Data from 269 patients (receiving tofacitinib: n = 133 or placebo: n = 136) were included in this post hoc analysis. Patient demographics and baseline disease characteristics have been reported previously [19]; they were generally similar across treatment groups. Briefly, in patients receiving tofacitinib or placebo, most patients were male (87.2% and 79.4%, respectively), were receiving NSAIDs (79.7% and 79.4%), and were bDMARD-naïve (76.7% and 77.2%). Of patients receiving tofacitinib or placebo who reported their race, 18.8% and 22.1% were Asian, respectively, and 80.5% and 77.9% were White, respectively. Mean disease duration since symptom onset was 14.2 (standard deviation [SD]: 9.8) years (tofacitinib-treated patients) and 12.9 (SD: 9.5) years (placebo) [19]. For tofacitinib-treated patients, mean FACIT-F total score was 27.2 (maximum score: 52; SD: 10.7); experience domain score was 8.9 (maximum score: 20; SD: 4.3), impact domain score was 18.3 (maximum score: 32; SD: 6.9), and Bath AS Disease Activity Index (Fatigue) (Question 1, numeric rating scale 0–10) score was 6.8 (SD: 1.5). Corresponding mean (SD) values for patients who received placebo were 27.4 (9.3), 8.7 (4.0), 18.8 (5.9), and 6.8 (1.7), respectively [14, 19].

In general, the median time to initial improvement events in the FACIT-F total score was shorter in patients receiving tofacitinib versus placebo (Fig. 1a, d; p < 0.05), indicating that fatigue initially improved more rapidly for tofacitinib versus placebo. Median time to a clinically meaningful initial improvement event of 6 points in the FACIT-F total score was 8 weeks with tofacitinib; however, with placebo, median time to an initial improvement event of 6 points was not reached within 16 weeks (Fig. 1a, d). Similarly, median time to an initial improvement event of 20% and 40% change in FACIT-F total score was 6 weeks and not reached, respectively, with tofacitinib (placebo: 16 weeks for 20% and not reached for 40% change).

Probability estimates for initial improvements (a–c). Median times to initial improvement events (d–f). Panels a–c: Median times to initial improvement events in fatigue were evaluated from baseline and were the first post-baseline week where patients experienced an improvement event in FACIT-F total score (6 points) or a domain score (3 and 4 points in experience and impact domains, respectively). Improvements at these thresholds were considered clinically meaningful (i.e., meaningful within-patient change) [25]. Panels d–f*: Test of equality over strata log-rank test, p < 0.05 (tofacitinib 5 mg twice daily versus placebo). Median times to initial improvement events in FACIT-F total score or domain scores as a function of the improvement event threshold (1–10 points; x-axis). Median time to initial improvement events (y-axis) was based on absolute changes in FACIT-F scores, according to the specified thresholds of improvement events (x-axis). The vertical dotted line represents the threshold for a clinically meaningful improvement event (≥ 6 points for total score, ≥ 3 points for experience domain score, and ≥ 4 points for impact domain score) [25]. FACIT-F Functional Assessment of Chronic Illness Therapy–Fatigue

Initial improvements in FACIT-F total score were observed in patients receiving tofacitinib and placebo at all thresholds within 16 weeks; however, a greater proportion of patients receiving tofacitinib experienced initial improvement versus placebo (Table 1). Initial improvement events of 20% and 40% in the FACIT-F total score were experienced by 66.2% and 43.6% of patients receiving tofacitinib (placebo: 50.7% and 25.7%), respectively (see Table S1 in the electronic supplementary material).

Similar trends were observed for the FACIT-F experience and impact domains (Fig. 1b, c, e, and f). More patients receiving tofacitinib versus placebo experienced initial improvement events for the FACIT-F experience and impact domains within 16 weeks (Table 1).

In general, median time to stable improvement events in FACIT-F total score (i.e., sustained on average at threshold up to week 16) was shorter in patients receiving tofacitinib versus placebo (Fig. 2a and d; p < 0.05]), indicating that sustained improvement in fatigue occurred more rapidly for tofacitinib versus placebo. Median time to a stable improvement event of 6 points in FACIT-F total score (considered clinically meaningful) was 12 weeks with tofacitinib and was not reached within 16 weeks with placebo (Fig. 2a, d). With placebo, only a median time to a stable improvement event of 2 points in FACIT-F total score was reached within 16 weeks (Fig. 2d). Median time to a stable improvement event of 20% and 40% change in FACIT-F total score was 8 weeks and not reached, respectively, with tofacitinib (placebo: not reached for both).

Probability estimates for stable improvements (a–c). Median times to stable improvement events (d–f). Panels a–c: Median times to stable improvement events in fatigue were evaluated from baseline and were the first post-baseline week where patients experienced an improvement event in FACIT-F total score (6 points) or a domain score (3 and 4 points in experience and impact domains, respectively) and then sustained on average at that threshold (based on at least two time points) up to week 16. Improvements at these thresholds were considered clinically meaningful (i.e., meaningful within-patient change) [25]. Panels d–f*: Test of equality over strata log-rank test, p < 0.05 (tofacitinib 5 mg twice daily versus placebo). Times to stable improvement in fatigue were evaluated based on the week at which an improvement event in FACIT-F total score or a domain score of 1–10 points was reached and then sustained on average at that threshold (based on at least two time points) up to week 16. Median time to a stable improvement event (y-axis) was based on absolute changes in FACIT-F scores, according to specified thresholds of improvement event (x-axis). The vertical dotted line represents a conservative threshold for a clinically meaningful improvement event (≥ 6 points for total score, ≥ 3 points for experience domain score, and ≥ 4 points for impact domain score). FACIT-F Functional Assessment of Chronic Illness Therapy–Fatigue

Stable improvements in FACIT-F total scores within 16 weeks were observed for patients receiving tofacitinib and placebo, although more patients receiving tofacitinib experienced stable improvement events versus placebo (Table 2). Stable improvement events of 20% and 40% in the FACIT-F total score were experienced by 57.1% and 32.3% of patients receiving tofacitinib (placebo: 27.9% and 14.0%), respectively (see Table S2 in the electronic supplementary material).

Similar trends were observed for the FACIT-F experience and impact domains (Fig. 2b, c, e, and f). Median time to stable improvement events of 20% in the FACIT-F experience and impact domains was 4 and 12 weeks, respectively, with tofacitinib (placebo: not reached); median time to a 40% improvement event was not reached in either treatment group for both domains.

Similar to FACIT-F total score, significantly more patients receiving tofacitinib versus placebo experienced stable improvement events in FACIT-F experience and impact domains within 16 weeks [except for the 10-point threshold in the experience domain (Table 2)].

In patients receiving tofacitinib, stable improvement events in FACIT-F total score occurred either simultaneously or shortly after initial improvement events (within 4 weeks); the same trend was observed for FACIT-F domains (see Fig. S1a in the electronic supplementary material). The time between achieving initial and stable improvement events in FACIT-F total score and domain scores was generally longer in patients receiving placebo (see Fig. S1b in the electronic supplementary material).

Patients receiving tofacitinib who experienced initial improvement events in FACIT-F total score within 16 weeks were more likely to also experience stable improvement events in the FACIT-F total score, compared with placebo (Table 3). More than 80% (80–96 out of 97–109) of patients receiving tofacitinib who experienced initial improvement events of 3–5 points in the FACIT-F total score then sustained this improvement on average to week 16 (Table 3).