Effect of tofacitinib on pain, fatigue, health-related quality of life and work productivity in patients with active ankylosing spondylitis: results from a phase III, randomised, double-blind, placebo-controlled trial

Abstract

Background: Ankylosing spondylitis (AS) impacts quality of life. We assessed patient-reported outcomes (PROs), pain, fatigue, health-related quality of life (HRQoL) and work productivity in a phase III trial of tofacitinib.

Methods: Adults with AS and with inadequate response/intolerance to ≥2 non-steroidal anti-inflammatory drugs received tofacitinib 5 mg twice daily or placebo for 16 weeks. Afterwards, all received open-label tofacitinib until week 48. Change from baseline to week 48 was determined for PROs: total back pain; nocturnal spinal pain; Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) overall spinal pain (Q2); Functional Assessment of Chronic Illness Therapy-Fatigue; BASDAI fatigue (Q1); AS Quality of Life (ASQoL); Short Form-36 Health Survey Version 2 (SF-36v2); EuroQoL-Five Dimension-Three Level health profile and Visual Analogue Scale; and the Work Productivity and Activity Impairment (WPAI) questionnaire. Improvements from baseline ≥minimum clinically important difference, and scores ≥normative values at week 16 were evaluated.

Results: In 269 randomised and treated patients, at week 16, there were greater least squares mean improvements from baseline with tofacitinib 5 mg twice daily versus placebo in BASDAI overall spinal pain (-2.85 vs -1.34), BASDAI fatigue (-2.36 vs -1.08), ASQoL (-4.03 vs -2.01) and WPAI overall work impairment (-21.49 vs -7.64) (all p<0.001); improvements continued/increased to week 48. Improved spinal pain with tofacitinib was seen by week 2. Patients receiving tofacitinib reported clinically meaningful PRO improvements at week 16. Percentages with PRO scores ≥normative values at week 16 were greater with tofacitinib in SF-36v2 Physical Component Summary, physical functioning and bodily pain domains (p≤0.05).

Conclusions: In patients with AS, treatment with tofacitinib 5 mg twice daily resulted in clinically meaningful improvements in pain, fatigue, HRQoL and work productivity versus placebo to week 16, which were sustained to week 48.

Trial registration number: NCT03502616.

Keywords: Antirheumatic Agents; Inflammation; Patient Reported Outcome Measures.

Figure 1

Changes from baseline to week 48 in (A) nocturnal and (B) BASDAI overall spinal pain. LS mean changes from baseline are shown to week 48 for (A) nocturnal spinal pain and (B) BASDAI overall spinal pain, in patients with AS receiving tofacitinib 5 mg twice daily or placebo→tofacitinib 5 mg twice daily.^† Results up to week 16, based on MMRM, include all postbaseline data to week 16 (data cut-off 19 December 2019; data snapshot 29 January 2020); results after week 16 are based on another MMRM including all postbaseline data to week 48 (reporting results after week 16 only). *p≤0.05, **p<0.01, ***p<0.001 for comparing tofacitinib 5 mg twice daily versus placebo (up to week 16) or placebo→tofacitinib 5 mg twice daily (up to week 48). P values are reported without adjustment for multiple comparisons. ^†Patients receiving placebo advanced to tofacitinib 5 mg twice daily at week 16 (dashed line). ∆, change from baseline; BASDAI, Bath Ankylosing Spondylitis Disease Activity Index; BID, twice daily; LS, least squares; MMRM, mixed model for repeated measures; N, number of patients in full analysis set; N1, number of patients with observation at visit, if different from the full analysis set.

Figure 2

PRO (A, B) improvements ≥MCID^† and NNTs,^‡ and (C, D) scores ≥normative values^§ at week 16. Data are from the week 16 analysis: data cut-off 19 December 2019; data snapshot 29 January 2020. Missing response was considered as non-response. P values are nominal. *p≤0.05, **p<0.01, ***p<0.001 for comparing tofacitinib 5 mg twice daily versus placebo at week 16; Cochran-Mantel-Haenszel approach adjusting for stratification factor (bDMARD-naïve versus TNFi-IR or bDMARD use (non-IR)). ^†MCID cut-offs: total back pain, nocturnal spinal pain, BASDAI overall spinal pain and BASDAI fatigue, decrease from baseline ≥1; FACIT-F total score, increase from baseline ≥4.0; ASQoL, decrease from baseline ≥1.8; SF-36v2 PCS and MCS scores, increase from baseline ≥2.5; eight SF-36v2 domain 0–100 scores, increase from baseline ≥5.0: EQ-VAS, increase from baseline ≥10 mm. ^‡NNT defined as the inverse of the difference in proportions of patients in the tofacitinib arm versus placebo arm reporting ≥MCID. ^§≥normative values: FACIT-F total score, ≥43.5; SF-36v2 PCS and MCS scores, ≥50; and eight SF-36v2 domain 0–100 scores: physical functioning, ≥88.23; role-physical, ≥87.96; bodily pain, ≥76.81; general health, ≥73.00; vitality, ≥60.55; social functioning, ≥87.66; role-emotional, ≥91.04; mental health, ≥76.70 (the domain-specific cut-offs were calculated as the study protocol’s age-distributed and sex-distributed means matched to the 1998 US population norms on the raw scale with a range of 0–100). AS, ankylosing spondylitis; ASQoL, Ankylosing Spondylitis Quality of Life; BASDAI, Bath Ankylosing Spondylitis Disease Activity Index; bDMARD, biologic disease-modifying antirheumatic drug; BID, twice daily; EQ-VAS, EuroQol Visual Analogue Scale; FACIT-F, Functional Assessment of Chronic Illness Therapy-Fatigue; IR, inadequate response; MCID, minimum clinically important difference; MCS, Mental Component Summary; N, number of patients in full analysis set; NNT, number needed to treat; PCS, Physical Component Summary; PRO, patient-reported outcome; SF-36v2, Short Form-36 Health Survey Version 2; TNFi, tumour necrosis factor inhibitor.

Figure 3

Changes from baseline to week 48: FACIT-F (A) experience, (B) impact and (C) BASDAI fatigue. LS mean changes from baseline to week 48 for FACIT-F (A) experience, (B) impact and (C) BASDAI fatigue in patients with AS receiving tofacitinib 5 mg twice daily or placebo→tofacitinib 5 mg twice daily.^† Results up to week 16, based on MMRM, include all postbaseline data to week 16 (data cut-off 19 December 2019; data snapshot 29 January 2020); results after week 16 are based on another MMRM including all postbaseline data to week 48 (reporting results after week 16 only). *p≤0.05, **p<0.01, ***p<0.001 for comparing tofacitinib 5 mg twice daily versus placebo (up to week 16) or placebo→tofacitinib 5 mg twice daily (up to week 48). P values are reported without adjustment for multiple comparisons. ^†Patients receiving placebo advanced to tofacitinib 5 mg twice daily at week 16 (dashed line). ∆, change from baseline; AS, ankylosing spondylitis; BASDAI, Bath Ankylosing Spondylitis Disease Activity Index; BID, twice daily; FACIT-F, Functional Assessment of Chronic Illness Therapy-Fatigue; HRQoL, health-related quality of life; LS, least squares; MMRM, mixed model for repeated measures; N, number of patients in full analysis set; N1, number of patients with observation at visit, if different from the full analysis set.

Figure 4

Spydergrams of SF-36v2 domains from baseline to (A) week 16 and (B) week 48. Spydergrams of SF-36v2 domain scores from baseline to (A) week 16 (data cut-off 19 December 2019; data snapshot 29 January 2020) and (B) week 48 versus age-matched and sex-matched norms, in patients with AS receiving tofacitinib 5 mg twice daily or placebo→tofacitinib 5 mg twice daily.^† Spydergrams were based on sample means generated using domain 0–100 scores. US age-sex norms were matched to the protocol population. Spydergrams are for illustrative purposes only. **p<0.01, ***p<0.001 for tofacitinib 5 mg twice daily versus placebo (week 16) without adjustment for multiple comparisons. P values at week 16 were generated using ANCOVA, including data at week 16 for comparisons with placebo based on LS mean changes from baseline in domain norm-based scores to week 16. ^†Patients receiving placebo advanced to tofacitinib 5 mg twice daily at week 16. ANCOVA, analysis of covariance; AS, ankylosing spondylitis; BID, twice daily; LS, least squares; SF-36v2, Short Form-36 Health Survey Version 2.