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The oral JAK inhibitor upadacitinib (Rinvoq) was more effective than the T-cell costimulation modulator abatacept (Orencia) in patients with moderate-to-severe rheumatoid arthritis who had an inadequate response to previous biologic therapy in a phase III trial.

At week 12, the mean change from baseline on the Disease Activity Index in 28 joints (DAS28, based on C-reactive protein [CRP]) was -2.52 points among patients randomized to upadacitinib compared with -2 points for those given abatacept, according to Andrea Rubbert-Roth, MD, of the Cantonal Clinic St. Gallen in Switzerland, and colleagues.

This represented a difference of -0.52 points (95% CI -0.69 to -0.35, P<0.001 for both noninferiority and superiority), the investigators reported in the .

However, upadacitinib was associated with more adverse events, including two venous thromboembolic events.

"Rheumatologists will be looking hard at future data to assess whether improved treatment outcomes justify an increased risk of adverse events," wrote Guro L. Goll, MD, PhD, and Tore K. Kvien, MD, PhD, of Diakonhjemmet Hospital in Oslo, Norway, in an .

The proliferation of biologic therapies and small molecules such as JAK inhibitors for rheumatoid arthritis in recent years has led to questions of what to do after a patient has an inadequate response or cannot tolerate their initial biologic therapy.

Current recommendations from the American College of Rheumatology and the European League Against Rheumatism suggest that the next step could be a JAK inhibitor, a tumor necrosis factor inhibitor, or a biologic with a different mechanism of action than the initial agent.

Both upadacitinib and abatacept have demonstrated efficacy in rheumatoid arthritis. To compare them head-to-head, the investigators conducted a double-blind trial at 120 sites in 28 countries, randomly assigning 612 patients to 15 mg oral upadacitinib daily or intravenous abatacept every 4 weeks, with weight-based dosing.

Stable background medications were permitted, including conventional disease-modifying antirheumatic drugs (DMARDs), nonsteroidal anti-inflammatory drugs, acetaminophen, and glucocorticoids.

The double-blind phase of the trial, which was known as SELECT-CHOICE and sponsored by AbbVie, followed patients for 24 weeks, and an extension phase is planned for up to 5 years.

More than 80% of patients were women, almost all were white, and mean age was 55.5.

Baseline DAS28-CRP was 5.70 in the upadacitinib group and 5.88 in the abatacept group.

At week 12, the proportion of patients achieving remission, defined as a DAS28-CRP below 2.6, was 30% in the upadacitinib group compared with 13.3% in the abatacept group, for a difference of 16.8 points (95% CI 10.4 to 23.2, P<0.001).

Mean changes at week 12 on the core components of the DAS28-CRP for the upadacitinib and abatacept groups, respectively, were:

• Tender joint counts, -10.49 vs -9.32 (difference -1.17, 95% CI -1.96 to -0.39)

• Swollen joint counts, -7.73 vs -7.31 (difference -0.41, 95% CI-0.97 to 0.14)

• Patient's global assessment, -33.85 vs -28.35 (difference -5.49, 95% CI -9.27 to -1.71)

• CRP, -12.34 mg/L vs -7.13 mg/L (difference -5.21, 95% CI -6.87 to -3.56)

Because the DAS28-CRP incorporates high-sensitivity CRP levels, the investigators also did exploratory analyses for endpoints not based on CRP, such as the DAS28-erythrocyte sedimentation rate and the Clinical Disease Activity Index, with "results in the same direction as the results for the primary endpoint," Rubbert-Roth and co-authors said.

Throughout the 24-week double-blind phase of the trial, numerically more adverse events were observed in the upadacitinib group. Serious adverse events occurred in 10 patients receiving upadacitinib and in five given abatacept, serious infections in three and one, respectively, and opportunistic infections in four and one. Herpes zoster infections developed in four patients in each group.

Hepatic abnormalities -- usually nonserious elevations of liver enzymes -- were observed in 23 patients in the upadacitinib group and five in the abatacept group. Changes in low-density lipoprotein and high-density lipoprotein from baseline through week 24 also were higher with upadacitinib.

One major cardiovascular event, a nonfatal stroke, occurred in a patient in the upadacitinib group; the patient had a previous cerebrovascular accident. The two thromboembolic events were a deep vein thrombosis in an obese patient with hypertension and a pulmonary embolism in a patient who had previously had a pulmonary embolism.

One treatment-emergent death from cardiac arrest following pneumonia occurred in the upadacitinib group and one death from unknown cause after the treatment period was seen in each group.

"By showing the superiority of upadacitinib over abatacept in difficult-to-treat patients with rheumatoid arthritis who had an inadequate response to a biologic DMARD, Rubbert-Roth et al. position JAK inhibitors in a treatment algorithm and help push JAK inhibitors to the forefront of treatment for rheumatoid arthritis," Goll and Kvien wrote.

However, "in order to compete in the crowded field of targeted treatments for rheumatoid arthritis, JAK inhibitors not only have to prove that they are efficacious and safe -- they also need to be less expensive than or clinically superior to biologic DMARDs," the editorialists cautioned.

Rubbert-Roth and co-authors added that longer-term data from larger studies will be needed to fully establish the safety and efficacy of upadacitinib.

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