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26th September 2022
Although dupilumab is licensed for moderate to severe atopic eczema from 6 years of age, the drug also appears to be effective in children under 6 years of age according to the findings of a randomised, double-blind, placebo-controlled trial by US researchers.
Atopic eczema is a common childhood condition with a global real-world prevalence study in the paediatric population finding that the 12-month prevalence ranged from 2.7% to 20.1% across countries but that severe disease was generally less than 15%. Dupilumab is a human monoclonal antibody against the interleukin-4 receptor alpha, inhibiting the signalling of interleukin-4 and interleukin-13. The drug has been shown to be effective for adults with moderate to severe disease. For example, in two identical randomised, placebo-controlled trials, where the primary outcome was the proportion of achieving a score of 0 or 1 (clear or almost clear) on the Investigator’s Global Assessment and a reduction of 2 points or more in their score from baseline at week 16, this occurred in 36% of those who received dupilumab every other week and in 36% who received dupilumab weekly. As mentioned earlier, whilst licensed from age 6, to date, there is limited data on the effectiveness in children under 6 years of age apart from one phase 2, open-label study, which found that a single-dose dupilumab was generally well tolerated and substantially reduced clinical signs/symptoms of eczema.
The present study was the first, large scale, randomised, placebo-controlled trial of dupilumab in children as young as 6 months old. The US team recruited children aged 6 months to under 6 years with moderate to severe atopic eczema (investigator’s Global assessment, IGA score of 3 – 4) with an inadequate response to topical corticosteroids. These children were then randomised 1:1 to either subcutaneous placebo or dupilumab 200 mg (body weight > 5 kg to < 15 kg) or 300 mg (> 15 kg but less than 30 kg) every 4 weeks in addition to a low-potency topical corticosteroid (hydrocortisone acetate 1%) for a total of 16 weeks. The primary endpoint at week 16 was the proportion of patients who achieved an IGA score of 0 or 1 (indicating that their skin was either clear or almost clear). For the secondary endpoint, the team assessed the proportion achieving an EASI75, i.e., a 75% improvement in their eczema area and severity index also at week 16.
Dupilumab and improvement in disease severity
A total of 162 children with a mean age of 4 years (61% male) were randomised to dupilumab (83) or placebo. Among those assigned to dupilumab, 76% had an IGA score of 4 and both groups received hydrocortisone.
At week 16, a significantly higher proportion of patients taking dupilumab achieved the primary outcome (28% vs 4%, p < 0.0001) and this also occurred for the secondary endpoint of an EASI75 (53% vs 11%, p < 0.0001).
A similar proportion of patients had at > 1 treatment-emergent adverse event (64% vs 74%, dupilumab vs placebo).
The authors concluded that dupilumab with concomitant low potency topical steroids significantly improved disease severity compared to placebo in children under 6 years of age and that the drug was well tolerated.
2nd May 2022
Having atopic eczema in older life increases the risk for developing Alzheimer’s disease, according to a study by researchers from UC Berkeley School of Public Health, Berkeley, California, USA.
Alzheimer’s disease (AD) is a neurodegenerative disorder which is progressive and characterised clinically by cognitive decline and physiologically by the presence of two core pathologies; amyloid β plaques (Aβ) and neurofibrillary tangles (NFTs). AD is the most common form of dementia which, according to the World Health Organization (WHO), affected some 55 million people in 2021 with AD accounting for 60-70% of all dementia cases.
Among those with AD, there is a sustained inflammatory response in the brain which is thought to represent a persistent immune response and a factor exacerbating both Aβ and NFTs. Moreover, there is emerging evidence that peripheral inflammation is an early event in the pathogenesis of AD. Atopy, which manifests as either allergic rhinitis, atopic eczema or asthma, represents a set of peripheral inflammatory diseases that have been found to be associated with a modestly increased risk of AD and dementia. To date, only one study has suggested that atopic eczema may be an independent risk factor for new-onset dementia and in particular, AD.
For the present analysis, the team set out to determine whether active atopic eczema among older adults was associated with incident AD and wondered if the strength of this association was dependent upon atopic eczema disease severity. They performed a longitudinal cohort study of patient data collected from the Health Improvement Network, which provides information on a representative sample of patients from UK general practitioners. For their analysis, the researchers included patients aged 60 to 100 years of age without a prior diagnosis of AD or dementia and for whom the primary exposure was the presence of active atopic eczema and for which at least two prescriptions for treatment of the condition had been issued. The severity of atopic eczema during follow-up was categorised as either mild moderate or severe and the primary outcome was a new diagnosis of dementia during the period of follow-up. The researchers also examined the reported disease codes for dementia and excluded those where the condition was drug- or alcohol-related or due to trauma or a rarer form (e.g. Huntington’s). The analysis was adjusted for potential confounders including gender, smoking, alcohol status, etc.
Atopic eczema and risk of Alzheimer’s disease
In a total of 1,767,667 individuals aged 60 to 100 years of age at baseline, 57,263 were diagnosed with dementia over mean of 6.8 years of follow-up. The median age of patients with a dementia diagnosis was 82 years, of whom, two-thirds (65%) were female.
Atopic eczema was diagnosed in 12% of the whole cohort and using mild disease severity as the default, 44% had moderate and 5% disease severity over the follow-up period.
Considering AD, the analysis showed that after adjustment for confounders, mild atopic eczema was associated with a 22% higher risk of AD (HR = 1.22) and this risk was higher still for those with moderate (HR = 1.37) and severe (HR = 1.52) disease.
With AD being the most common form of dementia, the researchers also examined the link between atopic eczema and the risk of developing dementia. The incidence of dementia was 57/10,000 person-years among those with atopic eczema compared to 44/10,000 person-years among those without the condition. Overall, patients with atopic eczema had a 27% higher risk for dementia after adjustment for potential confounders (hazard ratio, HR = 1.27, 95% CI 1.23 – 1.30). Further adjustment for co-morbidities slighted attenuated this risk but it remained significant (HR = 1.19, 95% CI 1.16 – 1.22).
The authors concluded that given the increased risk of AD among adults with atopic eczema, clinicians consider the impact of screening those with eczema for signs of cognitive impairment.
Magyari A et al. Adult atopic eczema and the risk of dementia: A population-based cohort study J Am Acad Dermatol 2022
4th April 2022
A Cochrane review on the use of topical steroids, has offered some, but not all, of the answers to help clinicians and patients to use these drugs optimally in the treatment of adults and children with atopic eczema, despite the fact that these agents have been used in practice for many decades.
Atopic eczema (atopic dermatitis) is defined as a chronic, itchy, inflammatory skin condition that affects people of all ages, although it presents most frequently in childhood. According to NICE guidance, which, although focusing on children, is applicable to adults, emollients should form the mainstay of atopic eczema management and should always be used, even when the condition has cleared. Where the disease flares, NICE advocates a stepped approach to management involving the use of emollients and topical steroids. The first use of topical steroids, in the form of cortisone acetate ointment (referred to as compound F) was reported in 1952 and topical steroids are categorised in terms of their potency which ranges from mild, moderate, potent and very potent with more potent agents inducing a greater degree of skin blanching (i.e., vasoconstriction). They are also available in different strengths and formulations, e.g., creams, ointments and foams, with designed to be used only once daily.
Nevertheless, despite the widespread availability of the drugs, there is surprising lack of clarity on how to best use topical steroids in clinical practice. The purpose of the current Cochrane review was therefore to try and answer several relevant questions to support clinicians and patients. In trying to answer these questions, the review included only randomised controlled trials in adults and children with eczema and which compared at least two strategies of topical corticosteroid use.
Optimal use of topical steroids
A total of 104 trials with 8443 participants were included in the analysis although 55 trials had a high risk of bias in at least one domain, mostly due to lack of blinding or missing outcome data.
The use of moderate compared to mild potency topical steroids resulted in more participants achieving treatment success, which was defined as cleared or marked improvement in eczema, based on an investigator global assessment scale (odds ratio, OR = 2.07, 95% CI 1.41 – 3.04).
In trials assessing adults and children with moderate or severe eczema, the use of potent topical steroids once compared to twice daily, did not reduce the number of patients achieving treatment success (OR = 0.97, 95% CI 0.68 – 1.38).
One strategy advocated by the NHS is weekend treatment, where a person whose eczema is under control, uses the topical corticosteroid every weekend on the trouble sites to prevent a disease relapse. flare. The review found supportive evidence for this approach and concluded that this resulted in a large decrease in likelihood of a relapse from 58% to 25% (risk ratio, RR = 0.43, 95% CI 0.32 – 0.57).
Another area explored included whether to use a cream or ointment formulation but there was no evidence to support use of either formulation. Advice from the NHS is that if a topical corticosteroid is prescribed, patients should wait about 15–30 mins after applying an emollient before using topical steroids. However, the review found no evidence to support this recommendation.
Although the Cochrane review provided some answers to support clinicians in their use of topical steroids, as the authors noted, there was a lack of evidence on adverse effects since studies were small and did not always use the most reliable methods. Therefore, the review offers some, but not all, of the answers to support the optimal use of topical steroids.
Lax SJ et al. Strategies for using topical corticosteroids in children and adults with eczema. Cochrane Database Sys Rev; March 2022
9th December 2021
Patients with moderate-to-severe atopic eczema prescribed the monoclonal antibody dupilumab experienced less severe COVID-19 symptoms according to the results of a prospective study by researchers from the Department of Dermatology, and Laboratory of Inflammatory Skin Diseases, Icahn School of Medicine at Mount Sinai, New York, US.
Atopic eczema is a chronic skin disease and is characterised by T helper 2 (Th2)-driven inflammation due to a Th1/Th2 imbalance. Moreover, cytokines released by Th2 cells including IL-4, IL-5 and IL-13 elevate production of IgE and increased inflammation in the skin and aggravate the skin barrier defect seen in atopic eczema. Interestingly, research suggests that infection with COVID-19 leads to an increased level of various interleukins, including IL-13. Since the mode of action for dupilumab involves blockage of the two interleukins, IL-4 and IL-13, it might be possible that the drug impacts on the severity of symptoms in those with COVID-19.
For the present study, the US researchers examined a disease registry within the department of dermatology at their hospital which included medication prescribed for patients with moderate-to-severe atopic eczema. They enrolled patients 9 years of age and older either at the time of a clinic visit or invited them to participate over the telephone. They included patients prescribed dupilumab, other systemic agents and either limited or no current treatment. Individuals were asked about the presence and duration of COVID-19 symptoms and based on their responses, categorised on a 1 – 5 scale ranging from mild disease (1), severe (3) through to 5 (fatal). The primary outcome was the presence of moderate-to-severe COVID-19 symptoms.
A total of 1237 patients were included, of which 632 with a mean age of 41.2 years (47% male), were prescribed dupilumab, 107 other systemic agents including oral JAK inhibitors, prednisolone, methotrexate and mycophenolate. The remaining 498 patients were on limited treatment or no treatment, with the majority (71%) prescribed only topical agents. In terms of COVID-19 severity, the majority (77%) of all individuals scored 0 on the 1 – 5 scale.
Among non-dupilumab treated patients, there was a nearly four-fold increased risk of experiencing moderate-to-severe COVID-19 symptoms (odds ratio, OR = 3.89, p = 0.01) compared to those prescribed dupilumab. Similarly, this risk was elevated for those with either limited or no treatment (OR = 1.95, p = 0.04).
In addition, when examining the relationship among those with a PCR confirmed COVID-19 diagnosis, non-dupilumab treated patients again had a significantly increased risk of moderate-to-severe COVID-19 symptoms compared to those prescribed dupilumab (OR = 13.79, p = 0.002), as did those with limited or no treatment (OR = 2.44, p = 0.05).
Commenting on their findings, the authors speculated that given the over-expression of Th2 cells in atopic eczema, patients were unable to mount a sufficient Th1 response to viral infections. With the use of dupilumab, which attenuated the Th2 response, the Th1/Th2 imbalance could be redressed allowing individuals to mount a greater Th1 response against the virus.
They concluded by suggesting that future studies should seek to understand the implications of their findings for other specific viral infections.
Ungar B et al. COVID-19 Symptoms Are Attenuated in Moderate-to-Severe Atopic Dermatitis Patients Treated with Dupilumab. J Allergy Clin Immunol Pract 2021
1st December 2021
Topical asivatrep, a transient receptor potential vanilloid subfamily V member 1 (TRPV1) antagonist, has been shown to be more effective than placebo in patients with mild to moderate atopic eczema. This was the finding from a Phase III trial by researchers from the Department of Dermatology, Hallym University, South Korea.
TRPVI is a non-selective cation channel which is expressed by keratinocytes, mast cells and sensory neurons related to itch, especially itch related to the release of histamine. Moreover, in vitro study data suggests that antagonism of TRPVI can suppress the atopic eczema-like symptoms by accelerating recovery of the skin’s barrier. More specifically, in animal models of atopic eczema-like dermatitis, topical asivatrep, has demonstrated improvements in eczema symptoms and the barrier function of the skin. In a dose ranging clinical study in adults with atopic eczema, topical asivatrep 1% was found to provide the greatest improvement in disease severity.
For the present study, the Korean team used a 1% formulation of asivatrep based on the results of the dose ranging study, for a Phase III, randomised, double-blind, placebo-controlled trial. Included patients were aged 12 years and older, with mild to moderate atopic eczema, defined by an investigators’ global assessment (IGA) score of 2 (mild) or 3 (moderate), and which affected between 5 and 30% of their body. The primary efficacy endpoint of the trial was the proportion of patients with an IGA score of 0 or 1 (i.e., clear or almost clear) after 8 weeks of treatment. Secondary endpoints included changes in EASI score, a pruritus visual analogue scale (VAS) score and a sleep disturbance score at several time points, including week 8.
A total of 240 patients with a mean age of 25.6 years (45.6% female) were included in the analysis with 157 assigned to topical asivatrep. Most (58.3%) had moderate severity atopic eczema. However, due to withdrawals and patient violations, the final analysis was based on a sample of 231 patients (153 asivatrep).
After 8 weeks of treatment, the proportion of patients achieving an IGA score of 0/1 was 36% in the asivatrep group and 12.8% in the placebo arm (p < 0.001). With respect to EASI scores, the greatest difference was observed at week 8 (44.3% vs 21.4%, asivatrep vs placebo, p < 0.001), with 9.8% of those receiving asivatrep achieving an EASI90 (i.e., 90% reduction in EASI score) compared to only 2.6% in the placebo group (p = 0.046).
There were also significant reductions in pruritus VAS scores and measures of sleep disturbance with asivatrep. In terms of safety, topical asivatrep was well tolerated and while the incidence of treatment-emergent adverse effects was slightly higher with asivatrep compared to placebo, the difference was non-significant.
The authors concluded that treatment with asivatrep cream, as a first-in-class topical agent, may be a novel treatment for patients with atopic eczema.
Park CW et al. Asivatrep, a TRPV1 antagonist, for the topical treatment of atopic dermatitis: Phase 3, randomized, vehicle-controlled study (CAPTAIN-AD). J. Allergy Clin Immunol 2021
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