On October 21, 2022, the United States (US) Food and Drug Administration (FDA) approved upadacitinib for the treatment of patients with non-radiographic axial spondyloarthritis (nr-axSpA).¹ The approval was based on the positive results of the SELECT-AXIS 2 phase 3 clinical trial which assessed the safety and efficacy of upadacitinib in adults with active nr-axSpA.¹

Axial spondyloarthritis (axSpA) is a chronic inflammatory rheumatic disease with an average symptom onset age of 28 years.² It is estimated that the prevalence of axSpA in adults in the US ranges from 0.9 % to 1.4 %, with half of them having nr-axSpA.² These patients usually present with predominantly axial involvement, characterized by inflammation of sacroiliac (SI) joints or the spine, or both.² Other associated manifestations include inflammatory back pain (IBP), peripheral joint and entheseal manifestations, and extra-articular manifestations (e.g., inflammation of the uvea).² In general, axSpA patients are treated with non-pharmaceutical therapy in conjunction with nonsteroidal anti-inflammatory drugs (NSAIDs).^3,4 Some patients with active disease who do not respond to NSAIDs should be escalated to biologic disease-modifying antirheumatic drugs (bDMARDs), such as tumor necrosis factor inhibitors (TNFis).^3,4 It is now known that the Janus kinase (JAK) pathway plays an important role in the pathogenesis of axSpA.⁴ Clinical trials in 2019 showed that upadacitinib, an oral selective JAK inhibitor, was safe and effective in improving the signs and symptoms of bDMARDs-naïve patients with ankylosing spondylitis (AS), and was subsequently approved by the FDA.⁴

More recently, the SELECT-AXIS 2 study, a randomized, double-blind, placebo-controlled, multicenter, phase 3 clinical trial, had been conducted to evaluate the safety and efficacy of upadacitinib in patients with nr-axSpA, another subtype of axSpA, and an inadequate response to NSAIDs .⁴ From November 26, 2019 to May 20, 2021, a total of 314 eligible patients were enrolled and randomized 1:1 to receive either upadacitinib 15mg daily or placebo using interactive response technology.⁴ The primary study endpoint was the proportion of patients achieving the Assessment in SpondyloArthritis international Society 40% (ASAS40) response at week 14.⁴

Results showed that upadacitinib demonstrated a significantly higher ASAS40 response rate when compared with placebo as early as week 2 (nominal p=0.043).⁴ At week 14, upadacitinib achieved a statistically higher ASAS40 response rate of 45% vs. 23% in the placebo group, with a treatment difference of 22% (95% CI: 12-32, p<0.0001).⁴ In the additional measure of disease activities, including the Bath Ankylosing Spondylitis Disease Activity Index 50% (BASDAI50), Ankylosing Spondylitis Disease Activity Score (ASDAS), ASAS partial remission, and ASAS 20%, upadacitinib also showed significantly higher response rates vs. placebo at week 14 (p<0.005).⁴ Moreover, patients’ quality of life was significantly improved with the upadacitinib treatment vs. placebo (p<0.0001).⁴

Regarding safety, similar rates of treatment-emergent adverse events (TEAEs) were observed with upadacitinib and placebo (48% vs. 46%).⁴ Serious TEAEs and adverse events leading to treatment discontinuation were reported in 3% of patients treated with upadacitinib and 1% in the placebo group.⁴ Throughout the study, no new safety signals with upadacitinib were identified, and no malignancies, major adverse cardiovascular events (MACEs), venous thromboembolism (VTE), or deaths associated with upadacitinib were observed.⁴  

In conclusion, the SELECT-AXIS 2 trial revealed the rapid and significant improvement in the signs and symptoms of nr-axSpA patients with an inadequate response to NSAIDs. The favorable safety profile of upadacitinib in nr-axSpA patients was demonstrated and was consistent with the safety findings reported in the previous clinical studies of upadacitinib. The results of SELECT-AXIS 2 supported the potential role of upadacitinib as a novel treatment option for active nr-axSpA patients.⁴