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31st August 2021
Atopic eczema (AE) affects between 15 and 20% of children. Although at the present time the cause remains uncertain, immune dysfunction characterised by over-production of interleukins, is clearly involved as evidenced by the effectiveness of dupilumab, which targets interleukin 4 and 13. One potential preventative therapy which has been explored in the use of probiotics, which are live micro-organisms that have been shown to reduce inflammation by suppression of various interleukins. Although there have been several reviews examining the effectiveness of probiotics in the prevention of atopic eczema, there has been heterogeneity in the findings.
This led a team from the Department of Clinical Epidemiology, University of the Philippines, Manila, Philippines, to perform a network meta-analysis to synthesize the available evidence and compare different probiotics products in the prevention of AE. The use of a network meta-analysis offer advantages over a standard meta-analysis in that the former allows for a pairwise comparison of probiotics that have not been directly compared in studies. The team included studies with patients deemed to be at high-risk of developing AE, in particular those in which a family member already had allergic disease. They considered the oral administration of any probiotic strain or mixture of strains and also included studies in which probiotics were given to mothers during pregnancy. The primary outcome of interest was the prevention of AE and the secondary outcome of interest was the presence or absence of adverse effects.
A total of 35 studies were included, 14 of which were follow-ups of completed randomised controlled trials, using 15 different probiotics mixtures and 5406 children diagnosed with AE. There were only three probiotic mixtures that appeared to reduce the risk of developing AE compared to placebo, based on the 95% confidence intervals not crossing the line of no-effect. These mixtures were Mix8, Mix3 and Mix6. Compared to placebo, Mix8 reduced the risk of developing AE by 54% (relative risk, RR = 0.46, 95% CI 0.25 – 0.85), Mix3 by 50% (RR = 0.50, 95% CI 0.27 – 0.94) and Mix6 by 42% (RR = 0.58, 95% CI 0.37 – 0.92). In subgroup analysis, 8 studies compared administration of probiotics prenatally to pregnant women and postnatally to infants. However, pairwise comparisons were not statistically significant, suggesting no real effect. There was no evidence of any adverse effects from the use of probiotics although the wide confidence intervals for the relative risks precluded any definitive conclusions.
Commenting on their findings, the authors indicated that the data did suggest a possible beneficial effect from the use of some probiotics in preventing the development of AE. They also noted that it was probiotic mixtures that seemed to be most effective and speculated that there was a likely synergistic effect between the individual probiotic species. However, they concluded that based on the available data, it was not possible to determine the optimum timing, dose or duration of probiotics for a maximal effect.
Tan-Lim CSC et al. Comparative effectiveness of probiotic strains on the prevention of pediatric atopic dermatitis: A systematic review and network meta-analysis. Pediatr Allergy Immunol 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
14th December 2020
Atopic eczema is a chronic, inflammatory skin condition that affects up to 20% of children. The condition usually begins within the first year of life and treatment involves the regular use of emollients and disease flares are managed with topical steroids to dampen down the localised inflammatory response. Previous work has revealed how immune dysfunction in the skin is characterised by the production of pro-inflammatory cytokines but that there are also changes in the level of systemic markers during a disease flare.
In an attempt to gain a better understanding of how these markers change during therapy with topical steroids, researchers from the Department of Paediatric Dermatology, Children’s Health at Crumlin, Dublin, Ireland, examined the changes in cytokine markers in an observational study of children with atopic eczema experiencing a disease flare treated with the topical steroid, hydrocortisone 1%, in line with normal clinical practice guidance. All children were less than a year old with moderate to severe eczema based on a SCORAD (disease severity) score of 25 or greater. Team also included a control group of healthy children to compare any changes in cytokine levels. Samples of the skin and plasma were taken and both analysed for a large number of different biomarkers including inflammatory cytokines such interleukin-18 (IL-18), IL-5, IL-13, CXCL8, il-1 alpha and CCL17 and CCL22.
A total of 47 children with atopic eczema and 20 controls were included in the analysis and changes in biomarkers were compared between baseline and after 6 weeks of topical steroid therapy. The most pronounced differences in cytokine levels in the skin between eczema and healthy controls were for those associated with innate immune activation, e.g, IL-18, CXCL8, IL-1alpha, CCL17 and CCL22 although levels in eczema patients did not reduce to the levels observed in healthy controls. In contrast, the largest changes in the blood were with CCL17, IL-13, CCL22, IL-5 and CCL26. Interestingly, these latter changes, which represent key cytokines in the pathophysiology of atopic eczema, only occurred in the blood and not in the skin.
Commenting on their results, the authors suggested that their data indicates that topical steroids had both a local and systemic effect to minimise the inflammation response induced by an eczema flare.
McAleer MA et al. Topical corticosteroids normalise both skin and systemic inflammatory markers in infant atopic dermatitis. Br J Dermatol 2020 doi: 10.1111/bjd.19703