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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
28th June 2021
It has become increasing clear that severe manifestations of COVID-19 are largely driven by an exaggerated immune response by interleukin-6, tumour necrosis factor and other cytokines and which has been described as a cytokine storm. Tofacitinib is an oral Janus kinase inhibitor which blocks signal transduction once a cytokine has attached to its cell surface receptor, hence attenuating the cellular response. Furthermore, tofacitinib suppresses the production of both interleukin-17 and interferon-gamma which are implicated in the pathogenesis of acute respiratory distress syndrome, a common complication from infection with COVID-19. Thus, tofacitinib has the potential to act on more than one pathway to help ameliorate the damage that occurs in those infected with COVID-19. Based on these likely benefits, a team from the Hospital Israelita, Albert Einstein, Sao Paulo, Brazil, undertook a randomised, double-blind, placebo, controlled trial, to investigate the safety and efficacy of tofacitinib in patients hospitalised with COVID-19 pneumonia and who were not in receipt of either non-invasive or invasive ventilation. Patients were 18 years and over and a positive PCR test for COVID-19 and who had radiographic evidence of pneumonia and randomised (1:1) to tofacitinib or placebo. Tofacitinib was given as an oral dose of 10mg twice daily for up to 14 days or until hospital discharge. All participants received standard care and which included the use of glucocorticosteroids, antibiotics, anticoagulants and antiviral agents although concomitant use of other JAK inhibitors or interleukin-6 inhibitors were not permitted. All patients were assessed daily up to day 28 while in hospital. The primary outcome was death or respiratory failure during the 28-day follow-up period and a secondary outcome was the cumulative incidence of death through any cause up to day 28.
A total of 289 patients with a mean age of 56 years (34.9% female) were included and randomised to tofacitinib (144) or matching placebo (145). Furthermore, a third (34.9%) of patients were aged 65 years and over and the majority (83.4%) of White ethnicity. The most common co-morbidity was hypertension (50.2%) followed by diabetes (23.5%) and dyslipidaemia (17.3%) and the median body mass index was 29.7. Death or respiratory failure (the primary outcome) occurred in 18.1% of those receiving tofacitinib and in 29% of those assigned to placebo (risk ratio, RR = 0.63, 95% CI 0.41–0.97, P = 0.04). In addition, death due to any cause (a secondary outcome) occurred in 2.8% of the tofacitinib group and 5.5% of the placebo group although this difference was not statistically significant.
Discussing their findings, the authors commented how the beneficial effects of tofacitinib appeared to be independent of age, gender or use of standard care therapy such as corticosteroids. They proposed that the data in the current study suggested an added benefit from the use of JAK inhibitors in patients with COVID-19-related pneumonia.
Guimaraes PO et al. Tofacitinib in Patients Hospitalised with Covid-19 Pneumonia. N Eng J Med 2021