The impact of tofacitinib on fatigue, sleep, and health-related quality of life in patients with rheumatoid arthritis: a post hoc analysis of data from Phase 3 trials

Abstract

Background: Fatigue, a common symptom of rheumatoid arthritis (RA), is detrimental to health-related quality of life (HRQoL). We evaluated the impact of tofacitinib on fatigue, sleep, and HRQoL and explored associations between fatigue, related patient-reported outcomes (PROs), and disease activity in RA patients.

Methods: This post hoc analysis pooled data from three Phase 3 studies of tofacitinib (ORAL Scan; ORAL Standard; ORAL Sync) in RA patients. Patients received tofacitinib 5 or 10 mg twice daily, placebo, or adalimumab (active control; ORAL Standard only, not powered for superiority) with conventional synthetic disease-modifying antirheumatic drugs. Assessed through Month (M)12 were changes from baseline in disease activity, Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F), Medical Outcomes Study Sleep scale (MOS-SS), and Short Form-36 Health Survey (SF-36) composite/domain scores, and proportions of patients reporting improvements from baseline in FACIT-F total and SF-36 domain scores ≥ minimum clinically important differences (MCIDs) or ≥ population normative values. Pearson correlations examined associations among PROs at M6. Treatment comparisons were exploratory, with p < 0.05 considered nominally significant.

Results: Generally, active treatment led to significant improvements from baseline in FACIT-F total, and MOS-SS and SF-36 composite/domain scores vs placebo, observed by M1 and maintained through M6 (last placebo-controlled time point). Through M6, more patients achieved improvements from baseline ≥ MCID and achieved scores ≥ population normative values in FACIT-F total and SF-36 domain scores with tofacitinib vs placebo. Through M12, some nominally significant improvements with tofacitinib vs adalimumab were observed. With active treatment at M6, FACIT-F scores were moderately (0.40-0.59) to highly (≥ 0.60) correlated with SF-36 composite/domain scores (particularly vitality), moderately correlated with most MOS-SS domain scores, and highly correlated with MOS-SS Sleep Problems Index I scores. Disease activity correlations were moderate with FACIT-F scores and low (0.20-0.39) to moderate with SF-36 general health domain/composite scores.

Conclusion: Tofacitinib and adalimumab generally conferred significant, clinically meaningful improvements in fatigue, sleep, and HRQoL (including vitality) vs placebo through M6, with improvements maintained to M12. M6 correlations between FACIT-F, PROs of sleep, HRQoL, and disease activity underscore the interrelatedness of multiple PROs and disease activity in RA.

Trial registration: ClinicalTrials.gov NCT00847613 (registered: February 19, 2009); NCT00853385 (registered: March 2, 2009); NCT00856544 (registered: March 5, 2009).

Keywords: Fatigue; Health-related quality of life; Patient-reported outcomes; Rheumatoid arthritis; Sleep; Tofacitinib; Vitality.

Fig. 1

Changes from baseline in disease activity up to month 12. LS mean change from baseline in a DAS28-4(ESR) and b CDAI to month 12 across treatment groups^a pooled from Phase 3 ORAL Scan, ORAL Standard, and ORAL Sync study datasets (full analysis set). ^aAll treatments were administered in combination with background conventional synthetic disease-modifying antirheumatic drugs. ^*** p < 0.001 for tofacitinib and adalimumab vs placebo; ^† p < 0.05 and ^†† p < 0.01 for tofacitinib vs adalimumab. The horizontal dashed lines represent the MCIDs. The arrows on the y-axes indicate the direction of improvement. ADA, adalimumab; BID, twice daily; CDAI, Clinical Disease Activity Index; DAS28-4(ESR), Disease Activity Score in 28 joints, erythrocyte sedimentation rate; LS, least squares; MCID, minimum clinically important difference; Q2W, once every 2 weeks; SE, standard error

Fig. 2

Changes from baseline in PROs up to month 12. LS mean change from baseline in a FACIT-F total score, b MOS-SS Sleep Problems Index I score^a, c MOS-SS Sleep Problems Index II score^b, d SF-36 PCS score, and e SF-36 MCS score to month 12 across treatment groups^c pooled from Phase 3 ORAL Scan, ORAL Standard, and ORAL Sync study datasets (full analysis set). ^aBased on six items of the MOS-SS: How often over the past 4 weeks did you … have trouble falling asleep; awaken during sleep; awaken short of breath/with headache; get enough sleep to feel rested upon waking; get amount of sleep needed; have trouble staying awake? ^bBased on the six items stated in footnote a and three additional items of the MOS-SS: How often over the past 4 weeks did you … feel that your sleep was not quiet; feel drowsy during day; how long did it usually take to fall asleep? ^cAll treatments were administered in combination with background conventional synthetic disease-modifying antirheumatic drugs. ^* p < 0.05, ^** p < 0.01, and ^*** p < 0.001 for tofacitinib and adalimumab vs placebo; ^† p < 0.05 and ^†† p < 0.01 for tofacitinib vs adalimumab. The horizontal dashed lines represent the MCIDs. The arrows on the y-axes indicate the direction of improvement. ADA, adalimumab; BID, twice daily; FACIT-F, Functional Assessment of Chronic Illness Therapy-Fatigue; LS, least squares; MCID, minimum clinically important difference; MCS, Mental Component Summary; MOS-SS, Medical Outcomes Study Sleep scale; PCS, Physical Component Summary; PRO, patient-reported outcome; Q2W, once every 2 weeks; SE, standard error; SF-36, Short Form-36 Health Survey

Fig. 3

Proportions of patients reporting improvements from baseline ≥ MCID in PROs to month 12. Proportions of patients reporting LS mean change from baseline ≥ MCID in a FACIT-F total score and b–i SF-36 domain scores, to month 12 across treatment groups^a pooled from Phase 3 ORAL Scan, ORAL Standard, and ORAL Sync study datasets (full analysis set). ^aAll treatments were administered in combination with background conventional synthetic disease-modifying antirheumatic drugs. ^* p < 0.05, ^** p < 0.01, and ^*** p < 0.001 for tofacitinib and adalimumab vs placebo; ^† p < 0.05 and ^†† p < 0.01 for tofacitinib vs adalimumab. ADA, adalimumab; BID, twice daily; FACIT-F, Functional Assessment of Chronic Illness Therapy-Fatigue; MCID, minimum clinically important difference; PRO, patient-reported outcome; Q2W, once every 2 weeks; SE, standard error; SF-36, Short Form-36 Health Survey

Fig. 4

Proportions of patients achieving normative values in PROs up to month 12. Proportions of patients who met or exceeded population normative values for a FACIT-F total score and b–i SF-36 domain scores, to month 12 across treatment groups^a pooled from Phase 3 ORAL Scan, ORAL Standard, and ORAL Sync study datasets (full analysis set). ^aAll treatments were administered in combination with background conventional synthetic disease-modifying antirheumatic drugs. Patients were not normative at baseline. ^* p < 0.05, ^** p < 0.01, and ^*** p < 0.001 for tofacitinib and adalimumab vs placebo; ^† p < 0.05 and ^†† p < 0.01 for tofacitinib vs adalimumab. ADA, adalimumab; BID, twice daily; FACIT-F, Functional Assessment of Chronic Illness Therapy-Fatigue; PRO, patient-reported outcome; Q2W, once every 2 weeks; SE, standard error; SF-36, Short Form-36 Health Survey