Phenotype-Targeted Treatment Sought for Psoriatic Disease

WASHINGTON — In psoriatic disease, psoriatic arthritis (PsA) remains one of the greatest unmet needs, with the transition from cutaneous psoriasis poorly understood, diagnosis challenging, and therapeutic accomplishments trailing far behind advances for skin disease. However, leading researchers in rheumatology and dermatology believe that they’re turning the corner toward a day when therapies are phenotype-targeted and diagnosis can be made early and treatment begun well before inflammation worsens and pain and joint damage ensue.

Dr Christopher Ritchlin

“The challenge right now is that we don’t understand the discrete and overlapping endotypes that underlie the phenotypes or domains” of PsA, said Christopher Ritchlin, MD, MPH, professor of medicine in the division of allergy/immunology and rheumatology and the Center of Musculoskeletal Research at the University of Rochester (N.Y.), who spoke about PsA at the annual research symposium of the National Psoriasis Foundation.

“We know that mechanistically, there is dominance of the IL [interleukin]-23 and IL-17 pathways, as well as TNF [tumor necrosis factor], but we think there are tissue-specific cellular interactions [and] other pathways and mechanisms to be defined, and the goal now is to go into the tissues to find out,” he said at the meeting.

Ritchlin is co-leading a new research team dedicated to psoriatic spectrum diseases as part of the $64.5 million Autoimmune and Immune-Mediated Diseases Program (AIM) of the Accelerating Medicine Partnership (AMP), a huge public-private partnership involving the National Institutes of Health that is collecting and analyzing troves of biological data in order to better understand the cellular and molecular compositions and interactions that lead to disease.

As part of its work, this eight-center project – coined ELLIPSS, for Elucidating the Landscape of Immunoendotypes in Psoriatic Skin and Synovium – hopes to define at a molecular and single-cell level how the transition to PsA unfolds in the setting of psoriasis. Up to 30% of patients with cutaneous psoriasis also develop PsA.

Dr Jose U. Scher

The NPF, meanwhile, has invested over $3 million for research and development and validation of a diagnostic test for PsA – one that could potentially be used by dermatologists and primary care physicians to decrease the time to diagnosis. Researchers like Jose U. Scher, MD, director of the Psoriatic Arthritis Center at New York University and the NYU Colton Center for Autoimmunity, are in the thick of using multiple “-omics” tools and other sophisticated technologies to identify new targets and biomarkers.

As this work unfolds over the next several years, there is growing interest in combination therapy for PsA, Scher and Ritchlin said, and in addressing extra-articular traits, such as obesity and centralized pain, that are believed to have an impact on disease and on response to treatment.

A Deep Dive Into the Tissue

Ritchlin is among those rheumatology clinician-researchers who advocated early on for a “domain” approach to the diagnosis and management of PsA – that is, consideration of the key domains of peripheral arthritis, axial disease, enthesitis, dactylitis, and skin and nail psoriasis.

The approach is an especially important part of treatment recommendations from the Group for Research and Assessment of Psoriasis and Psoriatic Arthritis. But while interventions can be tailored to some extent to these domains, or phenotypes, there are limitations without an understanding of the different pathophysiology and mechanisms driving the heterogeneity in tissue involvement.

Ritchlin draws inspiration from pulmonology, which subtyped asthma into various phenotypes (for example, eosinophilic, allergic, intrinsic, exercise-induced) and “drilled down” on understanding underlying mechanisms to guide more specific treatment. Similar phenotype-endotype research has been done for chronic obstructive pulmonary disease, he said at the meeting, pointing to a phase 3 randomized controlled trial, published in the New England Journal of Medicine, that found dupilimab (Dupixent) was effective for patients with COPD who had type 2 inflammation as indicated by elevated eosinophil counts.

“It’s a beautiful example of how to define an endotype from a phenotypic biomarker and then use a specific intervention to improve outcomes,” Ritchlin said. “We need to do this for psoriasis and PsA.”

The ELLIPSS project will utilize the host of -omics tools and technologies (for proteomics, metabolomics, and genomics, for instance) that are making it increasingly possible to dissect the heterogeneity of single diseases and achieve more precision with treatments.

Researchers will collect blood samples and skin and/or synovial tissue biopsies from cohorts of patients with psoriasis and PsA who are treatment naïve as well as patients who are treated with a biologic or DMARD (looking at responders and non-responders). They’ll also study a cohort of psoriasis patients who may be “on a transition pathway” for PsA based on risk factors such as family history, nail psoriasis, scalp psoriasis, and body surface area greater than 5%.

Patients in all cohorts will represent distinct synovio-entheseal domains of PsA and the heterogeneity of psoriasis (for example, plaque, general, pustular, palmoplantar) and will be followed longitudinally.

With regards to PsA, one goal is to “find new pathways in the joint, then find surrogate markers in the blood that we can use to help mark particular subphenotypes [that will be identified through deep phenotyping],” Ritchlin said in an interview after the meeting. “This will lead us hopefully to a more precision-based approach.”

The ELLIPSS team joins other researchers who have been studying rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE) in an earlier iteration of the AIM program, and that will continue this work. Research on RA has thus far elucidated T-cell subsets in the rheumatoid synovium, as well as interactions of mesenchymal cells with the endothelium, for instance, and led to the identification of key molecules such as granzyme A that weren’t previously known to be involved in RA pathogenesis, Ritchin said in the interview. The current AIM work also includes Sjögren’s disease.

Finding Biomarkers, Diagnostic Signatures

The psoriasis-PsA team has the advantage today of being able to utilize a new technology called spatial transcriptomics, which takes transcriptomics (RNA) from the single-cell level to the tissue level, enabling a look at how disease is affecting cellular organization/tissue architecture, gene activity, and cellular signaling within tissues. “It’s a huge advance in technology,” said Ritchlin. “We can actually see how the cells are interacting in the synovium [and other tissues].”

A paper published in Science Immunology and discussed at the NPF meeting demonstrates the power of special transcriptomics for learning about the skin. Scher, Ritchlin, first authors Rochelle L. Castillo, MD, and Ikjot Sidhu, MS, and other co-investigators reported a “dynamic re-organization of the immune milieu and fibroblasts in PsO lesional and non-lesional skin,” the presence of B cells in lesioned skin, and cellular organization/ecosystems that vary occurring according to clinical severity, among other findings.

Scher is using the tool for his NPF-funded diagnostic test research and as part of his work at NYU Langone for the ELLIPPS project. Among his goals: To “discover new cell populations in the microenvironment and study how they interact with each other, then compare those cells between psoriasis and PsA patients to first understand if they’re any different,” he explained after the meeting. Researchers can then investigate the synovial tissue, comparing cell populations and interactions in both compartments and looking for any shared markers/cytokines/proteins, he said.

Multiomics research, meanwhile, is showing that a test for early PsA detection could potentially combine clinical parameters with integrated multi-omic markers into a “diagnostic signature” of sorts.

Dr Vinod Chandran

At the meeting, Vinod Chandran, MD, PhD, a rheumatologist at the University of Toronto who also has an NPF PsA diagnostic test grant, said that his multi-omics analysis of blood samples from patients with psoriasis and PsA has identified signatures with a “high discriminatory value” and that certain metabolic pathways appear to play “a central role in the development and differentiation of PsA.” (Validation in other cohorts and economic analyses are ongoing, Chandran said. Low-cost alternatives that can be applied broadly in the clinic will need to be pursued, Scher said.)

Scher has also focused on skin microbiomics in looking for biomarkers for the transition to PsA. “There are potential biomarkers … that need to be validated and expanded. We have clues,” he said at the meeting, noting that microbial signatures from nonlesional skin appear to differentiate psoriasis from PsA.

The microbiome of the skin and of the gut will also be investigated by the ELLIPPS team as they analyze biosamples and try to define psoriasis and PsA endotypes. The microbiome “is critical to psoriasis and PsA,” Ritchlin said at the meeting. “I think [our knowledge] will really expand dramatically in the next 5 years.”

Wilson Liao, MD, professor and associate vice-chair of research in the department of dermatology at the University of California, San Francisco, whose work has contributed to development of a diagnostic test, was among several experts who emphasized the importance of early diagnosis in the prevention of joint damage. Identifying the disease, he said, is “one of our true unmet needs” in psoriasis.

Liao’s research identified genes and proteins differentially expressed in PsA, psoriasis, and healthy subjects across 30 immune cells types and then identified potential biomarkers through machine learning classification of these genes and proteins along with previously published genetic risk factors for PsA.

Eyes on Combination Therapy

“The likelihood that all patients will respond to one biologic is very low in PsA, so we’ve been thinking about combination therapy for some time,” Ritchlin said at the meeting. “I think [dual inhibition] is coming.”

Safety has been the concern, but a phase 2 trial published this year compared a combination of IL-23 and TNF inhibition (guselkumab [Tremfya] plus golimumab [Simponi]) with monotherapy of both biologics in patients with ulcerative colitis and showed that the combination safely drove synergistic restoration of a normal epithelium and mucosal healing, he said.

A phase 2 trial in PsA, designed by Ritchlin and Scher and named AFFINITY, will study the safety and efficacy of the same combination of IL-23 and TNF blockade, compared with guselkumab (IL-23 inhibition) alone. The trial is currently completing enrollment of patients who have failed one or two anti-TNF agents.

In the meantime, combination therapy is being employed in clinics for “PsA patients who’ve been channeled through multiple biologics and are still not responding … when [physicians] feel they’re forced to, not right away,” Ritchlin said in an interview after the meeting. “As we get a better understanding [through clinical trials], it might be something you’ll see earlier in the treatment process.”

It is wise, Ritchlin said, to devote more time to addressing “extra-articular traits” (for example, obesity, diabetes, uveitis, colitis, centralized pain) and treatable lifestyle/behavioral risk factors (for example, smoking, exercise, nutrition, adherence to therapy, social support) that can contribute to PsA and treatment nonresponse. He calls this the “treatable traits” strategy.

In practice, “there’s a big focus on inflammation and immune dysfunction, but the problem is, there are other factors involved in nonresponse, and I think ‘treatable traits’ gets to those,” Ritchlin said after the meeting. Rheumatologists and dermatologists lack time and alliances to address these issues, but “if we can find ways to do it, I think we’ll have improved outcomes.”

Ritchlin, Chandran, and Liao reported no relevant disclosures. Scher reported ties to Janssen, Pfizer, Sanofi, UCB, and Bristol-Myers Squibb.

This story originally appeared on, part of the Medscape Professional Network.

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