**Background:** Axial spondyloarthritis (axSpA) is a chronic inflammatory condition affecting the sacroiliac joints and spine, comprising radiographic (r-axSpA/AS) and non-radiographic (nr-axSpA) subsets. Patients with nr-axSpA experience significant disease burden including pain, functional impairment, reduced HRQoL, and work disability. Treatment goals include maximizing HRQoL through inflammation control and functional normalization. Upadacitinib, an oral JAK inhibitor, was recently approved for active nr-axSpA based on the SELECT-AXIS 2 trial. This analysis evaluated its effect on HRQoL and work productivity.
**Methods:** SELECT-AXIS 2 was a 52-week global, multicenter, phase 3 RCT. Patients with active nr-axSpA and inadequate response/intolerance to ≥2 NSAIDs were randomized 1:1 to upadacitinib 15 mg once daily or placebo. Key inclusion required objective inflammation signs (MRI or elevated CRP). Prior treatment with ≤1 bDMARD was permitted for 20-35% of patients. Outcomes assessed through week 14 included mean changes from baseline in ASQoL, ASAS HI, SF-36 PCS (via MMRM), and WPAI domains (via ANCOVA). Proportions achieving ≥MCID were assessed using NRI-MI. ASQoL and ASAS HI were ranked secondary endpoints controlling for multiplicity; other P values were nominal. Subgroup analyses by prior TNFi status were performed post hoc.
**Key Results:** 313 patients were randomized (156 upadacitinib, 157 placebo). Most were female (58.5%), mean age ~42 years. Baseline HRQoL impairment was substantial (mean ASQoL 11.9, ASAS HI ~9.5, SF-36 PCS ~34.7; WPAI overall work impairment ~57.5). At week 14, upadacitinib showed significantly greater improvements versus placebo in ASQoL and ASAS HI (ranked, P<0.001) and SF-36 PCS (nominal P<0.001). Improvements were observed as early as week 2 (ASAS HI) and week 4 (ASQoL, SF-36 PCS). Greater proportions of upadacitinib vs. placebo patients achieved ≥MCID: ASQoL 62.6% vs. 40.9% (nominal P≤0.001), ASAS HI 44.8% vs. 28.8% (nominal P≤0.01), SF-36 PCS 69.3% vs. 52.0% (nominal P≤0.01). NNTs were 4.6, 6.2, and 5.8, respectively. Upadacitinib also improved WPAI presenteeism, overall work impairment, and activity impairment (nominal P<0.05), but not absenteeism (P=0.3387). In TNFi-naïve patients (n=226), MCID achievement was significantly higher with upadacitinib (ASQoL 64.0% vs. 38.7%, P≤0.001; ASAS HI 46.4% vs. 27.3%, P≤0.01; SF-36 PCS 70.4% vs. 54.1%, P≤0.01). In TNFi-IR patients (n=87), numerical improvements were observed (ASQoL 59.1% vs. 46.5%, P=0.2216; ASAS HI 40.9% vs. 32.6%, P=0.4166; SF-36 PCS 66.7% vs. 46.5%, P<0.05). Among patients achieving MCID, a higher proportion of upadacitinib-treated patients achieved ASDAS inactive disease (ASQoL: 21.5% vs. 9.4%; ASAS HI: 28.6% vs. 11.1%; SF-36 PCS: 20.3% vs. 8.6%; all nominal P<0.05).
**Clinical Implications:** Upadacitinib provides rapid and clinically meaningful improvements in HRQoL and work productivity in active nr-axSpA, with benefits observed as early as weeks 2-4 and sustained through week 14. NNTs <10 across all MCID outcomes indicate clinically relevant treatment effects. Improvements were consistent regardless of prior TNFi exposure, supporting upadacitinib as a treatment option for patients refractory to bDMARDs. Limitations include small sample size for subgroup analyses, short 14-week follow-up, and potential limited generalizability to real-world populations. These findings, combined with previously reported efficacy in AS, support upadacitinib's benefit across the full axSpA spectrum.