Tag: atopic dermatitis

Categories : Dermatology ImmunologyTags :

When This Itch Cytokine ‘Talks’, Neurons Respond

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Photo by FOX

Scratching an itch can be a relief, but for many patients it can get out of control, becoming a serious health problem. So what normally stops this progression?

A paper published in Science Immunology reports a breakthrough that could transform how doctors treat conditions from atopic dermatitis to allergies, they have discovered a feedback loop centred on a single immune protein called IL-31 that both causes the urge to itch and dials back nearby inflammation.

The findings, by Scientists at UC San Francisco, lay the groundwork for a new generation of drugs that interact more intelligently with the body’s innate ability to self-regulate.

Previous approaches suggested that IL-31 signals itch and promotes skin inflammation. But the UCSF team discovered that nerve cells, or neurons, that respond to IL-31, triggering a scratch, also prevent immune cells from overreacting and causing more widespread irritation.

“We tend to think that immune proteins like IL-31 help immune cells talk to one another, but here, when IL-31 talks to neurons, the neurons talk right back,” said Marlys Fassett, MD, PhD, UCSF professor of dermatology and lead author of the study. “It’s the first time we’ve seen the nervous system directly tamp down an allergic response.”

The discovery could eventually change how asthma, Crohn’s and other inflammatory diseases are treated, due to IL-31’s presence throughout the body.

“IL-31 causes itch in the skin, but it’s also in the lung and in the gut,” said Mark Ansel, Ph.D., UCSF professor of immunology and senior author of the study. “We now have a new lead for fighting the many diseases involving both the immune and nervous systems.”

More than an itch

IL-31 is one of several “itch cytokines” because of its ability to instigate itch in animals and people. Fassett, a dermatologist and a researcher, has wanted to know why since she arrived at UCSF in 2012, a few years after its discovery. She reached out to Ansel, a former colleague and asthma expert who welcomed her into his lab.

First, Fassett removed the IL-31 gene from mice and exposed them to the house dust mite, a common, itchy allergen.

“We wanted to mimic what was actually happening in people who are chronically exposed to environmental allergens,” Fassett said. “As we expected, the dust mite didn’t cause itching in the absence of IL-31, but we were surprised to see that inflammation went up.”

Why was there inflammation but no itching? Fassett and Ansel found that a cadre of immune cells had been called into action in the absence of the itch cytokine. Without IL-31, the body was blindly waging an immunological war.

IL-31 brings balance to the forces

Ansel and Fassett then homed in on the nerve cells in the skin that received the IL-31 signal. They saw that the same nerve cells that spurred a scratch also dampened any subsequent immune response. These nerve cells were integral to keeping inflammation in check, but without IL-31, they let the immune system run wild.

The findings squared well with what dermatologists were increasingly seeing with a new drug, nemolizumab, which blocked IL-31 and was developed to treat eczema. While clinical trial patients found that the dry, patchy skin of their eczema receded on the drug, other skin irritation, and even inflammation in the lungs, would sometimes flare up.

“When you give a drug that blocks the IL-31 receptor throughout the whole body, now you’re changing that feedback system, releasing the brakes on allergic reactions everywhere,” Ansel said.

Fassett and Ansel also found that these neurons released their own signal, called CGRP, in response to the itch signal, which could be responsible for dampening the immune response.

“The idea that our nerves contribute to allergy in different tissues is game changing,” Fassett said. “If we can develop drugs that work around these systems, we can really help those patients that get worse flares after treatment for itch.”

Fassett recently founded her own lab at UCSF to tease apart these paradoxes in biology that complicate good outcomes in the clinic. And Ansel is now interested in what this itch cytokine is doing beyond the skin.

“You don’t itch in your lungs, so the question is, what is IL-31 doing there, or in the gut?” Ansel asked. “But it does seem to have an effect on allergic inflammation in the lung. There’s a lot of science ahead for us, with immense potential to improve therapies.”

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Categories : Diseases, Syndromes and Conditions PaediatricsTags :

Strong Results from Methotrexate Trial for Severe Atopic Dermatitis in Kids

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Atopic dermatitis in a young patient. Source: NIH

Positive results from a clinical trial comparing the safety and efficacy of ciclosporin with methotrexate in children and adolescents with severe dermatitis will likely change treatment paradigms for this debilitating skin condition, its researchers have said. The trial, published in the British Journal of Dermatology, also examined whether the severity of the disease changed or returned after treatment ended.

For children and young people with atopic dermatitis, the most common skin condition in children, the main first line conventional systemic treatments are methotrexate and ciclosporin, two immuno-modulatory drugs.

There have been no adequately powered randomised clinical trial evidence for safety and treatment success for paediatric patients with this condition, and with new therapies being introduced at a high cost, establishing a gold standard for treatment with the conventional systemic therapies like methotrexate and ciclosporin is needed.

The trial, led by King’s College London, assessed 103 children with severe atopic dermatitis age 2–16 years across 13 centres in the UK and Ireland. The patients were given oral doses of methotrexate or ciclosporin and assessed over nine months of treatment and six months after the therapy ended.

The study found that ciclosporin works faster and reduces disease severity more at 12 weeks but was more expensive, whereas methotrexate was significantly cheaper and led to better objective disease control after 12 weeks and off therapy, with fewer participant-reported flares of atopic dermatitis after treatment had stopped. There were also no concerning safety signals.

Based on the TREAT trial findings, methotrexate is a useful and safe treatment in paediatric patients with severe atopic dermatitis and a good alternative to ciclosporin, especially in settings where health care resources are limited.

Professor Carsten Flohr, Chair in Dermatology and Population Health Sciences at King’s College London, and consultant dermatologist at St John’s institute of dermatology, Guy’s and St Thomas’ NHS Foundation Trust, said:

“This is the largest paediatric trial using conventional immuno-modulatory treatments in severe atopic dermatitis and was conducted across 13 centres in the UK and Ireland and is likely to change our treatment paradigm around this condition, not just for patients in the UK but also internationally.”

Source: King’s College London

Categories : Gastrointestinal ImmunologyTags :

Atopic Dermatitis Increases Risk of New-onset IBD

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Source: CC0

Adults with atopic dermatitis (AD) have a 34% increased risk of developing new-onset inflammatory bowel disease (IBD) compared to those without the skin condition, according to a new recently published in JAMA Dermatology. The study also shows for children, the risk increase is 44%. Additionally, as the severity of AD increased, the risk of developing IBD rose.

These findings clear up ambiguity from previous research, especially among populations of children and between the different types of IBD: ulcerative colitis and Crohn’s disease. While IBD is located in the gut and AD affects the skin, both diseases are driven by the immune system and are categorised by severe inflammation. Insight offered from this study from the Perelman School of Medicine at the University of Pennsylvania could lead to new treatments for both IBD and AD.

“It is imperative for clinicians to understand atopic dermatitis and the trajectory of our patients with it in order to provide the best standard of care,” said senior author Joel M Gelfand, MD, dermatology professor at Penn. “There are new and better treatments for AD today, and there will likely continue to be more. But providers have to understand how those treatments could impact other autoimmune diseases. For patients with AD and another autoimmune disease, some currently available medications can exacerbate symptoms of their other disease or can help treat two immune diseases at the same time.”

While this is not the first study to explore AD and IBD, its size, with one million adult and child participants with AD drawn from a UK medical database, and its separation between ulcerative colitis and Crohn’s disease advances previous research.

When looking at ulcerative colitis and Crohn’s disease separately, AD was not linked to higher ulcerative colitis in children unless the kids had severe AD. Children with AD, however, had a 54–97% increased relative risk of Crohn’s disease, and among children with severe AD, their risk was roughly five times higher. Results among adults were more straightforward. Adults with AD had a 32% increased relative risk of ulcerative colitis and a 36% increased relative risk of Crohn’s disease. Gelfand notes that the absolute extra risk of developing IBD in individuals with AD is still quite small, but the association is meaningful in better understanding health outcomes in AD. Moreover, since millions of people have AD, this small increase in risk spread among many people is likely important from a public health perspective.

Although Penn researchers did not look at the root cause of IBD linked to AD, they have strong hypotheses about the links.

“AD and IBD can cause changes in the microbiome, chronic inflammation, and the dysfunction in the skin and gut barrier respectively,” said Gelfand, who is also the director of the Center for Clinical Sciences in Dermatology at Penn. “There are also specific cytokines, certain kinds of proteins, that play a role in immune system activity and that seem to be related to AD and IBD. For example, we think dysfunction of types of T cells common to both AD and IBD, could be the culprits. Those need to be explored further to uncover both what’s happening at a microscopic level and what proteins or structures could be targeted to treat one or both conditions.”

As a leading expert on psoriasis, a disease known to be tied to IBD genetically, Gelfand is well aware of how closely skin health can affect other parts of the body. He and his colleagues are also studying AD’s relationship to infections, neurologic and psychiatric disorders, and cardiovascular disease.

“Investigating the relationship between skin diseases and other diseases doesn’t just offer new insight into how these diseases can affect a patient with both, but these studies are especially powerful because they also highlight unique characteristics of each disease and how they behave individually,” Gelfand shared.

Source: University of Pennsylvania School of Medicine

Categories : PaediatricsTags :

Some Countries Have a Substantial Burden of Eczema in Youth

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Atopic dermatitis
Source: Wikimedia CC0

New research published in Clinical & Experimental Allergy indicates that the burden related to eczema in young individuals is substantial in a number of countries. A median of 6% of both children and adolescents experience some form of eczema while 0.6% and 1.1% of children and adolescents, respectively, report symptoms of severe eczema. 

The results come from an analysis of data from 14 countries involving 74 361 adolescents aged 13–14 years and 47 907 children aged 6–7 years. 

Investigators estimated an average increase over 27 years in the prevalence of current eczema symptoms of 0.98% per decade in adolescents and 1.21% per decade in children, and of 0.26% and 0.23% per decade in severe eczema symptoms. However, there was substantial variation in changes in eczema prevalence over time by income and region.

“Eczema remains a big public health problem around the world,” said corresponding author Sinéad Langan, PhD, of the London School of Hygiene & Tropical Medicine. “Global research efforts are needed to address the burden related to eczema with continued international efforts to identify strategies to prevent the onset of eczema and to better manage the impact on individuals, their families, and health service.”

Source: Wiley

Categories : Diseases, Syndromes and Conditions New Compounds and TreatmentsTags :

Promising New Treatment for Moderate to Severe Atopic Dermatitis

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Atopic dermatitis
Source: Wikimedia CC0

An international clinical trial of a new monoclonal antibody therapy showed promising results for patients moderate to severe atopic dermatitis both while taking the drug and up to 20 weeks after the therapy was stopped, according to Mount Sinai researchers in The Lancet.

The researchers said the results indicate that the new biologic, rocatinlimab, has the potential to change the genetic makeup of a person’s atopic dermatitis for the long term, and possibly help sustain lasting results without continued use. Rocatinlimab inhibits OX40. an immune molecule involved in activating inflammatory cells that play a key role in the development of atopic dermatitis and other inflammatory diseases.

“Atopic dermatitis, the most common type of eczema, is a debilitating chronic inflammatory skin disease that affects 1 in 10 Americans and millions of people worldwide,” said Emma Guttman, MD, PhD, Mount Sinai professor. “It often develops at a very young age, causing the skin to become inflamed, red, extremely itchy, painful, and very dry – all symptoms that greatly affect a patient’s quality of life. We are very optimistic about the results of this trial and the potential for disease modification and long-lasting effects to improve patients’ quality of life.”

In this phase 2b multicentre, double-blind, placebo-controlled study, 274 patients were recruited and (rocatinlimab: n = 217; placebo: n = 57) equally randomised to rocatinlimab every four weeks (150mg or 600mg) or every two weeks (300mg or 600mg) or subcutaneous placebo up to week 18, with an 18-week active-treatment extension and 20-week follow-up.

Percent change from baseline in the Eczema Area and Severity Index (EASI) score was assessed as the primary endpoint at week 16, and significance versus placebo was achieved with all active rocatinlimab doses (-48% to -61%) doses compared to placebo (-15%). All active dose cohorts also continued improving after week 16, and most patients maintained the response for at least 20 weeks off treatment.

The results support rocatinlimab as a safe and effective treatment for moderate to severe atopic dermatitis, with potentially long-lasting efficacy and disease modification. Adverse events reported were generally similar between rocatinlimab groups. Common adverse events during the double-blind period included fever, chills, headache, aphthous ulcers (canker sores), and nausea.

“At week 36, all participants had been on the treatment for at least 18 weeks,” added Dr Guttman, senior author of the study. “By this time, we saw that while the drug achieved the primary endpoints in all doses versus the placebo, it’s also a drug that improves over time, which is really unusual and unique among currently available treatment options.”

Researchers plan to continue this investigation in a phase 3 program in 2023. Future studies will also include a larger study population, longer follow-up, and explore combination therapy (eg with topical corticosteroids).

Source: Mount Sinai Hospital

Categories : PaediatricsTags :

Do Emollients Help Prevent Atopic Dermatitis in Infants?

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Holding a baby's hand
Photo by William-Fortunato on Pexels

Atopic dermatitis (AD) is the most common, chronic, recurrent, inflammatory disorder of the skin, and it affects 5–30% of children worldwide. An analysis in the Journal of the European Academy of Dermatology & Venereology of relevant published studies found that early application of emollients is an effective strategy for preventing AD in high-risk infants.

The analysis included 11 randomised controlled trials involving 3483 infants. Three types of emollients, including cream, emulsion, and mixed types were comparable in preventing AD; however, an additional analysis suggested that emollient emulsion may be the best option.

This analysis revealed a surface under the cumulative ranking curve (SUCRA) of 82.6%, 78.0% for high-risk infants and 79.2% for infants with food sensitisation. However, subjects receiving emollients more frequently experienced adverse events.

“The results of this systematic review and network meta-analysis show that early application of skin emollients can effectively prevent AD development in infants,” the authors wrote. “Moreover, among the available three types of emollients, the emollient emulsion is probably the optimal option in infancy to prevent AD development more effectively.” 

Source: Wiley

Categories : Allergies Diet and NutritionTags :

Dietary Fibre Shown to Protect Against Atopic Dermatitis

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Research suggests that the gut-skin axis may have an influence on skin conditions. Photo by Romina Farias on Unsplash

A study published in Mucosal Immunology into the emerging gut-skin axis has found that microbial fermentation of dietary fibre in the gut can protect against atopic dermatitis. The research could potentially lead to novel treatments to prevent or treat allergies.

The Monash University led by Professor Ben Marsland showed that fermentation of fibre in the gut by bacteria and subsequent production of short chain fatty acids (SCFAs), in particular butyrate, protected against atopic dermatitis in mice.

Previous work had found that dietary fibre was connected to protection against flu through SFCAs activating cytotoxic T cells. SCFAs are also often found in sources including root vegetables such as chicory roots or the skins of citrus fruits

While it is well established that the gut microbiome shapes the immune system, the influence it has on the skin is less explored.

“Previous work from our group, and others, has focused on the local health benefits of SCFAs in the gut as well as at distal sites such as the lung and cardiovascular system,” Professor Marsland said. “We wondered if this might also extend to the skin, which is an area that has not really been investigated.

“People speculate that diet can influence skin health, but there is not a great deal of science behind this.”

The researchers fed mice a diet high in fermentable fibre or gave them purified SCFAs. “This treatment was profoundly protective against allergic skin inflammation,” Professor Marsland said.

They labelled the butyrate with isotopes and tracked it in the body, taking only minutes to reach the skin where it enhanced the metabolism of keratinocytes, priming them to mature and produce the key structural components required for a healthy skin barrier.

“The upshot of this was that the skin barrier was fortified against allergens – we were using house dust mite allergens – that would normally penetrate the skin barrier, activate the immune system and start an allergic reaction in these models,” he said.

“It turns out the immune system was secondary to this skin barrier function.”

Actively improving the skin barrier could have protective effects against environmental exposures that cause allergies and perhaps even other skin diseases which are underpinned by a damaged or weak skin barrier. SCFAs could be administered orally or directly on the skin as a cream, bypassing the gut, he said.

“The fact that short chain fatty acids can be given topically and are well-tolerated opens up possibilities for development of preventative strategies or disease-modifying interventions – that represents the most significant translational potential of our research.”

One possibility to explore is whether this could help children who are at risk of developing skin allergies that cascade towards food allergies and asthma, the so-called ‘Atopic March’.

Source: Monash University

Categories : Skin ConditionsTags :

No One Type of Emollient is Best for Children with AD

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Atopic dermatitis
Source: Wikimedia CC0

A trial has directly comparing emollients found that no one type of emollient is better than another when it comes to atopic dermatitis (AD) in children.  The results from the study are published in The Lancet Child & Adolescent Health and British Journal of General Practice.

Emollients are recommended for the one in five children with AD.  Lack of research in this area means guidelines vary widely in what is recommended, which leads to confusion and waste.

In the study, 550 children with AD aged under 12 years were randomised to use one of four types of emollient (lotion, cream, gel or ointment) as their main emollient for 16 weeks. Parents completed diaries about their child’s AD for a year, and some were interviewed to gain an in-depth understanding of how they used the emollients and what they thought of them.  All children also had an independent examination of their skin.

Used alongside other AD treatments, there was no difference in effectiveness of the four types of emollient used in the study.  Skin reactions such as itching or redness were common with all emollienttypes.  Awareness of the different types of emollient was low, and users had different preferences based on how the emollients look and feel.  For example, some people liked how lotions quickly soaked in whereas others preferred the “barrier” provided by ointments.

Professor Matthew Ridd, a GP and study lead from Centre for Academic Primary Care at the University of Bristol, said: “A study of this type has been long overdue.  It has not been in the interest of the manufacturers to directly compare types of moisturiser in the way we have done in this trial.  Our findings challenge conventions about how often moisturisers need to be applied, which types are less likely to cause problems and which patients should be recommended certain types. For example, ointments are often suggested for more severe eczema, yet they were found to be no better.”

Professor Hywel Williams, consultant dermatologist and co-researcher at the University of Nottingham, explained: “Along with anti-inflammatory treatments such as topical corticosteroids, emollients are a really key part of treatment for childhood eczema, preventing flares and helping to soothe the skin and improving the quality of life for children and their carers.

“Our study shows that one size does not fit all, and points to the need for doctors to make parents aware of the different emollient types and to help them choose which one is mostly likely to work for them.  At last we have evidence that supports the saying, ‘The best moisturisers are the ones the patient will use.’”

Further work is needed to determine if these findings apply to adolescents and adults with AD, and people with other dry skin conditions.

Source: EurekAlert!

Categories : Diseases, Syndromes and ConditionsTags :

Obesity in Mice Causes AD Treatments to Backfire

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Mouse
Photo by Kanasi on Unsplash

In a new study published in Nature, researchers found that treatments that were effective for atopic dermatitis (AD) in lean mice actually worsened the condition in obese mice.

Tracking the development of AD in obese and lean mice, the researchers found that obese mice developed more inflammation and more severe AD. This increased inflammation was present even after obese mice lost weight. There were similar results in an experimental model of asthma, with obese mice developing more inflammation.

The researchers next looked in detail at immune cells called T cells in lean and obese mice with AD. Lean mice had more TH2 cells, a class of T cells known to play a role in the development of AD. Obese mice had more of a class of T cells called TH17. These cells trigger a different type of inflammation.

Similar trends were seen in blood samples taken from people. Markers of TH17 cell activity increased along with body mass index (BMI) in a database of serum collected from people with AD. Conversely, in samples from patients with severe asthma, TH2 cell activity decreased as BMI increased.

Drugs that block TH2 cell activity are used in the treatment of severe AD as well as asthma and other inflammatory conditions. The researchers tested antibodies to block TH2 cell activity in lean and obese mice with severe AD. While the antibodies reduced skin inflammation in lean mice as expected, they made the condition worse in obese mice. Analysis of immune cells suggested that blocking TH2 cell activity in the obese mice worsened other forms of inflammation.

Obese mice were also found to have less activity of peroxisome proliferator-activated receptor-γ (PPARɣ) in their TH2 cells. When lean mice were engineered to lack PPARɣ, their inflammatory response resembled that of obese mice.

Drugs that increase PPARɣ activity increase insulin sensitivity and are approved for the treatment of type 2 diabetes. The researchers found that giving one of these drugs to obese mice changed their inflammatory response to resemble that of lean mice. It also restored their sensitivity to the antibodies that block TH2 cell activity.

“Our findings demonstrate how differences in our individual metabolic states can have a major impact on inflammation, and how available drugs might be able to improve health outcomes,” said Dr Ronald Evans from the Salk Institute, who helped lead the work.

Source: National Institutes of Health

Categories : AllergiesTags :

Avoid Goat’s Milk Skin Products in Inflammatory Skin Conditions

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Photo by Robin Worrall on Unsplash

Individuals with inflammatory skin conditions should avoid using skincare products that contain food products such as goat’s milk, according to a series of case studies published in Clinical & Experimental Allergy. Such skincare products have been marketed to those with ‘sensitive skin’.

In children, milk allergy is one of the most common food allergies, but usually resolves in the first years of life. Adult-onset milk allergy is rare. In patients with inflammatory conditions of the skin such as atopic dermatitis, associations between the use of food allergen-containing skin products and systemic sensitisation to that foodstuff has been demonstrated for several foods. This is of concern, as food-containing skin products are commonly promoted as a safer and more ‘natural’ way of managing a variety of skin conditions. These are widely available for unprescribed purchase in pharmacies and supermarkets.

The present study reports on seven patients with inflammatory skin conditions who experienced anaphylaxis after ingesting goat’s or sheep’s milk or cheese products.  All of the patients had a history of using goat’s milk skin products to treat their skin conditions prior to the onset of their allergic reaction. Six of them had atopic dermatitis.

“Marketing of skin products derived from goat’s milk is extensive and targeted to patients with ‘sensitive skin’ who commonly have underlying inflammatory skin conditions,” the authors wrote. “Our findings provide novel evidence of the origins of adult-onset milk allergy and adds to the growing body of evidence that use of foodstuffs as therapy for inflammatory skin conditions can lead to the development of new food allergies.” 

Source: Wiley