Tag: psoriasis

Effective Psoriasis Treatment Could be a ‘TWEAK’ Away

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A key protein called TWEAK damages skin cells in psoriasis patients, according to a new study in mice and with human skin cells, and targeting TWEAK may help control the disease.

Although there are effective treatments for psoriasis, an autoimmune disease that shows up as patches of red, inflamed skin and painful, scaly rashes, not everyone responds to these therapies – and for many, the relief is temporary.

“These therapies don’t reduce disease by 100 percent, and they don’t cure the disease” says La Jolla Institute for Immunology (LJI) Professor Michael Croft, PhD. “And if you take patients off those drugs, the disease almost always comes back.”

“We think TWEAK might be considered a potential target for the treatment of psoriasis,” said first author Rinkesh Gupta, PhD, a postdoctoral fellow at LJI. “It’s good to have this chance to develop a new therapeutic option.”

The findings build on the lab’s earlier research showing that TWEAK can interact with keratinocytes, the most common type of skin cell. By investigating TWEAK-deficient mice, the researchers found that TWEAK is a driver of inflammation in a model of psoriasis.
The new study, published in Science Immunology, shows that TWEAK does not work alone; it teams up with two other proteins, tumour necrosis factor (TNF) and interleukin-17 (IL-17), to trigger inflammation. These three seem to control inflammatory molecule production and the expression of additional inflammation-associated proteins in patients with psoriasis.

“The fact that they work together suggests the disease is essentially driven by all three of those particular proteins at the same time,” explained Prof Croft. “The primary implication is that TWEAK will also be a good drug target. as has already been proven for TNF and IL-17.”

The researchers tested this idea with a mouse model of psoriasis to compare how well a TWEAK-inhibitor measured up to therapies inhibiting IL-17 or TNF.

“If you inhibit TWEAK from working on its receptor on keratinocytes, you get the same therapeutic effect as when you inhibit TNF or IL-17,” said Dr Gupta. A particularly encouraging aspect of this finding since TNF and IL-17 are both FDA-approved drug targets for psoriasis.

Prof Croft thinks TWEAK inhibitors have potential as therapies for many types of skin diseases. “We think TWEAK is involved in skin inflammation in general,” he said.

His lab is now investigating the role of TWEAK in atopic dermatitis, and while a distinct disease from psoriasis, they do have a few things in common – and there are not as many good treatments for atopic dermatitis.

“There’s certainly a lot of room for improvement in treatment of atopic dermatitis patients,” he said.

Source: La Jolla Institute for Immunology

Interleukin-12 no Longer the Villain in Psoriasis

Psoriatic plaque, showing a silvery center surrounded by a reddened border. Source: Wikimedia. By James Heilman, MD – Own work, CC BY-SA 3.0

Considered to be the trigger for psoriais, the immune messenger molecule Interleukin-12 (IL-12) has now been shown to actually cause the skin disease but in fact protects against it. This finding also explains why common psoriasis drugs that block the messenger show insufficient treatment efficacy.

Psoriasis is a chronic inflammatory autoimmune disease that manifests as red, scaly skin patches. No causal treatment for the disease exists, but the symptoms can be significantly alleviated with modern therapies. The development of the skin disease arises from complex changes immune cell networks and the messengers they use for communication. Clinical trials showed that newly developed drugs that blocked only IL-23 are more effective than previous treatments targeting both IL-23 and IL-12 in psoriasis patients, but why this was so was not known. Now, researchers at the University of Zurich (UZH) have uncovered the underlying molecular mechanisms.

From human and mouse studies, they found that various cell types in the skin are also equipped with receptors for IL-12. Not only the T cells of the immune system, but also keratinocytes, horn-forming skin cells that build up the epidermis, can thus recognise the messenger. In fact, the recognition of interleukin-12 by these skin cells was responsible for the protective effect of the messenger, as the researchers found out. “Interleukin-12 is essential for the normal, physiological function of keratinocytes. For example, it prevents the increased cell division observed in psoriasis,” explained group leader Sarah Mundt from the Institute of Experimental Immunology at UZH.

“These results surprised us, because so far drugs for the treatment of psoriasis also aim at blocking interleukin-12,” said immunology professor Burkhard Becher.

“Our findings indicate that blocking IL-12 is not advisable, and such drugs should therefore no longer be used to treat psoriasis patients,” advised first author  Pascale Zwicky, PhD student. Accordingly, psoriasis drugs should only block the messenger substance IL-23, but no longer IL-23 and -12 together.

The UZH researchers’ findings could be important for the treatment of other diseases. “The combined blocking of IL-23 and -12 is also used in the treatment of chronic inflammatory bowel diseases and psoriatic arthritis,” said Prof Becher. “In these diseases, the role of IL-12 has not yet been sufficiently studied. But here, too, a protective role of the messenger substance is possible.”

Source: University of Zurich

Hypertension Drugs Linked to Psoriasis

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A review of studies has found an association with the use of antihypertensive medications and the development of psoriasis.

Psoriasis is a chronic inflammatory skin disease that, when inflicted, can be detrimental to the individual’s overall quality of life. The prevalence rate of psoriasis is 0.1–11%, more common in Caucasian and Scandinavian populations, and also more common in older people and in high-income countries as well.

In the analysis, which is published in the British Journal of Clinical Pharmacology, data from 13 studies indicated that angiotensin-converting-enzyme inhibitors, beta- blockers, calcium-channel blockers, and thiazide diuretics may increase the risk of psoriasis. However, there was no greater increase of any of the drugs relative to the others.

The authors of the analysis propose several mechanisms by which blood pressure medications may affect an individual’s risk of developing skin conditions.

“Our findings indicate that patients who take antihypertensive drugs should be carefully monitored for psoriasis,” said senior author Hye Sun Gwak, PharmD, PhD, of Ewha Womans University, in Seoul.

Source: Wiley

Glycerine’s Surprising Effectiveness in Psoriasis

Photo by Daria Nepriakhina on Unsplash

Patients with psoriasis have often reported that glycerine, common in many skin lotions, is effective at combatting their psoriasis and there is now objective evidence to support their reports.

Researchers found that whether applied topically or ingested in drinking water, glycerine, or glycerol, helps calm the classic scaly, red, raised and itchy patches in their psoriasis model, Dr. Wendy Bollag, cell physiologist and skin researcher at the Medical College of Georgia and Charlie Norwood VA Medical Center and her colleagues report in the International Journal of Molecular Sciences.

The studies also provide more evidence of the different ways glycerine enables the healthy maturation of skin cells through four stages that result in a smooth, protective skin layer. Psoriasis is an immune-mediated problem that typically surfaces in young adults in which skin cells instead multiply rapidly, piling up into inflamed patches.

“We have experimental data now to show what these patients with psoriasis are reporting,” said  Dr Bollag, who nearly 20 years ago first reported that glycerine, a natural alcohol and water attractor known to help the skin look better, also safely helped it function better by helping skin cells mature properly.

Dr Bollag’s early report led to many anecdotal reports from individuals and their reports ultimately led to the newly published study.

Topically, glycerine is known to have a soothing, emollient effect. But once glycerine enters skin cells through the aquaporin 3 channel, the enzyme phospholipase-D-2 converts it to the lipid phosphatidylglycerol. Phosphatidylglycerol ultimately regulates the function of keratinocytes and suppresses inflammation in the skin. Dr Bollag and team previously reported that topical application of phosphatidylglycerol reduced inflammation and raised skin patches in a mouse model of psoriasis. 

For this study, they focused on its glycerin precursor, which was either applied topically or fed to mice with induced psoriasis. Either way, glycerine helped reduce development of the characteristic skin lesions, showing that glycerin works in more than one way to improve the skin condition.

Glycerine worked as an emollient even in mice lacking phospholipase-D-2. It also seems to block hydrogen peroxide in the aquaporin 3 channel. At low levels, hydrogen peroxide is a cell signaling molecule, but at high levels results in destructive oxidative stress, possibly leading to psoriasis.
Topical glycerine reduced the levels of hydrogen peroxide entering skin cells. When they added glycerin and hydrogen peroxide at the same time directly to skin cells, they found that glycerin protected against the oxidative stress from hydrogen peroxide.

“Glycerol is basically outcompeting the hydrogen peroxide in getting in there and preventing it from being able to enter and increase oxidative stress,” Dr Bollag said. Glycerine could also help by maintaining the skin’s water permeability barrier.

On the other hand, when glycerin was ingested by the mice missing the phospholipase- D-2,  it simply did not work, Dr Bollag said, which confirmed their earlier findings that internally anyway, glycerine pairs with the enzyme to produce the signal essential to skin cell maturation.

Some of their other most recent work is detailing more about how phosphatidylglycerol decreases inflammation.

Dr Bollag would like next steps to also include clinical trials with dermatologists and patients and is working to find a formulation scientist who can make what she thinks will be the optimal combination: glycerin and phosphatidylglycerol in the same topical cream.

The addition of phosphatidylglyerol itself, rather than just the glycerine that makes it, is essentially a backup since there is some evidence that in psoriasis the essential conversion of glycerin to phosphatidylglycerol is not optimal. Dr Bollag’s lab and others have shown reduced levels of aquaporin 3 in psoriasis, which likely means less phosphatidylgycerol, so making more glycerine available could somewhat help raise the availability of this key lipid.

She suspects that this sort of two-punch combination, could help keep early signs of psoriasis at bay and, with more advanced disease, use existing psoriasis treatments to get the skin condition under control then start applying glycerin to help keep it that way.

While its exact cause is unclear, psoriasis is an immune-mediated condition and patients have higher levels of inflammation, as well as too many skin cells being produced then maturing abnormally. The heightened inflammation also puts them at increased risk for problems like heart disease.

Biologics used to treat psoriasis work different ways to stem this overactive immune response but in addition to their high cost, can put the patient at risk for problems like serious infections and cancer. The only side effect she has seen in about 20 years of working with glycerine and the clinical and cosmetic use already out there, is sticky-feeling skin.

Source: MedicalXpress

Discovery of Cell Type Linked to Skin Conditions

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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!

New Evidence-based Resources to Aid Plaque Psoriasis Treatment Decisions

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The Targeted Therapies Alliance has made a range of evidence-based resources available to help dermatologists and their patients in shared decision making in the treatment of plaque psoriasis.

Psoriasis, of which plaque psoriasis is the most common type, is the most prevalent immune-mediated inflammatory disease. It involves skin and in some cases, joints, and can be associated with abnormalities of other systems.

NPS MedicineWise spokesperson Jonathan Dartnell said: “While the condition currently does not have a cure, it can be well controlled, hence there is a need to support people with plaque psoriasis to understand and follow the treatment to get the best results.”

“The members of the Targeted Therapies Alliance have worked closely with the Australasian College of Dermatologists and Psoriasis Australia to create these resources which were developed with input from consumers with plaque psoriasis,” he said.

Australasian College of Dermatologists Fellow A/Prof Stephen Shumack said the resources were developed through a collaborative effort.

Jonathan Dartnell, Spokesperson, NPS MedicineWise said: “These resources were designed to support optimal patient outcomes by helping improve understanding of, and adherence to, the treatments for plaque psoriasis. The resources cover topical treatments such as creams and ointments, to phototherapy and systemic treatments.”

The new resources available include:

  • A consumers’ fact sheet with an overview of the topical treatment options (such as creams and ointments) and questions to ask their doctor to make sure they understand why, how and when to use their topical treatments.
  • A decision aid to help consumers speak to their doctor about treatment options should topical treatments not be enough.
  • An action plan and information to address some myths and help adherence to low-dose methotrexate.

The new dermatology resources complement existing Targeted Therapies Alliance resources focused on gastroenterological and rheumatological conditions. They also are part of a wider three-year programme to ensure the best possible health and economic outcomes from the use of biological and other specialised medicines.

Source: News-Medical.Net