable; and pain (total back pain/nocturnal spinal pain [model A] or pain measured by BASDAI Q2/3 [model B]), morning stiffness (BASDAI Q5/6) and CRP as mediator variables. Results Pooled data from 370/371 patients were included in models A/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 model A, 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 model B, 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). Conclusions In tofacitinib-treated patients with AS, improvements in fatigue were collectively mediated through combined treatment effects on morning stiffness and pain. Graphical Abstract |
| first_indexed | 2024-03-13T00:39:29Z |
| format | Article |
| id | doaj.art-3c522789b45749f6a6d68b464bcbeb6a |
| institution | Directory Open Access Journal |
| issn | 2198-6576 2198-6584 |
| language | English |
| last_indexed | 2024-03-13T00:39:29Z |
| publishDate | 2023-06-01 |
| publisher | Adis, Springer Healthcare |
| record_format | Article |
| series | Rheumatology and Therapy |
| spelling | doaj.art-3c522789b45749f6a6d68b464bcbeb6a2023-07-09T11:24:25ZengAdis, Springer HealthcareRheumatology and Therapy2198-65762198-65842023-06-011041073108710.1007/s40744-023-00570-0Pain and Inflammation as Mediators of Tofacitinib Treatment Effect on Fatigue in Patients with Ankylosing Spondylitis: A Mediation AnalysisLars Erik Kristensen0Victoria Navarro-Compán1Marina Magrey2Andrew G. Bushmakin3Joseph C. Cappelleri4Arne Yndestad5Oluwaseyi Dina6Peter C. Taylor7The Parker Institute, Copenhagen University Hospital, Bispebjerg and FrederiksbergUniversity Hospital La Paz, IdiPazDivision of Rheumatology, Case Western Reserve UniversityPfizer IncPfizer IncPfizer IncPfizer IncBotnar Research Centre, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of OxfordAbstract Introduction 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. Methods Data from phase 2 (NCT01786668)/phase 3 (NCT03502616) studies of patients receiving tofacitinib 5 mg twice daily (BID) or placebo were used. Initial models included treatment as the independent binary variable (tofacitinib 5 mg BID versus placebo); fatigue (Functional Assessment of Chronic Illness Therapy-Fatigue [FACIT-F; model A] or Bath AS Disease Activity Index [BASDAI] Q1 [model B]) as the dependent variable; and pain (total back pain/nocturnal spinal pain [model A] or pain measured by BASDAI Q2/3 [model B]), morning stiffness (BASDAI Q5/6) and CRP as mediator variables. Results Pooled data from 370/371 patients were included in models A/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 model A, 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 model B, 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). Conclusions In tofacitinib-treated patients with AS, improvements in fatigue were collectively mediated through combined treatment effects on morning stiffness and pain. Graphical Abstracthttps://doi.org/10.1007/s40744-023-00570-0Ankylosing spondylitisC-reactive proteinMediation modellingMorning stiffnessPainTofacitinib |
| spellingShingle | Lars Erik Kristensen Victoria Navarro-Compán Marina Magrey Andrew G. Bushmakin Joseph C. Cappelleri Arne Yndestad Oluwaseyi Dina Peter C. Taylor Pain and Inflammation as Mediators of Tofacitinib Treatment Effect on Fatigue in Patients with Ankylosing Spondylitis: A Mediation Analysis Rheumatology and Therapy Ankylosing spondylitis C-reactive protein Mediation modelling Morning stiffness Pain Tofacitinib |
| title | Pain and Inflammation as Mediators of Tofacitinib Treatment Effect on Fatigue in Patients with Ankylosing Spondylitis: A Mediation Analysis |
| title_full | Pain and Inflammation as Mediators of Tofacitinib Treatment Effect on Fatigue in Patients with Ankylosing Spondylitis: A Mediation Analysis |
| title_fullStr | Pain and Inflammation as Mediators of Tofacitinib Treatment Effect on Fatigue in Patients with Ankylosing Spondylitis: A Mediation Analysis |
| title_full_unstemmed | Pain and Inflammation as Mediators of Tofacitinib Treatment Effect on Fatigue in Patients with Ankylosing Spondylitis: A Mediation Analysis |
| title_short | Pain and Inflammation as Mediators of Tofacitinib Treatment Effect on Fatigue in Patients with Ankylosing Spondylitis: A Mediation Analysis |
| title_sort | pain and inflammation as mediators of tofacitinib treatment effect on fatigue in patients with ankylosing spondylitis a mediation analysis |
| topic | Ankylosing spondylitis C-reactive protein Mediation modelling Morning stiffness Pain Tofacitinib |
| url | https://doi.org/10.1007/s40744-023-00570-0 |
| work_keys_str_mv | AT larserikkristensen painandinflammationasmediatorsoftofacitinibtreatmenteffectonfatigueinpatientswithankylosingspondylitisamediationanalysis AT victorianavarrocompan painandinflammationasmediatorsoftofacitinibtreatmenteffectonfatigueinpatientswithankylosingspondylitisamediationanalysis AT marinamagrey painandinflammationasmediatorsoftofacitinibtreatmenteffectonfatigueinpatientswithankylosingspondylitisamediationanalysis AT andrewgbushmakin painandinflammationasmediatorsoftofacitinibtreatmenteffectonfatigueinpatientswithankylosingspondylitisamediationanalysis AT josephccappelleri painandinflammationasmediatorsoftofacitinibtreatmenteffectonfatigueinpatientswithankylosingspondylitisamediationanalysis AT arneyndestad painandinflammationasmediatorsoftofacitinibtreatmenteffectonfatigueinpatientswithankylosingspondylitisamediationanalysis AT oluwaseyidina painandinflammationasmediatorsoftofacitinibtreatmenteffectonfatigueinpatientswithankylosingspondylitisamediationanalysis AT peterctaylor painandinflammationasmediatorsoftofacitinibtreatmenteffectonfatigueinpatientswithankylosingspondylitisamediationanalysis |