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Upadacitinib Monotherapy Hinders Joint Damage in RA

Upadacitinib monotherapy was effective in inhibiting structural joint damage progression in patients with rheumatoid arthritis who were MTX-naïve or had an inadequate response to MTX.

Patients with moderate-to-severe rheumatoid arthritis (RA) receiving either upadacitinib monotherapy or in conjunction with methotrexate (MTX) was effective in inhibiting structural joint damage progression in MTX-naïve and MTX inadequate response (MTX-IR) patients through 1 year, according to a study published in Rheumatology.1

“Biologic disease-modifying antirheumatic drugs (DMARDs), such as tumor necrosis factor (TNF) inhibitors, have demonstrated sustained inhibition of radiographic progression with long-term treatment when administered as monotherapy or in combination with MTX in patients with early and established RA,” investigators explained. “In recent years, several novel targeted synthetic DMARDs have been approved for the treatment of RA, with demonstrated effects on structural joint progression.”

Radiographic progression was evaluated in 2 Phase 3 randomized, double-blind controlled trials. Both trials enrolled patients with active RA and elevated high-sensitivity c-reactive protein (CRP) who were at an increased risk of radiographic progression. The MTX-naïve (3 or fewer doses coupled with a 4-week washout period) cohort were randomized to receiving either upadacitinib 15 mg or 30 mg once daily or MTX monotherapy in the SELECT-EARLY trail (n = 945). Supplemental therapies (glucocorticoids, nonsteroidal anti-inflammatory drugs [NSAIDs], or low-potency analgesics) were allowed for patients who did not achieve 20% improvement by Week 12.

MTX-IRs, as defined as an inadequate response for ≥3 months, received upadacitinib 15 mg once daily, adalimumab 40 mg every other week, or placebo in addition to MTX in the SELECT-COMPARE trial (n = 1629). Patients initially receiving placebo were switched to upadacitinib by Week 26. Those in the adalimumab cohort who were not experiencing low disease activity by Week 26 were switched to upadacitinib. Conversely, those receiving upadacitinib who did not achieve low disease activity were switched to adalimumab. Both changes were done blindly. Mean changes from baseline were determined utilizing a van der Heijde modified total Sharp score (mTSS) and joint-space narrowing and erosion scores at 6 months and 1 year.

Bilateral radiographs of hands and feet were obtained via side-verifying positioning frames.

The mean time since diagnosis was 2.6 to 2.9 years in the SELECT-EARLY trial and 8.1 to 8.3 years in SELECT-COMPARE. In SELECT-COMPARE, mean MTX dose ranged from 16.8 to 17.1 mg per week across all groups.

Of the 945 patients in the MTX-naïve (SELECT-EARLY) cohort, 314 received MTX, 317 were treated with upadacitinib 15 mg, and 314 received upadacitinib 30 mg. Based on linear extrapolation (LE), upadacitinib was associated with inhibition of structural joint damage progression. Changes from baseline in mTSS were 0.03 for those receiving upadacitinib 15 mg, 0.14 for upadacitinib 30 mb, and 1.00 for MTX at 1 year. A clinically significantly higher proportion of patients in the upadacitinib 15 mg and 30 mg monotherapy group exhibited no radiographic progression when compared with MTX monotherapy at both 6 months and 1 year. Joint-space narrowing and erosion scores showed similar results, with both being significantly reduced from baseline in patients receiving upadacitinib monotherapy in the 15 mg and 30 mg doses, when compared with MTX monotherapy at 6 months and 1 year.

In the MTX-IR (SELECT-COMPARE) group, 651 were receiving placebo, 651 were receiving upadacitinib 15 mg, and 327 were being treated with adalimumab. Changes from baseline in mTSS reported significant reduction in radiographic progression in the upadacitinib 15 mg plus MTX cohort vwhen compared with placebo plus MTX at 1 year (0.28 vs 1.73; P < 0.001). The change in the adalimumab 40 mg plus MTX group was 0.39. Joint-space narrowing and erosion scores in the upadacitinib 15 mg with background MTX were significantly reduced when compared with placebo with background MTX at 1 year (−0.62 [−0.91, −0.34] and −0.66 [−0.95, −0.37], respectively).

Patients who were rescued or switched to upadacitinib by Week 26 in the SELECT-COMPARE trial limited the study, as there was no true placebo group to compare results with. An underestimation of standard errors may have occurred due to the assumption that the rate of change in radiographic progression was linear in the LE analysis, which attributed missing data. Further, the SELECT-COMPARE study was not designed to compare for radiographic endpoints. Biomarkers, not included in the analysis, may have better identified patients more likely to have radiographic progression.

A strength included the large population of both MTX-naïve and MTX-IR patients with active RA and progression-related characteristics.

“Upadacitinib significantly inhibited the progression of structural joint damage through 1 year in patients with active RA who were at increased risk for joint damage, both as monotherapy in MTX-naïve patients and in combination with background MTX in MTX-IR patients,” investigators concluded. “These findings provide further support that upadacitinib is an effective treatment for the management of RA.”


Peterfy CG, Strand V, Friedman A, et al. Inhibition of Structural Joint Damage Progression with Upadacitinib in Rheumatoid Arthritis: 1-Year Outcomes from the SELECT Phase 3 Program [published online ahead of print, 2021 Dec 13]. Rheumatology (Oxford). 2021;keab861. doi:10.1093/rheumatology/keab861