Are JAK Inhibitors Better at Pain Relief in RA? Save

Among rheumatoid arthritis (RA) patients responding to upadacitinib (Rinvoq) or adalimumab, those receiving the former had significantly less residual pain with treatment, according to a post-hoc analysis of phase III trial data.

Pain scores (rated 0-100) for patients whose inflammation had largely resolved fell 42.9 points with upadacitinib as compared with 34.7 points with adalimumab and 33.1 points with placebo (both P<0.05 vs upadacitinib) after 12 weeks in the head-to-head SELECT-COMPARE trial, according to Peter C. Taylor, PhD, of the University of Oxford in England, and colleagues.

The same analysis performed on data from the similarly designed SELECT-PsA 1 trial in psoriatic arthritis showed similar degrees of pain relief for the two drugs, both of which outperformed placebo, the researchers reported in RMD Open.

"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, apparently through direct pain modulation at a more central level," the group wrote.

Such analyses are often sponsored by drugmakers seeking to boost their products' reputations, and indeed this one was funded by AbbVie. But the company makes both upadacitinib and adalimumab, the latter holding the title of best-selling drug of all time and still a top moneymaker despite intense competition. A financial motive to promote upadacitinib, an oral Janus kinase (JAK) inhibitor, at adalimumab's expense is thus not immediately apparent.

Taylor and colleagues performed the study to help settle a persistent question in inflammatory disease management. Pain is usually the most important symptom for patients, but drug developers have focused more on objective (read: easily measured) outcomes such as swollen joints. Pain relief usually accompanies improvement in inflammation, but the correlation is far from perfect. Do some disease-modifying anti-rheumatic drugs (DMARDs) do better than others at relieving pain despite equivalent effects on inflammation?

AbbVie's two placebo-controlled trials comparing upadacitinib and adalimumab against placebo thus appear to be ideal data sources to address this question. These were huge studies, with more than 1,600 patients included in each with primary endpoints of overall disease improvement. In both, patients were randomized to upadacitinib, adalimumab, or placebo; the PsA study had two upadacitinib arms, with doses of 15 or 30 mg/day. Taylor's group excluded patients assigned to the higher dose, leaving about 1,300 in total. All 1,629 participating in the three-arm RA study were included in the new analysis.

The authors then divided participants according to their inflammation responses, categorized as having "attenuation of inflammation" (AoI) or remaining inflammation, after 12 and 26 weeks in the RA trial and 12 and 24 weeks in the PsA study. AoI was defined as a 66-joint swollen joint count of 0, plus a C-reactive protein (CRP) level below 6 mg/L. In the RA study, about 18% of patients achieved AoI at week 12, and 29% did so at week 26.

Upadacitinib generally outperformed adalimumab in the RA trial, with AoI rates about 50% greater. At week 12, AoI had been achieved by 18% with upadacitinib versus 11% with adalimumab; at week 26, the corresponding values were 29% and 18%, respectively. This same pattern was also seen in the PsA study.

Taylor and colleagues then directed their attention to patient-reported pain responses in the AoI subgroups. These clearly favored upadacitinib in the RA study at week 12, but not in the PsA study. This advantage in the RA study disappeared, however, by week 26.

Among patients with remaining inflammation, those with RA also saw greater pain relief with the JAK inhibitor versus the biologic at week 12, and this difference, too, did not last to week 26. On the PsA side, no significant difference in pain relief between the drugs was ever seen.

The investigators then used "mediation analysis" to try to separate direct analgesic effects from pain relief resulting with reduced inflammation. This involved establishing correlations between changes in pain scores and markers of inflammation including swollen joint count, CRP level, and erythrocyte sedimentation rate, with the placebo group as the reference. Effects on pain not accounted for by anti-inflammatory responses were considered to have stemmed from direct action against pain signalling.

Upadacitinib was determined to have significantly greater direct-acting analgesic effect compared with adalimumab. This was most prominent in RA patients at the 12-week time point, in which the direct effect was estimated at 12.4% of the total, versus 6.3% for adalimumab.

Limitations to the study included its post-hoc design, not prespecified in the original trial protocols. Also, the researchers acknowledged that their inflammation measures were "approximate" and "incomplete."