Beyond PASI 100: Striving for Molecular Clearance

Bruce Jancin

August 12, 2020

Dr Andrew Blauvelt

All PASI 100 responses to psoriasis therapy are not the same, Andrew Blauvelt, MD, declared at the virtual annual meeting of the American Academy of Dermatology.

He presented a first-of-its-kind study that potentially opens the door to a new, more rigorous standard for treatment success in psoriasis: Not simply cleared lesional skin as captured by a Psoriasis Area and Severity Index (PASI) 100 response, but also clearance of residual psoriasis signs and symptoms – as well as what he termed "molecular clearance."

"We've found that clearing skin with drugs utilizing different mechanisms of action may lead to differential consequences for our patients," observed Dr. Blauvelt, a dermatologist and clinical trialist who is president of the Oregon Medical Research Center, Portland.

A PASI 100 response, traditionally considered an elusive goal for the great majority of patients with severe psoriasis, can now often be achieved using today's top-tier, high-performance biologics. But Dr. Blauvelt and his coinvestigators are interested in pushing even beyond PASI 100 to a new frontier of therapeutic benefit.

He presented a secondary analysis of the previously reported VOYAGE 1 and 2 head-to-head randomized trials of guselkumab (Tremfya) versus adalimumab (Humira) for treatment of moderate to severe psoriasis. This new analysis, which focused exclusively on PASI 100 responders by week 24, demonstrated that patients with a PASI 100 response to guselkumab, an interleukin (IL)-23 inhibitor, had significantly fewer persistent symptoms and signs of psoriasis than those whose skin clearance was attained using adalimumab, a tumor necrosis factor (TNF) inhibitor.

Moreover, the investigators showed that the gene expression profile of PASI 100 responders who were free of signs and symptoms was more normalized than that of patients with residual symptoms despite their cleared skin.

The analysis included 16 participants in the VOYAGE trials who achieved PASI 100 at week 24 on guselkumab and 5 who did so on adalimumab. At baseline and again at week 24, these individuals completed the Psoriasis Symptoms and Signs Diary (PSSD). Also, biopsies of lesional and nonlesional skin were obtained at baseline and of cleared lesional skin at week 24 for transcriptomic microarray analysis of the expression of many thousands of genes.

Persistent Psoriasis Symptoms Despite Cleared Skin

The PSSD involves patient ratings of various psoriasis symptoms and signs. Total scores can range from 0 (symptom- and sign-free) up to 100. At week 24, a significantly higher proportion of guselkumab-treated PASI 100 responders had a total PSSD score of zero: 55%, versus 43% in the adalimumab group. This was consistently true across the board for each of the individual signs and symptoms assessed. For example, 61% of the guselkumab group gave themselves a zero for itch, as did 50% of the adalimumab group. Sixty-four percent on guselkumab and 52% on adalimumab reported being free of redness. And 78% of the guselkumab group reported being pain-free, compared with 69% with adalimumab, Dr. Blauvelt reported.

Gene Expression Analysis

At baseline, more than 2,300 dysregulated genes were identified in lesional skin while functioning normally in nonlesional skin. The great majority of these initially dysregulated genes became normalized in cleared lesional skin in PASI 100 responders at week 24. However, 25 of the genes remained dysregulated in cleared lesional skin, meaning they displayed less than 75% of normal function. Ten of these 25 genes with dysregulated expression at follow-up showed abnormal function in patients with residual symptoms despite cleared skin, but they functioned normally in those without persistent symptoms. This raises the possibility that the residual symptoms of psoriasis were attributable to the abnormal gene functioning, according to Dr. Blauvelt.

Of note, 9 of the 10 dysregulated genes in cleared lesional skin of patients with residual symptoms were present in the adalimumab group; these included two genes localized to the epidermal differentiation complex as well as the psoriasis-specific proline-rich 9 gene known as PRR9, which is induced by IL-17A. In contrast, only four genes, none of which were localized to the epidermal differentiation complex, were insufficiently normalized in the cleared lesional skin of guselkumab-treated PASI-100 responders.

"Nothing like this analysis has ever been done before," the dermatologist observed. "It's a pilot study. Perhaps with more data like this, we'll be using this type of information in clinical practice to go beyond clearing patients' skin."

Dr. Blauvelt reported serving as a scientific advisor to and paid clinical investigator for Janssen, which sponsored the study, as well as for roughly two dozen other pharmaceutical companies.

This article originally appeared on MDedge.com, part of the Medscape Professional Network.

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