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10th August 2021
Atopic eczema (AE) is a common, chronic, relapsing-remitting skin condition, characterised by inflammation and intense pruritus and which has a substantial impact on quality of life. It affects up to 22.6% of children, whereas the prevalence in adults varies between 1.2 to 17.1%. While the precise cause of AE remains to be clarified, it is driven by pro-inflammatory interleukins (IL) including IL-4 and IL-13. Evidence that these two cytokines have an important role in the pathophysiology comes from studies with the monoclonal antibody dupilumab.
Though dupilumab was the first biologic agent to be used in patients with moderate-to-severe atopic eczema, only just over a third of patients in two of the largest trials achieved the primary endpoint of clear or almost clear skin. Thus, other pathways are likely to be involved in AE and recent work has implicated the Janus Kinase pathway (JAK) in the signalling of several interleukins including IL-4 and IL-13. Upadacitinib is an oral JAK inhibitor which is currently licensed for use in rheumatoid arthritis.
Nevertheless, a recent phase 3 trial in patients with moderate-to-severe AE found that when combined with topical steroids, oral upadacitinib at a dose of either 15 or 30 mg, led to a significant improvement in disease severity in over 60% of patients. While such data highlights that upadacitinib is an effective treatment, what is less clear, is its position in the eczema treatment pathway.
This led a team from Oregon Medical Research Centre, Portland, US, to undertake a randomised trial, comparing upadacitinib with dupilumab. Eligible patients were adults aged 18 to 75 years, diagnosed with AE and who were candidates for systemic treatment, after a failure of topical therapy. All were randomised 1:1 to 30mg of upadacitinib given once daily until week 24 or 300mg dupilumab subcutaneously every 2 weeks (after a 600mg loading dose). The primary outcome was an EASI75, which represents a 75% improvement in disease severity at week 16.
A total of 348 participants with a mean age of 36.6 years (52.6% male) were randomised to upadacitinib and 344 with the same mean age (56.4% male) to dupilumab. After 16 weeks, 71% using upadacitinib and 61.1% given dupilumab achieved an EASI75 (p = 0.006). In addition, 27.9% using upadacitinib and 7.6% using dupilumab, achieved an EASI100 (p < 0.001), i.e., were completely clear of their eczema. There were also significantly better improvements in measure of itch severity using upadacitinib compared to dupilumab.
Based on these findings, the authors concluded that upadacitinib was well tolerated and provided superior efficacy to dupilumab.
Blauvelt A et al. Efficacy and Safety of Upadacitinib vs Dupilumab in Adults with Moderate-to-Severe Atopic Dermatitis. A Randomised Clinical Trial. JAMA Dermatol 2021
21st July 2021
Ankylosing spondylitis (AS) is a chronic, inflammatory, rheumatic disease that affects the axial skeleton and presents with back pain and morning stiffness. The condition is twice as common in males and usually starts in the third decade of life. Ankylosing spondylitis also leads to fatigue, sleep disturbance and depression and a potentially profound negative effect on health-related quality of life. In recent years there has been an increased understanding of the pathogenesis of AS and in particular, the use of JAK inhibitors, which have wide ranging effects of cytokine production. Furthermore, several trials have demonstrated that JAK inhibitors are both safe and effective in the treatment of ankylosing spondylitis. One such agent, upadacitinib has been shown to have a greater selectivity for JAK1 dependent disease drivers such as interleukin-6 and of value in the treatment of rheumatoid arthritis. In a 2019 study randomised, double-blind, placebo-controlled phase 2/3 trial (SELECT-AXIS 1), the use of upadacitinib was found to be both well-tolerated and efficacious in patients with active ankylosing spondylitis who had shown an inadequate response to non-steroidal anti-inflammatory drugs. Adult patients (18 years and over) were randomised on a 1:1 basis to either oral upadacitinib 15mg daily or placebo for a 14-week period. The primary endpoint was the composite outcome measure of the assessment of spondyloarthritis international society 40 (ASAS40). This is a validated endpoint that combines patient-oriented measures (e.g., back pain, morning stiffness, swelling) with laboratory inflammatory measures e.g., CRP or ESR levels. An ASAS40 response is defined as a >40% improvement in the items included within the measures e.g., patient global assessment, pain etc In the 2019 study, 51.6% of those assigned to upadacitinib achieved an ASAS40 response compared to 25.5% in the placebo group (p < 0.001). Now the same group from Oregon Health& Sciences University, Portland, US, who undertook the 2019 study have reported on the results from an open-label extension of SELECT-AXIS 1 from week 14 through to week 52.
From the original 187 randomised in SELECT-AXIS 1, 178 entered into the open-label extension arm of the trial. The majority of the patients were male (68%) with a mean age of 47 years with a mean duration of ankylosing spondylitis of 14.8 years. At the start of the extension (week 14), 52% of participating receiving upadacitinib had achieved an ASAS40 and this increased to 72%. In terms of safety, the most common adverse events were nasopharyngitis (37 events) and upper respiratory tract infections (26 events).
The authors concluded that upadacitinib demonstrated sustained and consistent efficacy over 1 year in patients with active ankylosis spondylitis and that longer-term efficacy and safety data will be published in the future.
Deodhar AA et al. Upadacitinib in active ankylosing spondylitis: 1-year results from the double-blind, placebo-controlled SELECT-AXIS 1 study and open-label extension. Arthritis Rheumatol 2021.