Day: November 10, 2021

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

Vascular Damage in Diabetes Arises from Red Blood Cell Changes

Photo by National Cancer Institute on Unsplash

Altered function of the red blood cells leads to vascular damage in type 2 diabetes, and new research shows that this effect is caused by low levels of an important red blood cell molecule. 

Patients with type 2 diabetes have an increased risk of cardiovascular disease, and type 2 diabetes may over time damage blood vessels, raising the risk for heart attack and stroke. However, the disease mechanisms underlying cardiovascular injury in type 2 diabetes are largely unknown and treatments to prevent such injuries are lacking.

Research has shown that red blood cells become dysfunctional in type 2 diabetes and can act as mediators of vascular complications. In this study, published in Diabetes, researchers examined cells from patients with type 2 diabetes and mice to see if molecular changes in the red blood cells could explain these harmful effects in type 2 diabetes.

The researchers found that levels of the small molecule microRNA-210 were markedly reduced in red blood cells from 36 patients with type 2 diabetes compared to healthy controls. Micro-RNAs belong to a group of molecules that serve as regulators of vascular function in diabetes and other conditions. The reduction in microRNA-210 caused alterations in specific vascular protein levels, and impaired blood vessel endothelial cell function. In laboratory experiments, restoration of microRNA-210 levels in red blood cells prevented the development of vascular injury via specific molecular changes.

“The findings demonstrate a previously unrecognised cause of vascular injury in type 2 diabetes,” said Zhichao Zhou, researcher at the Department of Medicine, Solna, Karolinska Institutet. “We hope that the results will pave the way for new therapies that increase red blood cell microRNA-210 levels and thereby prevent vascular injury in patients with type 2 diabetes.”

Source: Karolinska Institutet

No Evidence of Videogame and Violence Link in the Real World

New research finds no evidence that violence increases after the release of a new video game.

Violent video games like Call of Duty are often linked by the media and public to real-life violence, although there is limited evidence to support the link. Debate on the topic generally intensifies after mass public shootings, with some commentators linking these violent acts to the perpetrators’ interests in violent video games. But different factors have been pointed out as more likely explanations, such as mental health issues and/or easy access to guns.

Before governments introduce any policies restricting access to violent video games, it is important to establish whether violent video games do indeed increase players’ violence in the real world.

Taking data from the US, Dr Agne Suziedelyte at University of London, provides evidence of the effects of violent video game releases on the violent behaviour of children. Dr Suziedelyte examined the effects of violent video games on two types of violence: aggression against other people, and destruction of objects or property.

Appearing in the Journal of Economic Behavior & Organization, the study focused on boys aged 8 to 18 years: the group most likely to play violent video games.

By using econometric methods which identify plausibly causal effects of violent video games on violence, rather than only associations, Dr Suziedelyte found no evidence that violence against other people increases after the release of a new violent video game. Parents reported, however, that children were more likely to destroy things after playing violent video games.

Dr Suziedelyte said: “Taken together, these results suggest that violent video games may agitate children, but this agitation does not translate into violence against other people — which is the type of violence which we care about most.

“A likely explanation for my results is that video game playing usually takes place at home, where opportunities to engage in violence are lower. This ‘incapacitation’ effect is especially important for violence-prone boys who may be especially attracted to violent video games.

“Therefore, policies that place restrictions on video game sales to minors are unlikely to reduce violence.

Source: City University London