Tag: psoriasis

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New Therapy Eliminates ‘Problematic’ T Cells in Skin Autoimmune Diseases

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In a groundbreaking study published in Science, researchers discovered distinct mechanisms controlling different types of immune cells, and found that, by precisely targeting these mechanisms, they could selectively eliminate ‘problematic cells’ and reshape the skin’s immune landscape.

The skin is packed with specialised immune cells that protect against infections and cancer and promote healing. These cells, called tissue-resident T cells or TRM cells, stay in place to fight infections and cancerous cells in the skin.

However, when not controlled properly, some of these skin TRM cells can contribute to autoimmune diseases, such as psoriasis and vitiligo.

Researchers, led by University of Melbourne’s Professor Laura Mackay, a Laboratory Head and Immunology Theme Leader at the Peter Doherty Institute of Infection and Immunity (Doherty Institute), found a way to redress this imbalance.

University of Melbourne’s Dr Simone Park, an Honorary Research Fellow and former Postdoctoral Fellow in the Mackay Lab at the Doherty Institute, and lead first author of the study, said that this research is the first to describe the unique elements that control various types of skin TRM cells in animal models, offering precise targets for potential treatment strategies.

“Specialised immune cells in our skin are diverse: many are critical to prevent infection and cancer, but others play a big role in mediating autoimmunity,” said Dr Park.

“We discovered key differences in how distinct types of skin T cells are regulated, allowing us to precisely edit the skin’s immune landscape in a targeted way.”

University of Melbourne’s Dr Susan Christo, Senior Research Officer in the Mackay Lab at the Doherty Institute and co-first author of the study, explained how these discoveries could advance efforts to treat skin disease.

“Most autoimmune therapies treat the symptoms of the disease rather than addressing the cause. Conventional treatments for skin disorders often impact all immune cells indiscriminately, meaning that we could also be wiping out our protective T cells,” said Dr Christo.

“Until now, we didn’t know how to pick apart ‘bad’ T cells in the skin from the ‘good’ protective ones. Through this research, we discovered new molecules that allow us to selectively remove disease-causing T cells in the skin.”

The research team harnessed this new knowledge to eliminate ‘problematic’ cells that can drive autoimmune disorders, while preserving the ‘good’ ones that are essential to maintain protective immunity.

University of Melbourne’s Professor Laura Mackay, senior author of the study, explained that these findings could pave the way for more precise and long-lasting therapies for skin disease.

“Skin conditions like psoriasis and vitiligo are difficult to treat long-term. The T cells driving disease are hard to remove, so patients often need life-long treatment. Our approach has the potential to revolutionise the way we treat these skin disorders, significantly improving outcomes for people dealing with challenging skin conditions,” said Professor Mackay.

With the study demonstrating successful removal of specific skin T cells in animal models, further research is necessary to validate the efficacy of these strategies in human subjects.

Dr Park hopes the study will inspire the development of new treatments for skin disease.

“These discoveries bring us one step closer to developing new drugs that durably prevent autoimmune skin disorders without compromising immune protection,” said Dr Park.

Source: The Peter Doherty Institute for Infection and Immunity

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Researchers Develop Online Tool to Calculate Psoriatic Arthritis Risk

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In research published in Arthritis & Rheumatology, investigators developed and validated a tool called PRESTO that identifies patients with psoriasis who face an elevated risk for developing psoriatic arthritis and may therefore benefit from preventive therapies. The PRESTO calculator is available online.

The University of Toronto psoriasis cohort followed 635 patients with psoriasis, and 51 and 71 developed psoriatic arthritis during 1-year and 5-year follow-up periods, respectively. The risk of developing psoriatic arthritis within 1 year was higher in patients with younger age; male sex; family history of psoriasis; back stiffness; nail pitting (dents, ridges, and holes in the nails); joint stiffness; use of biologic medications; poor health; and pain severity. The risk of developing psoriatic arthritis within 5 years was higher in patients with morning stiffness, psoriatic nail lesion, psoriasis severity, fatigue, pain, and use of systemic non-biologic medication or phototherapy.

Taking these data into account, PRESTO uses a mathematical model to estimate a patient’s risk of developing psoriatic arthritis.

“The PRESTO tool could serve future efforts to reduce the progression from psoriasis to psoriatic arthritis. For example, PRESTO can be used to enrich prevention trials with at-risk populations. It can also identify patients with psoriasis who can benefit from early treatments, and it can serve as an educational tool for patients to increase awareness of psoriatic arthritis risk,” said corresponding author Lihi Eder, MD, PhD, of Women’s College Hospital and the University of Toronto, in Canada. “Ultimately, we hope that these efforts will improve the lives of people living with psoriatic disease.”

Source: Wiley

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Brepocitinib Promising in Treatment of Psoriatic Arthritis

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Brepocitinib is an oral drug that inhibits certain enzymes involved in inflammation (called tyrosine kinase 2 and Janus kinase 1) and is being tested for the treatment of several immunological diseases. A phase IIb randomised clinical trial published in Arthritis & Rheumatology recently generated promising efficacy and safety data for the use of brepocitinib in adults with moderately-to-severely active psoriatic arthritis.

Psoriatic arthritis is a type of arthritis that affects some people with psoriasis. It typically causes affected joints to become swollen, stiff and painful. Like psoriasis, psoriatic arthritis is a long-term condition that can get progressively worse.

Overall, 218 participants were randomised to receive either a low or high dose of brepocitinib or placebo for 1 year. After 16 weeks of treatment, 30 and 60mg daily doses of brepocitinib were superior to placebo at reducing signs and symptoms of psoriatic arthritis. Response rates were maintained or improved through week 52. Side effects were mostly mild or moderate.

“These data demonstrate striking efficacy and confirm the relevance of multiple signaling pathways dependent on the kinases targeted by brepocitinib in psoriatic arthritis,” said corresponding author Philip Mease, MD, of Swedish Medical Center/Providence St. Joseph Health and the University of Washington, in Seattle. “The safety is also reassuring for brepocitinib in this study.”

Source: Wiley

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New Oral Psoriasis Drug a Step Closer After Successful Clinical Trials

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In a Phase 2b clinical trial, patients who took the peptide-based drug candidate JNJ-2113 had a 75% improvement in their plaque psoriasis compared to placebo, passing an important milestone in developing an oral treatment for the common skin disease. The drug is being developed by a company launched from The University of Queensland’s Institute for Molecular Bioscience (IMB) in collaboration with Janssen.

Protagonist Therapeutics was spun out of work by Associate Professor Mark Smythe to develop new drugs for conditions previously only treated with injectables. Dr Smythe said the trial result was a significant achievement for patients and the scientists involved.

“The trial has shown it’s possible to treat systemic diseases like psoriasis with peptide-based drugs that are orally delivered,” Dr Smythe said.

“Diseases such as psoriasis and inflammatory bowel disease have targets that previously could only be blocked by large molecules called macromolecular antibodies, which had to be injected because they’re too big to be taken in pills.

“The key to finding a molecule that worked but was small enough to be taken orally was seeing the animal venom research of my IMB colleagues.

“I realised that the constrained peptide molecules in venoms could both block the right targets and were small.”

Dr Smythe and his team developed techniques to stabilise the peptides enough so that they could be developed into an oral drug.

Protagonist was founded in 2001 with commercial support from UniQuest Pty Ltd, UQ’s commercialisation company.

Protagonist is based in the USA with an office in Brisbane and is one of 15 spin-out companies from IMB and one of 125 start-ups based on UQ intellectual property.

Source: The University of Queensland

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Findings May Lead to Paradigm Shift in Psoriasis Treatment

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About a third of people with psoriasis develop inflammation in their joints (psoriatic arthritis) as a result of the chronic skin condition. Research published in Annals of the Rheumatic Diseases has now discovered a key starting point for inhibiting inflammation in both psoriasis and psoriatic arthritis. These findings may lead to major new developments for treatment, diagnostic and prevention strategies.

The study conducted by the research group led by Erwin Wagner at the Medical University of Vienna focused on the S100A9 gene. The team has discovered that the severity of psoriasis (Ps) and psoriatic arthritis (PsA) can be reduced by inhibiting S100A9 systemically throughout the whole body rather than locally on the skin.

With this finding, the researchers are laying the foundation for a paradigm shift in the treatment of Ps and PsA: “Our study is an important step towards the development of targeted therapeutic options in the form of drugs that act systemically rather than locally on the skin,” affirms Erwin Wagner. New diagnostic and prevention strategies can also build on the study.

Psoriasis, typically an adult-onset disease, have triggers such as stress and UV radiation. There can also be a genetic predisposition to developing Ps. S100A9 activation in skin and immune cells has been identified as a risk factor for the development of Ps and/or PsA.

Previous work by Erwin Wagner’s team showed that the symptoms of psoriasis disappear when the S100A9 gene is deactivated in all of the body’s cells. Their recent preclinical experiments highlighted the particular influence that those skin and immune cells in which S100A9 is produced have on disease severity. “We now know that the inflammatory responses in psoriasis and psoriatic arthritis are enhanced when S100A9 is only inhibited in skin cells,” Erwin Wagner explained. Therefore drugs inhibiting S100A9 would have to be administered systemically in the form of tablets or drips

Source: Medical University of Vienna

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Two Biomarkers Predict CVD Risk in Psoriatic Disease

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In a new study published in Arthritis & Rheumatology, scientists have found that two biomarkers predict cardiovascular disease (CVD) risk in people with psoriatic disease. People with psoriatic disease, which includes psoriasis and psoriatic arthritis, are more likely to develop CVD than the general population.

The study, which included 1000 adults with psoriatic disease, found that elevated blood levels of two indicators of cardiovascular health, namely, cardiac high-sensitivity troponin I (cTnI) and N-terminal pro-brain-type natriuretic peptide (NT-proBNP), were associated with higher risks of experiencing cardiovascular problems independent of traditional risk factors such as hypertension and high cholesterol.

These findings pave the way for further studies exploring the clinical potential of measuring cTnI and NT-proBNP levels in helping assess the heart health of individual patients with psoriatic disease.

“Our study provides new insights regarding the pathophysiology of cardiovascular diseases in psoriasis and psoriatic arthritis. However, at this time, ordering tests of cardiac biomarkers is not recommended for risk stratification of asymptomatic patients with psoriatic disease,” said senior Lihi Eder, MD, PhD, associate professor of medicine at Women’s College Hospital and University of Toronto.

Source: Wiley

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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

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Interleukin-12 no Longer the Villain in Psoriasis

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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

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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

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Glycerine’s Surprising Effectiveness in Psoriasis

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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