Tag: atopic dermatitis

An End to The ‘Therapeutic Drought’ in Atopic Dermatitis

Source: NCI

The end of a longstanding “therapeutic drought” in atopic dermatitis (AD) is in sight as improved understanding of the pathogenesis and pathophysiology has stoked development of multiple drug candidates, according to a leading expert in the field.

“We did have treatments like cyclosporine, that are not specific as we know, and they are not treatments we can give our patients for long-term disease control,” said Emma Guttman-Yassky, MD, of the Icahn School of Medicine at Mount Sinai, during the Inflammatory Skin Diseases Summit.

She said that overcoming this drought was not easy, mostly because “we didn’t have enough understanding of the disease and its pathogenesis, really preventing therapeutic development for patients with atopic dermatitis,” she said.

New AD therapies built on the trail made for psoriasis treatment, starting with basic studies that produced insights into pathogenesis, leading to hypotheses that eventually could be tested in clinical trials, she said. Progress was accompanied by many failures in early stages of therapeutic development in psoriasis.

“One failure that I remember very vividly from psoriasis was the failure of interferon-gamma targeting,” Dr Guttman-Yassky recounted. “In atopic dermatitis, we also had our share of this type of failure, but these failures really helped shape therapeutic directions for all the diseases we are now targeting, including atopic dermatitis.”

This rocky development has led to recognition that AD is a complex disease involving multiple pathogenetic components, including barrier dysfunction, immune abnormalities, disruption of the dermal microbiome, and the peripheral and central nervous systems that play a central role in itch and other disease manifestations.

“Of all the major components involved in AD pathogenesis, immune targeting is the most tractable,” said Dr Guttman-Yassky. “Immune abnormalities are the most important because they perpetuate the disease phenotype of atopic dermatitis, from the nonlesional skin to acute disease and chronic lesions.”

In contrast to psoriasis, AD is a more heterogeneous disease with multiple clinical phenotypes that correlate with differences in immune polarisation and barrier dysfunction. All of the phenotypes exhibit activation of the type 2 inflammatory pathway as a common feature. Across the spectrum of clinical phenotypes, additional cytokine targeting may be required to achieve disease control.

Understanding that AD arises from systemic inflammation has also helped therapy development. Several studies have suggested that, compared to psoriasis, AD is associated with higher levels of immune activation. Blood samples of patients with AD have shown increased levels of activated T cells, circulatory cytokines, and cardiovascular markers.
The accumulation of new insights into AD pathogenesis added no fewer than a dozen viable therapeutic candidates to the pipeline. Dupilumab (Dupixent) led the way in providing the proof of principle that Th2-specific targeting reverses key pathogenetic factors that drive the disease process in AD.

Dr Guttman-Yassky pointed out how targeting Th2 inflammation with dupilumab led to reversal of barrier defects and lichenisation typical of AD as early as 4 weeks, and that by 16 weeks lesional and nonlesional skin looked similar. Furthermore, markers of epidermal hyperplasia and proliferation were “completely wiped out.”

Dr Guttman-Yassky highlighted several key classes of AD drug candidates with potential to build on the success of targeting inflammation: Interleukin-13 inhibition, OX40 inhibition and JAK/STAT inhibition, which showed promising results.

“With these types of response rates, our treatment goals for our patients are evolving,” said Dr Guttman-Yassky.

Source: MedPage Today

Discovery of Cell Type Linked to Skin Conditions

Source: NCI on Unsplash

Researchers have found a cell type in human skin that contributes to inflammatory skin diseases such as atopic dermatitis (AD) and psoriasis (PSO). Their study findings were published in the Journal of Experimental Medicine. The team hails from A*STAR’s Singapore Immunology Network (SIgN).

Chronic inflammatory skin diseases such as AD and PSO are characterised by the presence of an activated T cell subtype which secretes pro-inflammatory cytokines in the skin. This immune dysregulation mediated by T cells is central to the pathogenesis of a wide range of inflammatory skin diseases. Thus, understanding the factors modulating T cell priming and activation in healthy and diseased skin is key to developing effective treatments for these diseases.

Recently, a single-cell RNA sequencing (RNA-seq) approach has been used to analyse immune cells in human skin, including dendritic cells (DCs) and macrophages, which are cells that can T cell activation. To tease out the role of DCs and macrophages in chronic inflammatory skin diseases, the team used a combination of complex approaches to yield an unbiased profile/ landscape of DCs and macrophages, and to describe their distinct molecular signatures and proportions in skin lesions of AD and PSO patients.

The researchers found an increase in the proportion of CD14+ DC3s in PSO lesional skin, where they were one of the major cell types co-expressing IL1B and IL23A, two cytokines essential for PSO pathogenesis. This finding suggests that targeting CD14+ DC3 might represent a novel therapeutic option in the treatment of PSO, and demonstrates the potential for the single-cell myeloid cell landscape database to provide important insights into skin biology in health and disease.

Last author Dr Florent Ginhoux, Senior Principal Investigator, SIgN said: “The findings from this study are significant as it will allow the design of new strategies to target or modulate myeloid cell populations for better health outcomes for patients of atopic dermatitis and psoriasis.”

“The roles of antigen-presenting cells in the development of inflammatory skin diseases remain unclear. This study clearly revealed the functions of each antigen-presenting cell subset, which is very informative and valuable to understand the pathogenesis of atopic dermatitis and psoriasis. We expect that this study will lead to the design of new treatment for refractory inflammatory skin diseases.” said Prof Kenji Kabashima, Adjunct Principal Investigator from SIgN and SRIS.

Source: EurekAlert!

Abrocitinib Promising in Teen Atopic Dermatitis

Credit: National Institute of Allergy and Infectious Diseases, National Institutes of Health

Following treatment with the investigational oral Janus kinase (JAK) inhibitor abrocitinib plus topical therapy, teenagers with moderate or severe atopic dermatitis (AD) showed significant improvement to placebo, according to a new study published in JAMA Dermatology.

Up to 20% of children and adolescents are affected by AD, which has an adverse impact on QoL, academic performance, and social relationships, as well as the QoL of caregivers. Subcutaneous dupilumab is safe and effective in moderate-to-severe AD in adolescents, but there is a lack of an oral option, they said.

Nearly half of the patients had clear or almost clear skin by clinician assessment (IGA), and about 70% of patients treated with either of two doses of the JAK inhibitor had at least 75% improvement in the Eczema Area and Severity Index (EASI-75). In contrast, a fourth of patients who received placebo in addition to topical therapy met the clinician assessment outcome and about 40% met EASI-75 criteria.

Abrocitinib, a JAK-1-selective inhibitor, had already shown to be tolerable and effective in adults. The present trial included 285 patients aged 12 to 17, with coprimary endpoints being an IGA score of 0/1 with at least a two-grade improvement from baseline, plus an EASI-75 response, with both outcomes assessed at 12 weeks. Secondary endpoints included improvement in pruritis.

An IGA 0/1 response was seen in 46.2% of patients treated with abrocitinib 200 mg and 41.6% of those assigned to abrocitinib 100 mg, compared to 24.5% in the placebo group. The proportion of patients who met EASI-75 response criteria was 72% with abrocitinib 200 mg, 68.5% with abrocitinib 100 mg, and 41.5% with placebo. Significant improvement was seen in pruritis compared to placebo, showing an improvement in pruritis. The researchers noted that improved indicators could lead to better sleep and QoL indicators.

AE rates were 62.8% with the higher dose of abrocitinib, 56.8% with the lower dose, and 52.1% in the placebo group, with nausea occurring more often with abrocitinib 200 mg than with abrocitinib 100 mg (18.1% vs 7.4%).

These results suggest abrocitinib has great potential for treating teenage AD, said John C. Browning, MD, of Texas Dermatology and Laser Specialists in Dallas. Current there are no JAK inhibitors indicated for AD, and an oral option is very exciting he to MedPage Today via email. “Not everyone responds to current systemic therapies, so there is a definite need for new treatments.”

“I think more teens will be open to trying an oral option, but they will need to be committed to taking it every day,” he said, adding that compliance is an issue. “Both abrocitinib and dupilumab are effective, so there is not a tradeoff in going from injections to oral therapy.”

Source: MedPage Today

Severe Atopic Dermatitis Threatens Mental Health

Photo by Romina Farías on Unsplash
Photo by Romina Farías on Unsplash

US study showed that adults with atopic dermatitis (AD) had a higher burden of disease than those with other chronic diseases. Even mild dermatitis can negatively affect quality of life (QoL), increasing risk of anxiety, depression, and suicide.

Persistent itching and skin pain can disrupt sleep, leading to poor work or study performance. In moderate to severe disease, oozing, crusting lesions can lead to stigmatisation social isolation. More adults are affected than previously thought, with some 16.5 million adults in the US estimated to have AD.

In a study of 1278 patients using the US web-based Growth from Knowledge (GfK) panel, 60.1% had mild disease, 28.9% had moderate AD, and 11% had severe AD. Patients with more severe disease had higher scores on the dermatology life quality index and on the hospital anxiety and depression scale (HADS) when compared with controls.

This indicates “a worse impact on quality of life and an increased likelihood of anxiety or depression,” the researchers wrote in the Journal of Investigative Dermatology. “Our study confirms the high prevalence and disease burden of atopic dermatitis in this population.”

Quality of life threatened
A pair of studies in patients from the GfK panel reinforce these findings. The first, with 602 patients, showed that AD carried a “profound” disease burden, based on a comparison of patient-oriented AD measures between patients with and without AD. Those with moderate and severe AD had lower mean mental health scores compared with those who had mild disease, and lower QoL compared with patients with other chronic disorders.

“We recommend that clinicians incorporate QoL assessments in clinical practice to determine disease burden, identify patients requiring step-up treatment of their skin disease, and potentially screen for patients with mental health disturbance,” wrote Jonathan I Silverberg, MD, PhD, MPH, of George Washington University, and colleagues in the Annals of Allergy, Asthma and Immunology.

A subsequent study in 2137 patients from the GfK Knowledge Panel found that 40% of patients with AD had a higher prevalence of anxiety or depression in the previous 12 months compared with 17.5% of adults without AD. The researchers concluded that anxiety and depression were driven primarily by disease severity, and were heavily underdiagnosed.

Breaking the ‘vicious cycle’
AD can be life-threatening in some patients, warned the authors of a systematic review and meta-analysis of AD studies. The combination of pruritus, visible skin lesions, social isolation, depression, and anxiety likely sets up a “vicious cycle,” according to the authors.

This “may result in suicidal ideation, suicide attempts, and even completed suicide,” they reported in the Journal of the American Academy of Dermatology.

The investigators found a positive and significant association between AD in adulthood and depression, anxiety, and suicidal ideation, regardless of where the patients lived. And while only a few studies examined the risk of completed suicide, the majority showed a positive association, the authors said. A positive association between AD and depression in children was also identified.

They advised that “depression, anxiety, and suicidal ideation should be considered by doctors when treating patients with AD,” adding: “Because AD disease improvement appears to reduce these risks, this should be a priority.”

Better systemic and topical AD therapies are improving the QoL of patients. “It is important to recognise that improvement of AD often results in improvements in symptoms of depression and anxiety, as these mental health symptoms are caused or worsened by the AD,” Dr Silverberg told MedPage Today. “We already have data for dupilumab and the JAK inhibitors that show improvements of HADS scores and other patient-reported outcome measures of mental health.”

Robert Sidbury, MD, MPH, of the University of Washington School of Medicine in Seattle said, “relatively recent literature suggests screening for depression is particularly important for kids with AD, especially those with severe disease.”

AD affects children of all ages, including the very young, and more than 50% of children with AD are diagnosed by age 1 year, he noted.”Dupilumab has been the most effective new available therapy to date by far,” Dr Sidbury told MedPage Today. “Pipeline drugs, particularly the JAK inhibitors like upadacitinib  show tremendous promise.”

Source: MedPage Today

New JAK1 Inhibitor Abrocitinib Effective in Atopic Dermatitis

A phase III trial showed that a new oral Janus kinase 1 (JAK1) inhibitor, abrocitinib, bettered placebo, at higher doses, also outperformed dupilumab in treating signs and symptoms of atopic dermatitis.

More patients on the higher dose of abrocitinib had an Eczema Area and Severity Index 75 (EASI-75) response (75% improvement from baseline) as compared with the other three randomised groups, reported Hernan Valdez, MD, of Pfizer in New York City, and colleagues.

“In the JADE COMPARE trial, abrocitinib at a dose of either 200 mg or 100 mg once daily resulted in significantly greater reductions in signs and symptoms of moderate-to-severe atopic dermatitis than placebo on the basis of IGA and EASI-75 responses at weeks 12 and 16,” the authors stated. “The 100-mg dose of abrocitinib was not significantly different from dupilumab with respect to the three key secondary endpoints of the trial.”

“The 200-mg dose of abrocitinib was superior to dupilumab with respect to itch response at week 2 but not to an EASI-75 response at week 16; no conclusion could be drawn regarding the difference between the 200-mg dose of abrocitinib and dupilumab with respect to an IGA response… . Longer and larger trials are necessary to determine the efficacy and safety of abrocitinib and to compare it with other JAK inhibitors and with biologic agents used for the treatment of atopic dermatitis,” they added.

Several oral JAK inhibitors besides abrocitinib being clinically evaluatied for AD. According to the authors, targeting JAK1 results in inhibition of signaling by interleukin (IL)-4, IL-13, and other cytokines involved in AD. However, there is a lack of data on head-to-head trials of JAK inhibitors.

Despite the very positive reception of JAK inhibitors for the treatment of AD, there have been some studies which raised safety concerns. Tofacitinib, for example, has been associated with a higher rate of malignancies and major adverse cardiovascular events.

In this phase III trial, 838 patients with moderate or severe AD were randomised to abrocitinib 100 mg or 200 mg, dupilumab, or placebo. The trial had two primary endpoints: investigator’s global assessment (IGA) response at week 12 and EASI-75 response at week 12. Both endpoints were compared versus placebo. Secondary analyses included comparisons of itch response at week 2 versus placebo and dupilumab and IGA and EASI-75 responses versus placebo at week 16.

More patients on either of the two doses of abrocitinib had IGA responses at week 12 compared to placebo. The proportion of patients with an EASI-75 response at 12 weeks was 70.3% with abrocitinib 200mg, 58.7% for abrocitinib 100mg, 58.1% for dupilumab, and 27.1% for placebo. All treatment groups performed significantly better than placebo.

At week 2, 49.1% of patients had itch response with the higher dose of abrocitinib, 31.8% with the lower dose, 26.4% with dupilumab, and 13.8% with placebo. The 200-mg abrocitinib group was superior to dupilumab. 

Adverse events (AEs) occurred more often with 200-mg abrocitinib as compared with the other three groups (61.9% vs 50.0% to 53.4%), the most common of which was nausea.

Source: MedPage Today

Journal information:  Bieber T, et al “Abrocitinib versus placebo or dupilumab for atopic dermatitis” N Engl J Med 2021; DOI: 10.1056/NEJM0a2019380.

New Bacteria-based Atopic Dermatitis Treatment Proves Effective

A skin bacteria-based treatment for atopic dermatitis (AD) was successful in clinical trials, with no serious adverse effects and indications that it reduces eczema symptoms as well.

Atopic dermatitis (AD) is a common, chronic skin disorder which can have great impacts on the lives of sufferers. The disorder seems to result from the complex interplay between the skin, environmental effects and the immune system. Treatment involves a multifaceted approach that involves education, optimal skin care practices, anti-inflammatory treatment with topical corticosteroids and/or topical calcineurin inhibitors, the management of pruritus, and the treatment of skin infections. Severe flare-ups or more difficult-to-control disease may be treated with systemic immunosuppressive agents. Topical corticosteroids are the first-line treatment of choice, and seem to be prophylactic against flareups.

AD is associated with S. aureus colonisation, which induces a proteolytic breakdown of the epidermal barrier and dermal immune dysregulation. Inflammation results in further dysregulation of the skin microbial system. Commensal, coagulase-negative staphylococci (CoNS) were observed to produce bacteriocins which inhibit bacteria such as S. aureus, and these were not seen in the skin of most patients with AD. They hypothesised that reintroduction of CoNS would improve AD in patients.

Patients treated with MSB-0221, which incorporated the naturally occurring skin bacteria S. hominis (ShA9), had fewer AD-related adverse events (AEs) as compared with patients treated with a topical placebo, reported Richard L Gallo, MD, PhD, of the University of California San Diego and co-founder of the company developing MSB-0221.

“Besides its effect on decreasing the redness and itch in a subset of patients, and dramatically and rapidly decreasing the colonisation by Staph aureus, one of the unique aspects of this is that it’s specific for this organism,” said Dr Gallo. “It was not detrimental to other members of the microbiome that could help restore balance.”

Applying MSB-0221 to 54 adults, they found a reduction in S. Areus, which was associated with a significant decrease in AD symptoms compared to placebo.

The next step would be a larger, 150 patient clinical trial over 12 weeks.

“We don’t fully understand all of the ramifications, but there seems to be at least a subset of patients with atopic dermatitis whose disease is influenced and exacerbated by certain bacteria, such as Staph aureus,” said Bruce Brod, MD, of the University of Pennsylvania. “There is still sort of a chicken-and-egg aspect to the relationship. Did the skin inflammation come first or the Staph aureus?

“This is a proof-of-concept study that provides some evidence that shifting the balance of another bacteria that’s not pathogenic might have some therapeutic benefit in some patients with atopic dermatitis,” he added. “It provides support for larger studies looking at safe bacteria to shift the flora to a more favourable environment. At this point, it’s just another piece of a puzzle that could one day lead to different therapies. It’s probably not the whole picture, but in some patients, it may play a significant role.”

Source: MedPage Today

Journal information: Nakatsuji T, et al “Development of a human skin commensal microbe for bacteriotherapy of atopic dermatitis and use in a phase I randomized clinical trial” Nature Med 2021; DOI: 10.1038/s41591-021-01256-2.