Conference Coverage

New developments in pustular psoriasis


 

FROM THE GRAPPA 2020 VIRTUAL ANNUAL MEETING

Pustular psoriasis is a rare condition that presents significant challenges to clinicians, not least because it comes in varied forms that are not well understood.

Dr. Kristina C. Duffin is cochair of the department of dermatology at the University of Utah, Salt Lake City

Dr. Kristina Callis Duffin

It has various dermatologic and rheumatologic manifestations and sometimes overlaps with plaque psoriasis. Pustular palmoplantar psoriasis (PPP) affects the palmar and plantar areas of the skin, while generalized pustular psoriasis (GPP) can affect large areas of skin and tends to be more severe, even life threatening. PPP can accompany psoriatic arthritis or can be a side effect of tumor necrosis factor (TNF) inhibitor therapy, or a non–drug-induced component of rheumatologic syndromes, according to Kristina Callis Duffin, MD, an associate professor and chair of dermatology at the University of Utah, Salt Lake City.

“Each phenotype could be considered an orphan disease, and the response to therapy is often unpredictable,” Dr. Duffin said during a session on pustular psoriasis at the virtual annual meeting of the Group for Research and Assessment of Psoriasis and Psoriatic Arthritis.

But there is some positive news. A study in 2011 of several people with GPP opened the door to better understanding the pathophysiology of pustular psoriasis. Researchers identified a causal autosomal mutation in the IL36RN gene, which encodes an antagonist to the interleukin-36 receptor (Am J Hum Genet. 2011 Sep 9;89[3]:432-7). “As a result of this paper and others, drug development in this space has recently accelerated,” Dr. Duffin said.

In fact, she added,“it’s my opinion that pustular psoriasis is now where plaque psoriasis was 20 years ago, when accelerated drug development was driving a better understanding of the pathogenesis of psoriatic disease and its comorbidities, and also driving outcome measure development.”

In another presentation at the meeting, Hervé Bachelez, MD, PhD, professor of dermatology and immunologist at the University of Paris and Saint-Louis Hospital, Paris, discussed recent advances in drug development for pustular psoriasis. He noted other recent findings of genetic variants related to the disease, including AP1S3, CARD14, and SERPINA3.

For GPP, he said, the current algorithm for management is based on weak evidence for treatments like acitretin, cyclosporine, methotrexate, and infliximab. The story is similar for other biologics, with evidence in the form of case series; open-label studies; controlled, prospective studies; or retrospective analyses. Most of the evidence has been amassed for TNF inhibitors. A retrospective study of all TNF inhibitors suggested they may be effective as induction and maintenance therapy, he noted.

Among IL-17A inhibitors, a prospective study of 12 patients in Japan found secukinumab showed efficacy against GPP, as did studies of ixekizumab and brodalumab. A small phase 3 study in Japan demonstrated efficacy for the IL-23 inhibitor guselkumab in patients with erythrodermic psoriasis and GPP (J Dermatol. 2018 May;45[5]:529-39).

The limited data are a reflection in part of the difficulty in studying GPP, since its flares tend to be more self-remitting than with psoriasis vulgaris or PPP.

There are two monoclonal antibodies against the IL-36 receptor currently being developed. A proof-of-concept study of one of them, spesolimab, showed promise against GPP, with five of seven patients reaching “clear” or “almost clear” scores on the Generalized Pustular Psoriasis Physician Global Assessment within a week after infusion and in all seven by the fourth week (N Engl J Med. 2019 Mar 7;380[10]:981-3).

With respect to PPP, the strongest evidence for conventional therapies comes from two randomized, controlled trials of cyclosporine, with response rates of 48% and 89%, compared with 19% and 21%, respectively, in the placebo groups, although the primary endpoint was poorly designed, according to Dr. Bachelez. Retinoids like etretinate and acitretin, combined with psoralen and UVA, also have some supporting evidence regarding efficacy.

Among biologics, secukinumab did not fare well in a phase 3 study of patients with PPP. A subset of patients may benefit from it, but there are no biomarkers available to identify them, Dr. Bachelez said. A phase 2 study of guselkumab in Japan told a similar story, with only weak signs of efficacy. While there are many more ongoing clinical trials evaluating treatments for PPP, which is encouraging, PPP seems to be more challenging at this stage to tackle than GPP, Dr. Bachelez added. “The genetically inherited IL-36 antagonist abnormalities are clearly driving the advances regarding the pathogenesis of the disease, mainly for GPP rather than PPP.”

Part of the efforts to develop therapies for pustular psoriasis relies on the development of new outcome measures, or adaptation of existing ones. “We have a need to adapt or develop new investigator-reported measures, we need to adapt or develop new patient-reported outcomes,” Dr. Duffin said.

Many existing measures use inconsistent language and anchoring definitions, and some may be proprietary, she added. “The language varies by sponsor and is sometimes tweaked or modified by the agencies. Often synonyms are being used … it raises questions, does it change the validity of the instrument?”

Dr. Duffin called for the research community to use the pause in clinical research during the COVID-19 pandemic to reassess the research agenda, develop consensus on performing and training for GPP and PPP assessments, develop patient-reported outcomes, and strengthen connections to industry.

Dr. Duffin and Dr. Bachelez have consulted, served on the advisory board, been a speaker for, and/or received research support from a wide range of pharmaceutical companies, including those that manufacture and develop psoriasis treatments.

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