Abstracts From the 2020 IDEOM Meeting

¹University of Utah, Salt Lake City, UT, USA

Background: Up to 30% of psoriasis patients develop psoriatic arthritis (PsA), an inflammatory joint disease that can lead to joint destruction, functional limitations, and increased mortality. Diagnosis and treatment of PsA at an early stage of the disease is known to favorably impact function, quality of life, and work disability.

Methods: We investigated a cohort of 1360 psoriasis patients recruited from 2002 to 2014 at the Department of Dermatology, University of Utah Health. A physician-administered questionnaire was performed to determine psoriasis and PsA phenotypic features, including erythema, induration, scale, physician global assessment (PGA), body surface area (BSA), product of PGA and BSA (PGA×BSA), fingernail involvement, pustulosis, palmoplantar Ps, Koebner phenomenon, plaque size, plaque thickness, guttate Ps, inverse location, hyperlinearity of palms, erythrodermic disease, PsA, and duration of psoriasis and PsA at enrollment. Clinical evaluation and medical record review were performed to identify diagnoses of PsA after enrollment. Association of phenotypic features with subsequent PsA diagnosis was evaluated by a Cox proportional hazard regression adjusted for sex. Using Proximity Extension Assay, we assessed concentration of 273 proteins related to inflammatory, cardiometabolic, or cardiovascular diseases in plasma samples collected from 150 cutaneous-only psoriasis patients (PsC). Association of each protein to a phenotype was tested by regression adjusted for age, sex, and body mass index.

Results: PsA incidence rate increased for >60 years following psoriasis onset (trend p < 0.0001). Multivariate Cox regression yielded a model with history of fingernail involvement (hazard ratio 2.21 [1.52-3.22], p < 0.001) and psoriasis severity measured as untreated induration (hazard ratio 1.41 [1.22-1.62], p < 0.001). We identified significant (Bonferroni corrected p < 0.05) associations of peptidase inhibitor 3 (PI3 or elafin), IL-17C, IL-17A, and KLK6 with psoriasis severity. The top protein associated with psoriasis induration is PI3 with a p-value of 0.0002.

Conclusion: This study identified potential phenotypic and proteomic markers that may have clinical utility for the early detection of PsA among psoriasis patients.

Disclosure

The PERCH software, for which Bing-Jian Feng is the inventor, has been non-exclusively licensed to Ambry Genetics Corporation for their clinical genetic testing services and research. Dr. Feng also reports funding and sponsorship to his institution on his behalf from Pfizer Inc., Regeneron Genetics Center LLC., and Astra Zeneca.

¹Medical College of Wisconsin, Milwaukee, WI, USA

²Clinical Research and Probity Medical Research Inc, Waterloo, Ontario, Canada

³SKiN Centre for Dermatology, Queen’s University and Probity Medical Research, Peterborough, Ontario, Canada

⁴Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan

⁵The University of Melbourne, St Vincent’s Hospital Melbourne & Probity Medical Research, Skin & Cancer Foundation Inc, Melbourne, Victoria, Australia

⁶University of Lübeck, Lübeck, Germany

⁷Bristol Myers Squibb, Princeton, NJ, USA

Background: In a Phase 2 trial of the oral, selective tyrosine kinase 2 (TYK2) inhibitor deucravacitinib in patients with moderate to severe plaque psoriasis (NCT02931838),¹ 67% to 75% achieved PASI 75 (≥75% reduction from baseline on the Psoriasis Area and Severity Index) at Week 12 at doses of ≥3 mg twice daily (BID) versus 7% with placebo (P < 0.001), with an acceptable adverse event profile. We investigated the effect of deucravacitinib on standard laboratory parameters, many of which become abnormal on treatment with other kinase inhibitors.

Methods: Patients were randomized to 1 of 5 doses of deucravacitinib or placebo for 12 weeks. Mean absolute values (with associated SD) in hematologic, hepatic, and lipid (total cholesterol, triglycerides) parameters; creatinine, creatine phosphokinase (CPK) and glucose levels; blood pressure; and weight/body mass index were assessed for the 3 most effective doses (3 mg BID, 6 mg BID, and 12 mg once daily [QD]) and placebo.

Results: In total, 267 patients were randomized. Most laboratory parameters stayed within normal range during treatment, including hematologic (lymphocytes, neutrophils, platelets, hemoglobin), liver enzymes, creatinine, glucose, and lipid panel. CPK levels were elevated in placebo (baseline: 142.6 U/L [SD, 91.3]; Week 12: 155.5 U/L [88.8]) and treatment groups (baseline: 3 mg BID: 130.0 U/L [99.6], 6 mg BID: 143.6 U/L [159.8], 12 mg QD: 143.6 U/L [86.6]; Week 12: 3 mg BID: 139.7 U/L [106.2], 6 mg BID: 156.1 U/L [137.9], 12 mg QD: 194.5 U/L [357.8]). The CPK increases were asymptomatic, mostly adverse event grades 1 or 2, and were observed in 12/44 patients (27%) who received placebo and 57/221 (26%) who received deucravacitinib. Safety results were not dose-dependent and no events resulted in discontinuation from the study.

Conclusion: No consistent differences between placebo and treated groups and no clear dose-dependence were seen in laboratory parameters investigated. Results of ongoing Phase 3 trials of deucravacitinib in psoriasis (NCT03624127, NCT03611751, NCT04167462, NCT03924427) will provide long-term safety and laboratory data.

Acknowledgments

Professional medical writing from Ann Marie Fitzmaurice, PhD and editorial assistance was provided by Peloton Advantage, LLC, an OPEN Health company, Parsippany, NJ, and was funded by Bristol Myers Squibb.

Funding

The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This work was sponsored by Bristol Myers.

Reference

1. Papp K, Gordon K, Thaçi D, et al. Phase 2 trial of selective tyrosine kinase 2 inhibition in psoriasis. N Engl J Med. 2018;379(14):1313-1321.

Relationships and Activities

KG: Grant support and consulting fees: AbbVie, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Eli Lilly, Janssen, Novartis, UCB; Consulting fees: Amgen, Almirall, Dermira, Leo Pharma, Pfizer, Sun Pharma.

KP: Speakers bureau: AbbVie, Amgen, Astellas, Celgene, Eli Lilly, Galderma, Janssen, Kyowa Hakko Kirin, Leo, Merck Sharp & Dohme, Novartis, Pfizer, Valeant; Grant/research support: AbbVie, Akros, Allergan, Amgen, Anacor, Arcutis, AstraZeneca, Baxalta, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Coherus, Dermira, Dow Pharma, Eli Lilly, Galderma, Genentech, GlaxoSmithKline, Janssen, Kyowa Hakko Kirin, Leo, MedImmune, Meiji Seika Pharma, Merck Serono, Novartis, Pfizer, Regeneron, Roche, Sanofi-Aventis/Genzyme, Takeda, UCB, Valeant; Consultant: AbbVie, Akros, Amgen, Arcutis, Astellas, AstraZeneca, Baxalta, Baxter, Boehringer Ingelheim, Bristol Myers Squibb, CanFite, Celgene, Coherus, Dermira, Dow Pharma, Eli Lilly, Forward Pharma, Galderma, Genentech, Janssen, Kyowa Hakko Kirin, Leo, Meiji Seika Pharma, Merck Sharp & Dohme, Merck Serono, Mitsubishi Pharma, Novartis, Pfizer, Regeneron, Roche, Sanofi-Aventis/Genzyme, Takeda, UCB, Valeant; Honoraria: AbbVie, Akros, Amgen, Baxter, Boehringer Ingelheim, Celgene, Coherus, Eli Lilly, Forward Pharma, Galderma, GlaxoSmithKline, Janssen, Kyowa Hakko Kirin, Merck Sharp & Dohme, Merck Serono, Novartis, Pfizer, Takeda, UCB, Valeant; Scientific officer/steering committee/advisory board: AbbVie, Akros, Amgen, Anacor, Astellas, Baxter, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Dow Pharma, Eli Lilly, Galderma, Janssen, Kyowa Hakko Kirin, Merck Sharp & Dohme, Merck Serono, Novartis, Pfizer, Regeneron, Sanofi-Aventis/Genzyme, Valeant.

MG: Speakers bureau, consultant, investigator/advisor: AbbVie, Akros, Amgen, Arcutis, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Dermira, Eli Lilly, Galderma, GlaxoSmithKline, Incyte, Janssen, Kyowa Hakko Kirin, Leo Pharma, Merck, MedImmune, Novartis, Pfizer, Regeneron, Roche, Sanofi Genzyme, Takeda, UCB, Valeant.

AM: Grant/research support, consultant, speakers bureau: AbbVie, Eli Lilly, Janssen, Kyowa Hakko Kirin, Leo Pharma, Maruho, Mitsubishi-Tanabe, Novartis.

PF: Speakers bureau, consultant, investigator, advisor, travel grants: 3M/iNova/Valeant, Abbott/AbbVie, Amgen, Biogen Idec, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Celtaxsys, Cutanea, Dermira, Eli Lilly, Galderma, GlaxoSmithKline/Stiefel, Janssen, Leo/Peplin, Novartis, Regeneron, Sanofi Genzyme, Schering-Plough/Merck Sharp & Dohme, Sun Pharma, UCB, Wyeth/Pfizer. DT: Research support/principal investigator (clinical trials): AbbVie, Almirall, Amgen, Biogen Idec, Boehringer Ingelheim, Celgene, Chugai, Dermira, DS-Pharma, Eli Lilly, Galderma, GSK, Janssen-Cilag, Leo, MSD, Novartis, Pfizer, Regeneron, Roche, Sandoz-Hexal, Sanofi, UCB; Consultant: AbbVie, Almirall, Celgene, Dignity, Galapagos, Leo Pharma, Maruho, Mitsubishi, Novartis, Pfizer, Xenoport; Lectures: AbbVie, Almirall, Amgen, DS-Pharma, Janssen, Leo Pharma, MSD, Novartis, Pfizer, La Roche-Posay, Sandoz-Hexal, Sanofi, Target-Solution, UCB; Scientific advisory board: AbbVie, Amgen, Celgene, DS Pharma, Eli Lilly, Galapagos, Janssen-Cilag, Leo Pharma, Morphosis, MSD Novartis, Pfizer, Sandoz, Sanofi, UCB.

DT: Research support/principal investigator (clinical trials): AbbVie, Almirall, Amgen, Biogen Idec, Boehringer Ingelheim, Celgene, Chugai, Dermira, DS-Pharma, Eli Lilly, Galderma, GSK, Janssen-Cilag, Leo, MSD, Novartis, Pfizer, Regeneron, Roche, Sandoz-Hexal, Sanofi, UCB; Consultant: AbbVie, Almirall, Celgene, Dignity, Galapagos, Leo Pharma, Maruho, Mitsubishi, Novartis, Pfizer, Xenoport; Lectures: AbbVie, Almirall, Amgen, DS-Pharma, Janssen, Leo Pharma, MSD, Novartis, Pfizer, Roche-Posay, Sandoz-Hexal, Sanofi, Target-Solution, UCB; Scientific advisory board: AbbVie, Amgen, Celgene, DS Pharma, Eli Lilly, Galapagos, Janssen-Cilag, Leo Pharma, Morphosis, MSD Novartis, Pfizer, Sandoz, Sanofi, UCB.

SK, RK, LW, SB: Employees and shareholders: Bristol Myers Squibb.

¹Krembil Research Institute, Toronto, Ontario, Canada

²University of Toronto, Toronto, Ontario, Canada

³Memorial University, St. John’s, Newfoundland, Canada

⁴Women’s College Hospital, Toronto, Ontario, Canada

⁵University of Waterloo, Waterloo, Ontario, Canada

⁶University of British Columbia, Vancouver, British Columbia, Canada

Background: Psoriatic arthritis (PsA) is an inflammatory arthritis that occurs in around 24% of patients with psoriasis. PsA is difficult to diagnose as the presentation can be subtle, disease manifestations heterogenous and clinical symptoms may mimic more common but less inflammatory conditions such as osteoarthritis and fibromyalgia. Our preliminary data strongly suggest that a successful diagnostic test for PsA will need to combine easily identified clinical features with biological markers (genes, gene products, proteins, metabolites) into a diagnostic signature. Systematic interrogation of new and existing technologies by our group has identified numerous high priority gene, protein and metabolite markers that have shown promise as diagnostic markers. Our goal is to develop a clinically applicable diagnostic test that will detect PsA in patients with psoriasis in a sensitive, specific, and non-invasive manner.

Methods: We will profile biological samples from PsA (N = 100), Psoriasis without PsC (N = 100) and healthy controls (N = 50) using PsA-weighted SNP typing, RNA and miRNA-sequencing, protein immunoassays and metabolomics. We will then use advanced machine learning algorithms and integrative computational biology to identify markers and techniques that best classify patients with PsA. Subsequently, we will develop an integrated multi-omics algorithm that improves sensitivity and specificity of the classifier by integrating-omics, network features and clinical data, and can be introduced in clinics.

Significance and future direction: This project will establish proof-of-concept of our approach and is thus the first step toward developing and validating a diagnostic test for PsA. With future funding we will expand our project and develop a diagnostic algorithm/test that can easily be applied in the clinic. It will then be validated internally and externally in clinical settings where the pretest probability of PsA is low, intermediate, or high as in primary care, dermatology, and rheumatology clinics, respectively. Acceptance of the test by clinicians as well as patients, and cost effectiveness will be determined, and a partner for commercialization sought. Such a test will lead to appropriate early referral to rheumatologists, efficient disease management, improve quality of life, and ultimately reduce health care costs.

¹Division of Allergy, Immunology and Rheumatology, School of Medicine and Dentistry, University of Rochester, Rochester, NY, USA

²Department of Pharmacology & Physiology, University of Rochester Medical Center, Rochester, NY, USA

³Department of Clinical and Translational Research, University of Rochester Medical Center, Rochester, NY, USA

⁴Division of Neonatology, Department of Pediatrics, University of Rochester, Rochester, NY, USA

⁵Department of Orthopaedics, Center for Musculoskeletal Research, University of Rochester Medical Center, Rochester, NY, USA

Background: Psoriatic arthritis (PsA) is a prevalent inflammatory musculoskeletal disorder associated with psoriasis that develops in 20-30% of patients with psoriasis. Currently, we lack a diagnostic test for PsA, and biomarkers to identify psoriasis patients at risk for the development of arthritis are not available. This study aimed to compare whole blood transcriptome and serum metabolome of Ps and PsA patients to identify progression markers for psoriasis (Ps) patients at higher disposition risk for developing PsA.

Methods: To identify novel transcriptomic biomarkers, we monitored Ps and PsA patients’ cohorts longitudinally, collected serial blood and serum samples, and evaluated molecular differences in psoriasis patients who did and did not progress to PsA. We compared the whole blood gene expression profiles using the Clariom D microarrays and assessed the gene expression changes using the normalized gene expression data. To confirm our findings from microarray analysis, we further evaluated the expression levels of the top differentially expressed coding genes using quantitative RT-PCR (qRT-PCR). We also performed a metabolomics analysis to compare serum metabolites in PsA and Ps patients compared to healthy subjects.

Results: Analysis of our transcriptomic data revealed several critical genes related to immune response and metabolic pathways to be differentially expressed in PsA compared to Ps, indicating a potential metabolic connection to aberrant immune activation and disease progression in PsA. We identified 7 coding and 3 non-coding genes that are differentially expressed (p < 0.05) in patients who developed PsA compared to those who did not develop PsA and healthy controls. Our gene set and pathway enrichment analysis indicated significant differences between the Ps converter and non-converters in T cell functions, ribosomal activity, and metabolic pathways. Analysis of the serum metabolites in this current work enabled us to identify metabolites that are differentially abundant in PsA compared to healthy subjects or Ps patients. Most importantly, analyzing longitudinally collected serum samples, we also identified 20 putative predictive biomarkers for PsA.

Conclusion: Our current study enabled us to identify a set of genes and metabolites as potential biomarkers for diagnosing patients with PsA or individuals at risk of developing PsA. While this study holds the potential to find biomarkers of disease severity and response to therapy, additional investigations that address this unmet need will be carried out in the future.

Funding

The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This work was supported by funding from the National Psoriasis Foundation (PsA Diagnostic Test Grant), UBS (IPART grant), Department of Medicine Pilot Grant (University of Rochester Medical Centre), and Health Sciences Center for Computational Innovation (HSCCI) Pilot Grant (University of Rochester).