Residual Lesional Gene Expression in Psoriasis Patients with Complete Skin Clearance Treated with Guselkumab or Adalimumab in VOYAGE 1 and 2

Psoriasis can impair health-related QOL and negatively impact mental health, emotional wellbeing, and work productivity (Armstrong et al., 2012Armstrong A.W. Schupp C. Wu J. Bebo B. Quality of life and work productivity impairment among psoriasis patients: findings from the National Psoriasis Foundation survey data 2003-2011.PLoS One. 2012; 7e52935Crossref Scopus (240) Google Scholar). In addition to healthcare provider-assessed clinical measures, patient-reported outcomes are important factors in the selection and assessment of treatment by dermatologists (Feldman et al., 2019Feldman S.R. Regnier S.A. Chirilov A. Hey F. Gilloteau I. Cella D. Patient-reported outcomes are important elements of psoriasis treatment decision making: a discrete choice experiment survey of dermatologists in the United States.J Am Acad Dermatol. 2019; 80: 1650-1657Abstract Full Text Full Text PDF PubMed Scopus (20) Google Scholar) and reflect the patient's perspective on their disease activity and treatment. Some patients who achieve complete skin clearance with treatment report persistent signs and symptoms. Notably, cleared psoriatic lesions have been shown to display residual psoriasis-related gene dysregulation (<75% improvement) termed the "molecular scar" (Suárez-Fariñas et al., 2011Suárez-Fariñas M. Fuentes-Duculan J. Lowes M.A. Krueger J.G. Resolved psoriasis lesions retain expression of a subset of disease-related genes.J Invest Dermatol. 2011; 131: 391-400Abstract Full Text Full Text PDF PubMed Scopus (166) Google Scholar). Understanding the molecular response to psoriasis treatment may account for differences in clinical responses observed between therapeutic agents and why some patients have persistent self-reported signs and symptoms despite skin clearance. Guselkumab targets the IL-23p19 subunit and adalimumab targets TNFα; both are approved for treating moderate-to-severe psoriasis and psoriatic arthritis. We compared patient-reported signs and symptoms in a subset of patients who achieved complete skin clearance (PASI 100 response) following treatment with guselkumab or adalimumab at week 24 in the VOYAGE 1 and VOYAGE 2 studies (Blauvelt et al., 2017Blauvelt A. Papp K.A. Griffiths C.E. Randazzo B. Wasfi Y. Shen Y.K. et al.Efficacy and safety of guselkumab, an anti-interleukin-23 monoclonal antibody, compared with adalimumab for the continuous treatment of patients with moderate to severe psoriasis: results from the phase III, double-blinded, placebo- and active comparator-controlled VOYAGE 1 trial.J Am Acad Dermatol. 2017; 76: 405-417Abstract Full Text Full Text PDF PubMed Scopus (657) Google Scholar; Reich et al., 2017Reich K. Armstrong A.W. Foley P. Song M. Wasfi Y. Randazzo B. et al.Efficacy and safety of guselkumab, an anti-interleukin-23 monoclonal antibody, compared with adalimumab for the treatment of patients with moderate to severe psoriasis with randomized withdrawal and retreatment: results from the phase III, double-blind, placebo- and active comparator-controlled VOYAGE 2 trial.J Am Acad Dermatol. 2017; 76: 418-431Abstract Full Text Full Text PDF PubMed Scopus (554) Google Scholar). Patients provided written informed consent before study initiation. Sterling was the central US IRB for the VOYAGE 1 (4809C) and VOYAGE 2 (4810C) studies. Additionally, we assessed residual psoriasis-related gene expression at sites of cleared psoriatic plaques in a subset of VOYAGE 1 patients with PASI100 response following treatment. Baseline Psoriasis Symptoms and Signs Diary (PSSD) scores (Mathias et al., 2016Mathias S.D. Feldman S.R. Crosby R.D. Colwell H.H. McQuarrie K. Han C. Measurement properties of a patient-reported outcome measure assessing psoriasis severity: the Psoriasis Symptoms and Signs Diary.J Dermatolog Treat. 2016; 27: 322-327Crossref PubMed Scopus (31) Google Scholar) were comparable among guselkumab- (n = 286) and adalimumab-treated (n = 119) patients with a PASI100 response at week 24 from both studies (Supplementary Table S1). Significantly higher proportions of PASI100 responders in the guselkumab group achieved a PSSD score of 0 for symptoms (54.6% vs 42.9%) and signs (46.2% vs 35.4%) than in the adalimumab group. Similarly, greater proportions of PASI100 responders in the guselkumab group achieved a PSSD symptom score of 0 for itch and pain or a PSSD sign score of 0 for cracking, scaling, shedding redness, and bleeding (Figure 1). As previously reported, a numerically higher proportion of PASI100 responders treated with guselkumab achieved a Dermatology Life Quality Index (DLQI) 0/1 response at week 24 (79.4%) than those treated with adalimumab (65.8%) (Armstrong et al., 2019Armstrong A.W. Reich K. Foley P. Han C. Song M. Shen Y.K. et al.Improvement in patient-reported outcomes (Dermatology Life Quality Index and the Psoriasis Symptoms and Signs Diary) with Guselkumab in moderate-to-severe plaque psoriasis: results from the phase III VOYAGE 1 and VOYAGE 2 studies.Am J Clin Dermatol. 2019; 20: 155-164Crossref PubMed Scopus (34) Google Scholar). The greater benefit of guselkumab was consistently reflected across Dermatology Life Quality Index subdomains (reported as a subdomain score of 0) in PASI100 responders (Supplementary Figure S1). Paired lesional skin (LS) and non-lesional skin (NLS) biopsies were collected at baseline from 37 patients from VOYAGE 1. Additionally, 29 cleared LS (CLS) samples were collected from 21 patients who achieved a PASI100 response at week 24 and/or week 48 following treatment; 6 were from patients treated with adalimumab (21%) and 23 with guselkumab (79%). Among these samples, 17 were collected when patients (59%) were symptom-free based on PSSD reporting, while 12 were collected when patients (41%) reported residual symptoms. Gene expression profiling of skin biopsy samples was performed using microarrays (Affymetrix GeneChip HC HG-U133 Plus PM 96-array) as previously reported (Blauvelt et al., 2024Blauvelt A. Langley R.G. Branigan P.J. Liu X. Chen Y. DePrimo S. et al.Guselkumab reduces disease- and mechanism-related biomarkers more than adalimumab in patients with psoriasis: a VOYAGE 1 substudy.J Investig Dermatol. 2024; 4: 100287Google Scholar). The "psoriasis transcriptome" was defined as genes dysregulated between LS and NLS at baseline (fold change > 1.5 and false discovery rate < 0.05). Overall, 2383 genes were identified as being dysregulated in LS versus NLS; these genes were largely consistent with the meta-analysis-derived 3 psoriatic skin transcriptomic signature previously described (Blauvelt et al., 2024Blauvelt A. Langley R.G. Branigan P.J. Liu X. Chen Y. DePrimo S. et al.Guselkumab reduces disease- and mechanism-related biomarkers more than adalimumab in patients with psoriasis: a VOYAGE 1 substudy.J Investig Dermatol. 2024; 4: 100287Google Scholar; Tian et al., 2012Tian S. Krueger J.G. Li K. Jabbari A. Brodmerkel C. Lowes M.A. et al.Meta-analysis derived (MAD) transcriptome of psoriasis defines the "core" pathogenesis of disease.PLoS One. 2012; 7e44274Crossref Scopus (148) Google Scholar). Following either guselkumab or adalimumab treatment, expression of most LS genes dysregulated relative to NLS at baseline returned to normal in CLS (Figure 2a). In the 12 samples from patients with persistent symptoms based on PSSD scores, the expression of 25 genes was insufficiently normalized (ie, not returned to normal) in CLS relative to NLS. Among these, the expression of 10 genes returned to normal in CLS from patients who were symptom-free (FABP7, HBA1/HBA2, HBB, KRT6B, MYH14, NABP1, PLEKHG5, PRR9, TNNT2, WIF1) (Figure 2b, Supplementary Table S2). When analyzed according to treatment; 6 of the 10 genes had returned to normal in CLS in guselkumab treatment compared to 1 gene in adalimumab treatment (Figure 2c). Collectively, these findings suggest that continued dysregulation of select genes in CLS may constitute a molecular scar contributing to the persistence of patient-reported symptoms (Suárez-Fariñas et al., 2011Suárez-Fariñas M. Fuentes-Duculan J. Lowes M.A. Krueger J.G. Resolved psoriasis lesions retain expression of a subset of disease-related genes.J Invest Dermatol. 2011; 131: 391-400Abstract Full Text Full Text PDF PubMed Scopus (166) Google Scholar). Furthermore, they suggest that guselkumab may more effectively normalize expression of genes related to symptom persistence than adalimumab. Notably, a subset of the 10 genes that remained dysregulated in CLS from patients with persistent symptoms show clear relevance to cutaneous biology. The psoriasis-specific IL-17A-induced PRR9 gene is located within the epidermal differentiation complex on chromosome 1q21 which represents a cluster of genes involved in the terminal differentiation of keratinocytes (Ray-Jones et al., 2020Ray-Jones H. Duffus K. McGovern A. Martin P. Shi C. Hankinson J. et al.Mapping DNA interaction landscapes in psoriasis susceptibility loci highlights KLF4 as a target gene in 9q31.BMC Biol. 2020; 18: 47Crossref PubMed Scopus (13) Google Scholar). PRR9 expression was normalized with guselkumab but not with adalimumab. KRT6B, which plays a role in barrier function and wound healing also remained dysregulated in patients with persistent symptoms treated with adalimumab. WIF1 and PLEKHG5 expression did not return to normal with either treatment, suggesting that dysregulated WNT and NF-κB signaling may contribute to the persistence of symptoms in some patients with clear skin. Limitations of this analysis, including the small sample size, may restrict the generalizability of our findings. Additionally, there were more CLS samples from guselkumab-treated patients than adalimumab-treated patients, which may have affected our findings. The low number of insufficiently normalized genes identified in these analyses precluded interrogation of functional pathways associated with persistent symptoms. In conclusion, our findings demonstrate that residual dysregulated gene expression may correlate with the persistence of patient-reported symptoms, even among those who achieve PASI100 following treatment. In turn, clearing skin with therapies utilizing different mechanisms of action may lead to differential consequences for patients beyond objectively observable clinical manifestations of psoriasis. To our knowledge, this is the first example of a psoriasis study linking clinical response and persistence of patient-reported symptoms at a molecular level. These data are important for bridging the knowledge gap between the persistence of patient-reported symptoms and skin clearance with treatment. Moreover, this work may provide a rationale for future investigations into the molecular basis for this phenomenon. The data sharing policy of Janssen Pharmaceutical Companies of Johnson & Johnson is available at https://www.janssen.com/clinical-trials/transparency. As noted in this site, requests for access to the study data can be submitted through the Yale Open Data Access project site at http://yoda.yale.edu. This data set has been deposited to NIH GEO online data base with accession number GSE252029 (https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE252029). Andrew Blauvelt: http://orcid.org/0000-0002-2633-985X Kenneth B. Gordon: http://orcid.org/0000-0002-9347-0292 Richard G. Langley: http://orcid.org/0000-0003-4730-2164 Patrick J. Branigan: http://orcid.org/0000-0001-9741-9067 Yanqing Chen: http://orcid.org/0000-0002-9534-6199 Megan Miller: http://orcid.org/0000-0002-8676-6706 Chenglong Han: http://orcid.org/0000-0001-7175-7834 Steven Fakharzadeh: http://orcid.org/0000-0003-0423-9388 Ernesto J. Muñoz-Elías: http://orcid.org/0000-0002-2894-157X April W. Armstrong: http://orcid.org/0000-0003-0064-8707 Andrew Blauvelt has served as a speaker (received honoraria) for AbbVie, Bristol Myers Squibb, Eli Lilly, Pfizer, Regeneron, and Sanofi; served as a scientific adviser (received honoraria) for AbbVie, Abcentra, Affibody, Aligos, Almirall, Alumis, Amgen, Anaptysbio, Arcutis, Arena, Aslan, Athenex, Bluefin Biomedicine, Boehringer Ingelheim, Bristol Myers Squibb, Cara Therapeutics, Dermavant, EcoR1, Eli Lilly, Escient, Evelo, Evommune, Forte, Galderma, HighlightII Pharma, Incyte, InnoventBio, Janssen, Landos, Leo, Merck, Novartis, Pfizer, Rapt, Regeneron, Sanofi Genzyme, Spherix Global Insights, Sun Pharma, TLL Pharmaceutical, TrialSpark, UCB Pharma, Vibliome, and Xencor; and has acted as a clinical study investigator (institution received clinical study funds) for AbbVie, Acelyrin, Almirall, Alumis, Amgen, Arcutis, Athenex, Boehringer Ingelheim, Bristol Myers Squibb, Concert, Dermavant, Eli Lilly, Evelo, Evommune, Galderma, Incyte, Janssen, Leo, Merck, Novartis, Pfizer, Regeneron, Sun Pharma, and UCB Pharma. Kenneth B Gordon has received research or grant support from AbbVie, Amgen, Boehringer Ingelheim, Celgene, Eli Lilly, Janssen, Novartis, and UCB Pharma; and honoraria for consultation from AbbVie, Amgen, Boehringer Ingelheim, Celgene, Dermira, Eli Lilly, Janssen, Novartis, and UCB Pharma. Richard G Langley has received grant funding and/or honoraria as principal investigator and has served on the advisory board or as a speaker for AbbVie, Amgen, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Eli Lilly, Janssen, Leo Pharma, Merck, Novartis, Pfizer, Sun Pharma, and UCB Pharma. Patrick Branigan, Yanqing Chen, and Megan Miller are employees of Janssen Research & Development, LLC, a wholly-owned subsidiary of Johnson & Johnson, and own stock or stock options in Johnson & Johnson. Chenglong Han and Steven Fakharzadeh are employees of Janssen Global Services, LLC, a wholly-owned subsidiary of Johnson & Johnson, and own stock or stock options in Johnson & Johnson. Ernesto J Muñoz-Elías is a former employee of Janssen Research & Development, LLC, and is listed as an inventor on pending patent applications. April W Armstrong has served as a research investigator and/or consultant to AbbVie, Bristol Myers Squibb, Dermavant, Dermira, Eli Lilly, Janssen, KHK Pharma, Leo Pharma, Modernizing Medicine, Novartis, Ortho Dermatologics, Regeneron, Sanofi, Sun Pharma, and UCB. The data included in this manuscript were previously presented, in part, at the 2020 Annual Meeting of the American Academy of Dermatology (March 20–24, 2020; Denver, CO). We thank Jeanne McKeon, PhD, of Lumanity Communications Inc., for writing and editorial support in the preparation of this manuscript, which was funded by Janssen Global Services, LLC, Horsham, PA, USA. We also thank Michael Song and Xuejun Liu, formerly of Janssen Research & Development, LLC, for their contributions to these analyses. Editorial support was funded by Janssen Global Services. The Clinical Trial was funded by Janssen Research & Development, LLC, Spring House, PA, USA. Conceptualization: AB, KBG, PB, CH, SF, EM-E, AWA; Data Curation: AB, PB, YC, CH; Formal Analysis: YC, CH, SF; Investigation: AB, KBG, RGL, EM-E, AWA; Methodology: PB, YC, CH; Project Administration: MM; Supervision: MM, EM-E; Writing - Original Draft: YC, CH; Writing - Review and Editing: AB, KBG, RGL, PB, YC, MM, CH, SF, EM-E, AWA Supplementary Table S1PSSD Scores at Baseline Among PASI100 Responders at Week 24Reported SymptomsGuselkumab n = 286Adalimumab n = 119PSSD symptoms, mean (SD) Itch6.3 (2.4)6.2 (2.4) Burning4.8 (2.9)4.5 (2.9) Stinging4.5 (3.0)4.2 (3.0) Skin tightness5.7 (2.5)5.7 (2.4) Pain5.0 (3.1)5.0 (2.9)PSSD signs, mean (SD) Dryness6.4 (2.3)6.4 (2.2) Cracking5.1 (2.7)5.3 (2.7) Scaling6.3 (2.2)6.2 (2.1) Shedding6.4 (2.3)6.1 (2.2) Redness6.0 (2.4)6.0 (2.4) Bleeding3.1 (2.7)3.2 (2.8)Total PSSD symptoms, mean (SD)52.6 (25.0)51.1 (23.6)Total PSSD signs, mean (SD)55.6 (21.2)55.2 (20.5)Abbreviations: PASI, Psoriasis Area and Severity Index; PSSD, Psoriasis Symptoms and Signs Diary. Open table in a new tab Supplementary Table S2Insufficiently Normalized Genes in Cleared Lesional Skin from Patients with Persistent PSSD Symptoms at Week 24Gene NameGene SymbolBiological Function% Return to Normal% Return to NormalSymptom-FreePersistent SymptomsAdalimumabGuselkumabFatty acid binding protein 7FABP7Lipid binding, metabolism, gene regulation, cell growth and differentiation8265−17103Hemoglobin subunit alpha 1,2HBA1, HBA2Oxygen transport in blood945215112Hemoglobin subunit betaHBBOxygen transport in blood8234−3109Keratin 6BKRT6BCytoskeletal component (intermediate filaments)1287072112Myosin heavy chain 14, non-muscleMYH14Involved in cytokinesis, cell shape, secretion, and capping76497464Nucleic acid binding protein 1NABP1Involved in DNA replication, recombination, gene damage detection, and repair83578071Pleckstrin homology and RhoGEF domaining containing G5PLEKHG5Guanine exchange factor involved in endothelial cell chemotaxis and migration84221467Proline-rich protein 9PRR9Psoriasis-associated gene and component of epidermal differentiation complex131404898Troponin T2, cardiac typeTNNT2Tropomyosin-binding subunit of troponin89493479WNT inhibitory factor 1WIF1Binds and inhibits WNT proteins82325163Abbreviations: PSSD, Psoriasis Symptoms and Signs Diary; WNT, wingless-type. Open table in a new tab Abbreviations: PASI, Psoriasis Area and Severity Index; PSSD, Psoriasis Symptoms and Signs Diary. Abbreviations: PSSD, Psoriasis Symptoms and Signs Diary; WNT, wingless-type.