Upadacitinib may be more effective in reducing pain than adalimumab or placebo in patients with rheumatoid arthritis, including in patients with and without attenuation of inflammation, while producing pain improvements similar to adalimumab in patients with psoriatic arthritis, according to post hoc analyses of two phase III randomized trials.
The findings derive from SELECT-COMPARE in rheumatoid arthritis (RA) and SELECT-PsA 1 in psoriatic arthritis (PsA). In SELECT-COMPARE, patients who had RA and active disease despite receiving treatment with methotrexate were randomly assigned to receive either upadacitinib 15 mg once daily, adalimumab 40 mg every other week, or placebo for 26 weeks.
In SELECT-PsA 1, patients with PsA and inadequate response or intolerance to at least one nonbiologic disease-modifying antirheumatic drug were randomly assigned to receive either upadacitinib 15 mg once daily, adalimumab 40 mg every other week, or placebo.
Pain was assessed using the Patient’s Global Assessment of pain (PtGA) and 28-joint tender joint count. The patients were stratified by attenuation of inflammation, defined as a swollen joint count of 0 and C-reactive protein level of less than 6 mg/L.
RA Outcomes
Among patients with attenuation of inflammation, least squares mean change in PtGA pain at week 12 was −42.9 with upadacitinib vs −34.7 with adalimumab and −33.1 with placebo. The improvements were similar across the groups by week 26.
Upadacitinib-treated patients were more likely to achieve attenuation of inflammation at weeks 12 and 26 (18.1% and 28.7%) compared with adalimumab (11.3% and 18.3%) or placebo (4.1% and 6.3%).
Among the patients with remaining inflammation, upadacitinib produced greater response rates for 30%, 50%, and 70% pain reduction at week 12 vs placebo and adalimumab, with effects maintained vs placebo at week 26.
Mediation analysis showed that the direct effect of upadacitinib on pain in RA was nearly double that of adalimumab between weeks 2 and 12 and was maintained at week 26. The indirect effects mediated through inflammatory markers were generally similar between treatments.
PsA Outcomes
Among patients with attenuation of inflammation, the least squares mean change in PtGA pain with upadacitinib was −2.7 at week 12 and −3.8 at week 24 compared with −1.8 and −2.8 with placebo. Improvements were similar between upadacitinib and adalimumab. In patients with remaining inflammation, upadacitinib also demonstrated greater improvements vs placebo at weeks 12 and 24.
The total effects on elicited pain, assessed by tender joint count improvement at weeks 16 and 24 were 2.16 and 2.30 with upadacitinib vs placebo and 1.35 and 1.71 with adalimumab vs placebo. The direct effects on PtGA pain in PsA were 0.98 at weeks 16 and 24 for upadacitinib vs 0.83 and 0.82 for adalimumab.
Interpretation and Limitations
The researchers reported that residual pain persisted despite attenuation of inflammation and that pain reduction was observed both with and without inflammatory control. In RA, overall pain improvement was greater with upadacitinib vs placebo compared with adalimumab vs placebo, driven mainly by direct effects.
The study was limited by its post hoc design, differing trial designs between diseases, and lack of early data in PsA. The researchers noted that their indices of inflammation were approximate and may not have captured all aspects of inflammation.
“Whereas pain improvement in both RA and PsA is associated with inflammation resolution, it is apparent that some pain amelioration can occur independent of reduction in inflammation,” noted lead study author Peter C. Taylor, of the Nuffield Department of Orthopaedics in Rheumatology and Musculoskeletal Sciences at the University of Oxford, and colleagues.
Full disclosures can be found in the study.
Source: RMD Open
