Axial spondyloarthritis is a chronic inflammatory rheumatic disease of the spine and sacroiliac joints, with an estimated prevalence of up to 1·4%,1 encompassing non-radiographic axial spondyloarthritis and radiographic axial spondyloarthritis, also known as ankylosing spondylitis.1, 2 Patients with non-radiographic axial spondyloarthritis and ankylosing spondylitis share common epidemiological, genetic, and clinical features, such as inflammatory back pain, functional impairment, and extra-musculoskeletal manifestations, as well as similar disease burden,3, 4, 5 response to therapy,6, 7, 8, 9, 10 and treatment recommendations.11, 12 However, radiographic findings serve as an important differentiating characteristic, as patients with non-radiographic axial spondyloarthritis do not fulfil the criteria for radiographic sacroiliitis.1 Additionally, patients with non-radiographic axial spondyloarthritis are more frequently female, have lower C-reactive protein levels, and are less likely to be HLA-B27-positive compared with patients with ankylosing spondylitis.1, 4 Non-radiographic axial spondyloarthritis is considered an earlier form of axial spondyloarthritis that can progress to ankylosing spondylitis, particularly in patients with certain predictors for radiographic progression, including elevated C-reactive protein levels, active inflammation on MRI of the sacroiliac joints, and positive HLA-B27 status.1
Research in context
Evidence before this study
We searched PubMed for articles published in English between Jan 1, 2012, and April 7, 2022, using the search terms “non-radiographic axial spondyloarthritis” and “Janus kinase inhibitors”. Ten articles were retrieved describing the disease, treatment landscape, and the 2019 American College of Rheumatology treatment recommendations. Axial spondyloarthritis is a rheumatic disease that manifests as inflammation of the spine and sacroiliac joints and is classified into two subtypes: radiographic axial spondyloarthritis (also termed ankylosing spondylitis) and non-radiographic axial spondyloarthritis. Only treatments with two different modes of action, tumour necrosis factor inhibitors and interleukin-17 inhibitors, are approved for non-radiographic axial spondyloarthritis. Janus kinase (JAK) inhibitors have been shown to be effective in ankylosing spondylitis but, to our knowledge, no randomised trials have investigated JAK inhibitors in non-radiographic axial spondyloarthritis.
Added value of this study
SELECT-AXIS 2 is the first phase 3 clinical trial to investigate the efficacy and safety of upadacitinib, a JAK inhibitor, for the treatment of non-radiographic axial spondyloarthritis. Upadacitinib met the primary endpoint of Assessment of SpondyloArthritis international Society 40 response and 12 of 14 ranked secondary endpoints at week 14 versus placebo. Patients treated with upadacitinib had significant improvements in disease activity, pain, objective signs of inflammation, and quality of life compared with placebo. Treatment with upadacitinib was well tolerated, and the safety profile of upadacitinib was consistent with what has been observed in patients with rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis. This trial showed, for the first time to our knowledge, the potential use of upadacitinib as an oral treatment option in patients with non-radiographic axial spondyloarthritis.
Implications of all the available evidence
The results from this phase 3 trial show that upadacitinib could be a safe and effective treatment option for patients with non-radiographic axial spondyloarthritis, who might prefer to use an oral therapy. The findings from this trial complement those observed in SELECT-AXIS 1 in patients with ankylosing spondylitis, showing the potential use of upadacitinib across the full spectrum of patients with axial spondyloarthritis, including those who have not received treatment or have had an inadequate response to biological therapy. The SELECT-AXIS 2 trial of patients with non-radiographic axial spondyloarthritis is ongoing to assess the long-term efficacy and safety of upadacitinib in patients with non-radiographic axial spondyloarthritis.
Because of the overall disease burden and the progressive nature of axial spondyloarthritis, treatment is recommended to manage signs and symptoms. International treatment recommendations advise using non-steroidal anti-inflammatory drugs (NSAIDs) as a first-line therapy for axial spondyloarthritis.11, 12 In patients who do not respond to NSAIDs, biologic disease-modifying antirheumatic drugs (bDMARDs), such as tumour necrosis factor (TNF) inhibitors or interleukin-17 (IL-17) inhibitors are available to treat axial spondyloarthritis.3 The Janus kinase (JAK) pathway has been found to play a part in the pathogenesis of axial spondyloarthritis,13 and JAK inhibitors have emerged as an alternative, oral treatment option in patients with ankylosing spondylitis.1, 14, 15 Upadacitinib is engineered for greater inhibitory potency for JAK1 versus other JAK isoforms; similarly, filgotinib is a JAK1 selective inhibitor.16 Other JAK inhibitor compounds have different selectivity profiles, such as baricitinib, a selective JAK1 and JAK2 inhibitor, and tofacitinib, a potent inhibitor of JAK1 and JAK3 that is less active against JAK2 and tyrosine kinase 2.16
Upadacitinib 15 mg once daily has been shown to be safe and effective in improving the signs and symptoms of ankylosing spondylitis for 2 years in a phase 2/3 clinical trial of patients naive to bDMARDs.17, 18, 19 Overall, few treatment options are available for non-radiographic axial spondyloarthritis and, to our knowledge, no clinical trials have evaluated a JAK inhibitor in patients with non-radiographic axial spondyloarthritis. Therefore, we aimed to investigate the efficacy and safety of upadacitinib 15 mg in a population with non-radiographic axial spondyloarthritis, including patients who were naïve to or had an inadequate response to bDMARDs.