For psoriasis, molecular signature in healthy-appearing skin may be best predictor of response to anti-TNF treatment

It's common for people with psoriasis to develop dry, inflamed skin lesions. However, the normal-appearing skin may hold the key to predict whether certain medications will work for patients.

A Michigan Medicine study, published in the Journal of Allergy and Clinical Immunology, analyzed patients with chronic plaque psoriasis being treated with etanercept, a drug used to reduce tumor necrosis factor. TNF is a critical inflammatory mediator released by immune cells in psoriatic skin lesions and is found to be elevated in the blood of patients with psoriasis.

Investigators found that specific gene expression changes in healthy-appearing skin were a better predictor of clinical response than changes in inflamed psoriasis skin. The findings could have major implications for improving treatment efficacy and identifying patients who are likely to respond, thereby limiting unnecessary drug exposures, said Lam Tsoi, Ph.D., lead author of the paper and an assistant professor of dermatology at Michigan Medicine.

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"Up to one-fifth of psoriasis patients have been treated with the anti-TNF agent etanercept, yet only around half show a robust clinical response, and until now we have lacked the ability to predict who is going to respond and who will not," Tsoi said. "Efficient drug response assessment allows us to identify those who will do well on treatment and avoid wasting time and resources on medications that don't work."

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The team took several skin biopsies of both healthy-appearing and inflamed skin from approximately 40 patients being treated with etanercept over a period of 12 weeks. They used the Psoriasis Area and Severity Index, a commonly used assessment tool for psoriasis, to measure disease activity before and during treatment. Surprisingly, while the molecular profile in healthy-appearing skin was predictive of treatment effectiveness, inflamed skin provided very little predictive information.

Healthy-appearing skin from patients with psoriasis has been known to have subtle sub-clinical changes.  While the reason for those changes is unclear, Tsoi and the research team believe it may reflect the overall inflammation and effect of genetic factors carried by psoriasis patients.

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"The complex nature of the inflammation in inflamed psoriatic skin might make it more 'noisy' and therefore not as helpful in the drug response assessment," Tsoi said. "Future studies will need to assess whether this process can be replicated to predict response for other drugs in psoriasis."

Etanercept is one of several anti-TNF therapies approved to treat psoriasis and one of many biologic drugs used in its treatment.

"Finding these predictive signs in a patient's genetic profile is one of the first steps to applying precision medicine to complex inflammatory skin diseases," said Johann Gudjonsson, M.D., Ph.D., senior author of the paper and Arthur C. Curtis Professor of Skin Molecular Immunology at Michigan Medicine. 

A major emphasis of the work in Tsoi's and Gudjonsson's laboratories is to gain a deeper understanding of the pathologic mechanisms in psoriasis and assess how such information may be used to predict clinical course, treatment responses and help move the research field towards a cure for psoriasis.

Paper cited: "Cytokine responses in nonlesional psoriatic skin as clinical predictor to anti-TNF agents," Journal of Allergy and Clinical Immunology. DOI: 10.1016/j.jaci.2021.07.024

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