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24th August 2021
Psoriasis is best described as a complex, chronic, multifactorial and inflammatory disease characterised by increased proliferation of keratinocyte cells in the skin giving rise to silvery/white plaques. The disease typically presents on extensor surfaces such as the elbows, knees and lower back and there if often involvement of the scalp. The incidence of psoriasis appears to vary across the world, with a recent study noting a wide variation. For instance, the incidence was 30.3 per 100,000 person years in Taiwan but 321 per 100,000 person years in Italy. Among those with psoriasis, one study of over 9,000 patients, found that just over half (51.8%) had mild disease, with 35.8% and 12.4% having moderate and severe disease respectively. Patients with mild to moderate disease are normally managed with topical therapies, whereas those with moderate to severe disease are increasing treated with biological agents, in particular, monoclonal antibodies. Although the precise cause of psoriasis remains to be determined, several interleukins appear to be important disease drivers, especially the interleukin-17 (IL-17) pathway which includes six similar agents, IL-17A – IL-17F. Research suggests that two members of the IL-17 family, IL-17A and IL-17F are implicated in autoimmunity and IL17F appears to regulate pro-inflammatory gene expression and which requires the IL-17A receptor, suggesting that both are involved in the pathology of psoriasis. Bimekizumab is the first monoclonal antibody which selectively inhibits both IL-17A and IL-17F and is therefore a potentially important advancement in the management of patients with moderate to severe psoriasis.
The EU approval of bimekizumab was supported by the results of three phase 3 clinical trials, all undertaken in patients with moderate to severe psoriasis. The first, BE READY, randomised 435 patients (4:1) to bimekizumab 320 mg every 4 weeks or placebo. The co-primary endpoint was a PASI90 (i.e., 90% improvement in disease severity compared to baseline) and the proportion of patients achieving a score of 0 (i.e., clear skin) or 1 (almost clear), based on a 5-point investigator global assessment (IGA) score after 16 weeks of treatment. The results showed that a staggering 91% of those assigned to bimekizumab achieved a PASI90 compared to only 1% in the placebo group. In the BE VIVID trial, 567 patients were randomised to bimekizumab (at the same dosage as the BE READY trial) or this time, ustekinumab 45 or 90 mg every 12 weeks and which is an active comparator or placebo. Once again at week 16 there was a high response in the bimekizumab group with 85% achieving a PASI90 compared to 50% in the ustekinumab. The third trial, BE SURE, enrolled 478 patients who were randomised to either bimekizumab (same dosage as in the other trials) or adalimumab (another active comparator) at a dose of 40 mg every 2 weeks. At week 16, a PASI90 was achieved 85.3% of those using bimekizumab and 57.2% of those given adalimumab.
The most common adverse effects from bimekizumab are upper respiratory tract infections (14.5%) and patients are advised to seek medical advice if they display symptoms suggestive of an infection.
The EU approval applies to all 27 member states as well as Iceland, Liechtenstein and Norway at a dose of 320 mg administered by subcutaneous injections every 4 weeks for week 16 and every 8 weeks thereafter. The drug is currently under review by the US Food and Drug administration.
Source: UCB press release 2021
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
22nd July 2021
Systemic juvenile idiopathic arthritis (SJIA) is a rare and serious auto-inflammatory disease characterised by joint pain or stiffness, tiredness and blurry vision and which affects 10 – 20% of children with juvenile arthritis. The cause of the condition remains largely unknown and the treatment of SJIA has historically involved the use of large doses of systemic corticosteroids, delivered as mini-pulses and which serves to achieve disease control. Nevertheless, while effective, long-term use of corticosteroids can cause serious side-effects in children including osteoporosis, slowed growth and a greater risk of infections. Studies have shown that in children with SJIA there are elevated levels of interleukins, in particular, interleukin-1 and interleukin-6. Furthermore, in 2012, two studies emerged supporting the use of the biologics canakinumab, which is an anti-interleukin-1 agent and tocilizumab, an anti-interleukin-6, in the management of SJIA. Management guidelines from the American College of Rheumatology in 2013, advocated the use of biologics as a first-line treatment for SJIA and it has been shown that biologic monotherapy is effective, avoiding the need for corticosteroids. However, what is less clear is whether the early introduction of a biologic will reduce the need for corticosteroids among children hospitalised with systemic juvenile idiopathic arthritis. Using a retrospective analysis, a team from the Children’s Hospital of Philadelphia, Division of Rheumatology, Philadelphia, US, sought to determine whether the early use of a biologic would reduce the need for corticosteroids children with SJIA. The team used electronic patient records to extract demographic and treatment data and set the primary outcome as the initiation of corticosteroids during the initial hospital stay for children with SJIA. Participants were then divided into two groups as either biologic initiators or non-initiators.
A total of 468 children with SJIA were included, of whom 71 were initiated on a biologic, with a mean age of 7 years (57.7% male). The most common agent was an interleukin-1 inhibitor although one received an anti-interleukin-6 agent (tocilizumab). A lower proportion of those given a biologic subsequently received a corticosteroid (36.8% vs 56.9%, biologic initiators vs non-initiators, p = 0.09). There was a non-significant trend towards a reduced odds of receiving a corticosteroid in the biological initiator arm (odds ratio, OR = 0.39, 95% CI 0.13–1.15).
Commenting on these findings, the authors felt that early use of a biologic appeared to reduce the need for concomitant corticosteroid therapy in children with new onset systemic juvenile idiopathic arthritis. They concluded by calling for future studies to provide an evidence base for the use of corticosteroids in children with this condition, given the problems associated with the long-term use of these drugs.
Peterson RG et al. Effect of first-line biologic initiation on glucocorticoid exposure in children hospitalized with new-onset systemic juvenile idiopathic arthritis: emulation of a pragmatic trial using observational data. Pediatr Rheumatol Online J 2021