Inflammatory Memory in Psoriasis: From Remission to Recurrence.

The routine use of targeted systemic immunomodulatory therapies has transformed outcomes for people with severe psoriasis, with skin clearance (clinical remission) rates up to 60% at one year of biologic treatment. However, psoriasis may recur following drug withdrawal, and so patients tend to remain on costly treatment indefinitely. Here, we review research into the 'inflammatory memory' in resolved psoriasis skin and the potential mechanisms leading to psoriasis recurrence following drug withdrawal. Research has implicated immune cells such as tissue-resident memory T cells, Langerhans cells and dermal dendritic cells, and there is growing interest in keratinocytes and fibroblasts. A better understanding of the interactions between these cell populations, enabled by single-cell technologies, will help to elucidate the events underpinning the shift from remission to recurrence. This may inform the development of personalised strategies for sustaining remission while reducing long-term drug burden.

Defining disease severity in atopic dermatitis and psoriasis for the application to biomarker research- an inter-disciplinary perspective.

More severe atopic dermatitis (AD) and psoriasis are associated with a higher cumulative impact on quality of life, multimorbidity and healthcare costs. Proactive, early intervention in those most at risk of severe disease may reduce this cumulative burden and modify the disease trajectory to limit progression. The lack of reliable biomarkers for this at-risk group represents a barrier to such a paradigm shift in practice. To expedite discovery and validation, the BIOMAP consortium (Biomarkers in AD and Psoriasis, a large-scale European, inter-disciplinary research initiative) has curated clinical and molecular data across diverse study designs and sources including cross-sectional and cohort studies (small scale through to large multi-centre registries), clinical trials, electronic health records and large-scale population-based biobanks. We map all dataset disease severity instruments and measures to three key domains (symptoms, inflammatory activity and disease course), and describe important co-dependencies and relationships across variables and domains. We prioritise definitions for more severe disease with reference to international consensus, reference standards and/or expert opinion. Key factors to consider when analysing datasets across these diverse study types include explicit early consideration of biomarker purpose and clinical context, candidate biomarkers associated with disease severity at a point in time and over time and how they are related, taking the stage of biomarker development into account when selecting disease severity measures for analyses and, validating biomarker associations with disease severity outcomes using both physician- and patient-reported measures and across domains. The outputs from this exercise will ensure coherence and focus across the BIOMAP consortium so that mechanistic insights and biomarkers are clinically relevant, patient-centric and more generalisable to current and future research efforts.

Acceptability of 'as needed' biologic therapy in psoriasis: insights from a multi-stakeholder mixed methods study.

OBJECTIVES: Biologic therapies have led to increasing numbers of patients with psoriasis who have clear or nearly clear skin. Current practice is that biologic therapy is continued indefinitely in these patients, contributing to a substantial long-term drug and healthcare burden. 'As needed' biologic therapy in psoriasis may address this, however our understanding of patient and clinician perceptions of this strategy is limited. METHODS: We first conducted UK-wide online scoping surveys of patients with psoriasis and dermatology clinicians to explore their views on 'as needed' biologic therapy. Using topic guides informed by these survey findings, we then carried out qualitative focus groups with patients and clinicians. Themes were identified using reflexive thematic analysis. RESULTS: Of 67 patients and 27 clinicians completing the scoping surveys, 67% (43/64) and 78% (21/27), respectively, supported the use of 'as needed' biologic therapy. Respondents highlighted advantages such as a reduction in healthcare burden and greater ownership of care. Challenges included logistics of 'as needed' drug provision and potential risks of disease flare and drug immunogenicity. Focus groups comprised 15 patients with psoriasis (9 female [60%], average disease duration 32 years [range 9-64 years]) and 9 dermatology clinicians (8 female [89%], average dermatology experience 20 years [range 8-33 years]). Both patients and clinicians felt that an 'as needed' treatment approach will deliver a reduction in treatment burden and present an opportunity for patient-led ownership of care. Both groups highlighted the importance of ensuring ongoing access to medication and discussing the potential impact of psoriasis recurrence. Patient preferences were influenced by their lived experiences, particularly previous difficulties with medication delivery logistics and establishing disease control. Clinician perspectives were informed by personal experience of their patients adapting their own dosing schedules. Clinicians highlighted the importance of targeted patient selection for an 'as needed' approach, ongoing disease monitoring, and prompt re-access to medications upon psoriasis recurrence. CONCLUSION: These data indicate that 'as needed' biologic therapy in psoriasis is acceptable for both patients and clinicians. Formal assessment of clinical effectiveness and cost effectiveness is warranted, to enable the real-world potential of this approach to be realised.

Single-cell analysis of psoriasis resolution demonstrates an inflammatory fibroblast state targeted by IL-23 blockade.

Biologic therapies targeting the IL-23/IL-17 axis have transformed the treatment of psoriasis. However, the early mechanisms of action of these drugs remain poorly understood. Here, we perform longitudinal single-cell RNA-sequencing in affected individuals receiving IL-23 inhibitor therapy. By profiling skin at baseline, day 3 and day 14 of treatment, we demonstrate that IL-23 blockade causes marked gene expression shifts, with fibroblast and myeloid populations displaying the most extensive changes at day 3. We also identify a transient WNT5A+/IL24+ fibroblast state, which is only detectable in lesional skin. In-silico and in-vitro studies indicate that signals stemming from these WNT5A+/IL24+ fibroblasts upregulate multiple inflammatory genes in keratinocytes. Importantly, the abundance of WNT5A+/IL24+ fibroblasts is significantly reduced after treatment. This observation is validated in-silico, by deconvolution of multiple transcriptomic datasets, and experimentally, by RNA in-situ hybridization. These findings demonstrate that the evolution of inflammatory fibroblast states is a key feature of resolving psoriasis skin.

GWAS meta-analysis of psoriasis identifies new susceptibility alleles impacting disease mechanisms and therapeutic targets.

Psoriasis is a common, debilitating immune-mediated skin disease. Genetic studies have identified biological mechanisms of psoriasis risk, including those targeted by effective therapies. However, the genetic liability to psoriasis is not fully explained by variation at robustly identified risk loci. To move towards a saturation map of psoriasis susceptibility we meta-analysed 18 GWAS comprising 36,466 cases and 458,078 controls and identified 109 distinct psoriasis susceptibility loci, including 45 that have not been previously reported. These include susceptibility variants at loci in which the therapeutic targets IL17RA and AHR are encoded, and deleterious coding variants supporting potential new drug targets (including in STAP2, CPVL and POU2F3). We conducted a transcriptome-wide association study to identify regulatory effects of psoriasis susceptibility variants and cross-referenced these against single cell expression profiles in psoriasis-affected skin, highlighting roles for the transcriptional regulation of haematopoietic cell development and epigenetic modulation of interferon signalling in psoriasis pathobiology.

Systematic review of deep learning image analyses for the diagnosis and monitoring of skin disease.

Skin diseases affect one-third of the global population, posing a major healthcare burden. Deep learning may optimise healthcare workflows through processing skin images via neural networks to make predictions. A focus of deep learning research is skin lesion triage to detect cancer, but this may not translate to the wider scope of >2000 other skin diseases. We searched for studies applying deep learning to skin images, excluding benign/malignant lesions (1/1/2000-23/6/2022, PROSPERO CRD42022309935). The primary outcome was accuracy of deep learning algorithms in disease diagnosis or severity assessment. We modified QUADAS-2 for quality assessment. Of 13,857 references identified, 64 were included. The most studied diseases were acne, psoriasis, eczema, rosacea, vitiligo, urticaria. Deep learning algorithms had high specificity and variable sensitivity in diagnosing these conditions. Accuracy of algorithms in diagnosing acne (median 94%, IQR 86-98; n = 11), rosacea (94%, 90-97; n = 4), eczema (93%, 90-99; n = 9) and psoriasis (89%, 78-92; n = 8) was high. Accuracy for grading severity was highest for psoriasis (range 93-100%, n = 2), eczema (88%, n = 1), and acne (67-86%, n = 4). However, 59 (92%) studies had high risk-of-bias judgements and 62 (97%) had high-level applicability concerns. Only 12 (19%) reported participant ethnicity/skin type. Twenty-four (37.5%) evaluated the algorithm in an independent dataset, clinical setting or prospectively. These data indicate potential of deep learning image analysis in diagnosing and monitoring common skin diseases. Current research has important methodological/reporting limitations. Real-world, prospectively-acquired image datasets with external validation/testing will advance deep learning beyond the current experimental phase towards clinically-useful tools to mitigate rising health and cost impacts of skin disease.

Real-World Implementation and Outcomes of Adalimumab Therapeutic Drug Monitoring in Psoriasis: A National Specialized Center Experience.

Serum adalimumab concentration is a biomarker of treatment response but therapeutic drug monitoring (TDM) is yet to be implemented in routine psoriasis care. We incorporated adalimumab TDM in a national specialized psoriasis service and evaluated it using the RE-AIM (Reach, Effectiveness, Adoption, Implementation, and Maintenance) implementation science framework. We undertook pre-implementation planning (validating local assays) and implementation interventions targeted to patients (pragmatic sampling at routine reviews), clinicians (introduction of a TDM protocol), and healthcare systems (adalimumab TDM as a key performance indicator). Over 5 months, 170 of 229 (74%) individuals treated with adalimumab received TDM. Clinical improvement after TDM-guided dose escalation occurred in 13 of 15 (87%) nonresponders with serum drug concentrations <8.3 µg/ml (median PASI reduction of 3.2 [interquartile range = 2.2-8.2] after 23.4 weeks) and in all nonresponders who had TDM-guided switch in biologic due to supratherapeutic drug concentrations (>8.3 µg/ml; n = 2) or positive antidrug antibody (n = 2) (PASI reduction of 7.8 [interquartile range = 7.5-12.9] after 20.0 weeks). Proactive TDM led to dose reduction in five individuals with clear skin and subtherapeutic or supratherapeutic drug concentrations; four (80%) sustained clear skin after 50 weeks (range = 42-52). Adalimumab TDM based on pragmatic serum sampling is clinically viable and may lead to patient benefit. Context-specific implementation interventions and systematic implementation assessment may bridge the biomarker research-to-practice gap.

Nonadherence to systemic immune-modifying therapy in people with psoriasis during the COVID-19 pandemic: findings from a global cross-sectional survey.

BACKGROUND: Nonadherence to immune-modifying therapy is a complex behaviour which, before the COVID-19 pandemic, was shown to be associated with mental health disorders in people with immune-mediated diseases. The COVID-19 pandemic has led to a rise in the global prevalence of anxiety and depression, and limited data exist on the association between mental health and nonadherence to immune-modifying therapy during the pandemic. OBJECTIVES: To assess the extent of and reasons underlying nonadherence to systemic immune-modifying therapy during the COVID-19 pandemic in individuals with psoriasis, and the association between mental health and nonadherence. METHODS: Online self-report surveys (PsoProtectMe), including validated screens for anxiety and depression, were completed globally during the first year of the pandemic. We assessed the association between anxiety or depression and nonadherence to systemic immune-modifying therapy using binomial logistic regression, adjusting for potential cofounders (age, sex, ethnicity, comorbidity) and country of residence. RESULTS: Of 3980 participants from 77 countries, 1611 (40.5%) were prescribed a systemic immune-modifying therapy. Of these, 408 (25.3%) reported nonadherence during the pandemic, most commonly due to concerns about their immunity. In the unadjusted model, a positive anxiety screen was associated with nonadherence to systemic immune-modifying therapy [odds ratio (OR) 1.37, 95% confidence interval (CI) 1.07-1.76]. Specifically, anxiety was associated with nonadherence to targeted therapy (OR 1.41, 95% CI 1.01-1.96) but not standard systemic therapy (OR 1.16, 95% CI 0.81-1.67). In the adjusted model, although the directions of the effects remained, anxiety was not significantly associated with nonadherence to overall systemic (OR 1.20, 95% CI 0.92-1.56) or targeted (OR 1.33, 95% CI 0.94-1.89) immune-modifying therapy. A positive depression screen was not strongly associated with nonadherence to systemic immune-modifying therapy in the unadjusted (OR 1.22, 95% CI 0.94-1.57) or adjusted models (OR 1.14, 95% CI 0.87-1.49). CONCLUSIONS: These data indicate substantial nonadherence to immune-modifying therapy in people with psoriasis during the pandemic, with attenuation of the association with mental health after adjusting for confounders. Future research in larger populations should further explore pandemic-specific drivers of treatment nonadherence. Clear communication of the reassuring findings from population-based research regarding immune-modifying therapy-associated adverse COVID-19 risks to people with psoriasis is essential, to optimize adherence and disease outcomes.

Characteristics associated with poor COVID-19 outcomes in people with psoriasis, psoriatic arthritis and axial spondyloarthritis: data from the COVID-19 PsoProtect and Global Rheumatology Alliance physician-reported registries.

OBJECTIVES: To investigate factors associated with severe COVID-19 in people with psoriasis (PsO), psoriatic arthritis (PsA) and axial spondyloarthritis (axSpA). METHODS: Demographic data, clinical characteristics and COVID-19 outcome severity of adults with PsO, PsA and axSpA were obtained from two international physician-reported registries. A three-point ordinal COVID-19 severity scale was defined: no hospitalisation, hospitalisation (and no death) and death. ORs were estimated using multivariable ordinal logistic regression. RESULTS: Of 5045 cases, 18.3% had PsO, 45.5% PsA and 36.3% axSpA. Most (83.6%) were not hospitalised, 14.6% were hospitalised and 1.8% died. Older age was non-linearly associated with COVID-19 severity. Male sex (OR 1.54, 95% CI 1.30 to 1.83), cardiovascular, respiratory, renal, metabolic and cancer comorbidities (ORs 1.25-2.89), moderate/high disease activity and/or glucocorticoid use (ORs 1.39-2.23, vs remission/low disease activity and no glucocorticoids) were associated with increased odds of severe COVID-19. Later pandemic time periods (ORs 0.42-0.52, vs until 15 June 2020), PsO (OR 0.49, 95% CI 0.37 to 0.65, vs PsA) and baseline exposure to TNFi, IL17i and IL-23i/IL-12+23i (OR 0.57, 95% CI 0.44 to 0.73; OR 0.62, 95% CI 0.45 to 0.87; OR 0.67, 95% CI 0.45 to 0.98; respectively; vs no disease-modifying antirheumatic drug) were associated with reduced odds of severe COVID-19. CONCLUSION: Older age, male sex, comorbidity burden, higher disease activity and glucocorticoid intake were associated with more severe COVID-19. Later pandemic time periods, PsO and exposure to TNFi, IL17i and IL-23i/IL-12+23i were associated with less severe COVID-19. These findings will enable risk stratification and inform management decisions for patients with PsO, PsA and axSpA during COVID-19 waves or similar future respiratory pandemics.

The Impact of Immune-Modifying Treatments for Skin Diseases on the Immune Response to COVID-19 Vaccines: a Narrative Review.

Purpose of Review: SARS-CoV-2 has had a devastating global effect, with vaccinations being paramount in the public health strategy against COVID-19. Vaccinations have uncoupled infection from adverse COVID-19 outcomes worldwide. While immune-modifying therapies are effective for the management of skin diseases such as psoriasis and atopic dermatitis, these medications also impair protective immune responses. There has been longstanding uncertainty and concern over the impact of immune-modifying therapies on the effectiveness of vaccines; for example, it is well recognised that methotrexate impairs humoral responses to both influenza and pneumococcal vaccines. This narrative review aims to discuss the evidence to date on the impact of immune-modifying therapies on the immune response to COVID-19 vaccines, with a focus on the first two vaccine doses. Recent Findings: Individuals receiving immune-modifying therapy are more likely to have attenuated humoral responses to a single dose of COVID-19 vaccine compared to healthy controls; however, this may be improved by a complete course of vaccination. B cell targeted biologics such as rituximab markedly impair the humoral response to both the first and second COVID-19 vaccination. There remains a paucity of data on cellular immune responses, with the few available studies indicating lower responses to two vaccine doses in individuals receiving immune-modifying therapies compared to healthy controls, which may impact the durability of immune responses. Summary: Inadequate humoral immune responses to a single dose of vaccine in the context of immune-modifying therapy are improved by a complete course of vaccination. Individuals receiving immune-modifying treatments should be encouraged to take up a complete vaccine course to mitigate their risk against COVID-19. Research in large patient populations on the longevity/kinetics of the complex humoral and cellular response to subsequent vaccine doses, including against newer variants of concern, is warranted, in addition to data on immune correlates of vaccine clinical effectiveness.

Single-cell analysis implicates TH17-to-TH2 cell plasticity in the pathogenesis of palmoplantar pustulosis.

BACKGROUND: Palmoplantar pustulosis (PPP) is a severe inflammatory skin disorder characterized by eruptions of painful, neutrophil-filled pustules on the palms and soles. Although PPP has a profound effect on quality of life, it remains poorly understood and notoriously difficult to treat. OBJECTIVE: We sought to investigate the immune pathways that underlie the pathogenesis of PPP. METHODS: We applied bulk and single-cell RNA sequencing (RNA-Seq) methods to the analysis of skin biopsy samples and peripheral blood mononuclear cells. We validated our results by flow cytometry and immune fluorescence microscopy RESULTS: Bulk RNA-Seq of patient skin detected an unexpected signature of T-cell activation, with a significant overexpression of several TH2 genes typically upregulated in atopic dermatitis. To further explore these findings, we carried out single-cell RNA-Seq in peripheral blood mononuclear cells of healthy and affected individuals. Memory CD4+ T cells of PPP patients were skewed toward a TH17 phenotype, a phenomenon that was particularly significant among cutaneous lymphocyte-associated antigen-positive skin-homing cells. We also identified a subset of memory CD4+ T cells that expressed both TH17 (KLRB1/CD161) and TH2 (GATA3) markers, with pseudotime analysis suggesting that the population was the result of TH17 to TH2 plasticity. Interestingly, the GATA3+/CD161+ cells were overrepresented among the peripheral blood mononuclear cells of affected individuals, both in the single-cell RNA-Seq data set and in independent flow cytometry experiments. Dual-positive cells were also detected in patient skin by immune fluorescence microscopy. CONCLUSIONS: PPP is associated with complex T-cell activation patterns and may explain why biologic drugs that target individual T helper cell populations have shown limited therapeutic efficacy.

Biomarkers of systemic treatment response in people with psoriasis: a scoping review.

BACKGROUND: Responses to the systemic treatments commonly used to treat psoriasis vary. Biomarkers that accurately predict effectiveness and safety would enable targeted treatment selection, improved patient outcomes and more cost-effective healthcare. OBJECTIVES: To perform a scoping review to identify and catalogue candidate biomarkers of systemic treatment response in psoriasis for the translational research community. METHODS: A systematic search of CENTRAL, Embase, LILACS and MEDLINE was performed for relevant articles published between 1990 and December 2021. Eligibility criteria were studies involving patients with psoriasis (any age, n ≥ 50) reporting biomarkers associated with systemic treatment response. The main outcomes were any measure of systemic treatment efficacy or safety. Data were extracted by one reviewer and checked by a second; studies meeting minimal quality criteria (use of methods to control for confounding) were formally assessed for bias. Candidate biomarkers were identified by an expert multistakeholder group using a majority voting consensus exercise and mapped to relevant cellular and molecular pathways. RESULTS: Of 71 included studies (67 studying effectiveness outcomes and eight safety outcomes; four studied both), most reported genomic or proteomic biomarkers associated with response to biologics (48 studies). Methodological or reporting limitations frequently compromised the interpretation of findings, including inadequate control for key covariates, lack of adjustment for multiple testing, and selective outcome reporting. We identified candidate biomarkers of efficacy to tumour necrosis factor inhibitors [variation in CARD14, CDKAL1, IL1B, IL12B and IL17RA loci, and lipopolysaccharide-induced phosphorylation of nuclear factor (NF)-κB in type 2 dendritic cells] and ustekinumab (HLA-C*06:02 and variation in an IL1B locus). None were supported by sufficient evidence for clinical use without further validation studies. Candidate biomarkers were found to be involved in the immune cellular crosstalk implicated in psoriasis pathogenesis, most notably antigen presentation, T helper (Th)17 cell differentiation, positive regulation of NF-κB, and Th17 cell activation. CONCLUSIONS: This comprehensive catalogue provides a key resource for researchers and reveals a diverse range of biomarker types and outcomes in the included studies. The candidate biomarkers identified require further evaluation in methodologically robust studies to establish potential clinical utility. Future studies should aim to address the common methodological limitations highlighted in this review to expedite discovery and validation of biomarkers for clinical use. What is already known about this topic? Responses to the systemic treatments commonly used to treat psoriasis vary. Biomarkers that accurately predict effectiveness and safety would enable targeted treatment selection, improved patient outcomes and more cost-effective healthcare. What does this study add? This review provides a comprehensive catalogue of investigated biomarkers of systemic treatment response in psoriasis. A diverse range of biomarker types and outcomes was found in the included studies, serving as a key resource for the translational research community.

Biomarkers of disease progression in people with psoriasis: a scoping review.

BACKGROUND: Identification of those at risk of more severe psoriasis and/or associated morbidities offers opportunity for early intervention, reduced disease burden and more cost-effective healthcare. Prognostic biomarkers of disease progression have thus been the focus of intense research, but none are part of routine practice. OBJECTIVES: To identify and catalogue candidate biomarkers of disease progression in psoriasis for the translational research community. METHODS: A systematic search of CENTRAL, Embase, LILACS and MEDLINE was performed for relevant articles published between 1990 and December 2021. Eligibility criteria were studies involving patients with psoriasis (any age, n ≥ 50) reporting biomarkers associated with disease progression. The main outcomes were any measure of skin severity or any prespecified psoriasis comorbidity. Data were extracted by one reviewer and checked by a second; studies meeting minimal quality criteria (longitudinal design and/or use of methods to control for confounding) were formally assessed for bias. Candidate biomarkers were identified by an expert multistakeholder group using a majority voting consensus exercise, and mapped to relevant cellular and molecular pathways. RESULTS: Of 181 included studies, most investigated genomic or proteomic biomarkers associated with disease severity (n = 145) or psoriatic arthritis (n = 30). Methodological and reporting limitations compromised interpretation of findings, most notably a lack of longitudinal studies, and inadequate control for key prognostic factors. The following candidate biomarkers with future potential utility were identified for predicting disease severity: LCE3D, interleukin (IL)23R, IL23A, NFKBIL1 loci, HLA-C*06:02 (genomic), IL-17A, IgG aHDL, GlycA, I-FABP and kallikrein 8 (proteomic), tyramine (metabolomic); psoriatic arthritis: HLA-C*06:02, HLA-B*27, HLA-B*38, HLA-B*08, and variation at the IL23R and IL13 loci (genomic); IL-17A, CXCL10, Mac-2 binding protein, integrin b5, matrix metalloproteinase-3 and macrophage-colony stimulating factor (proteomic) and tyramine and mucic acid (metabolomic); and type 2 diabetes mellitus: variation in IL12B and IL23R loci (genomic). No biomarkers were supported by sufficient evidence for clinical use without further validation. CONCLUSIONS: This review provides a comprehensive catalogue of investigated biomarkers of disease progression in psoriasis. Future studies must address the common methodological limitations identified herein to expedite discovery and validation of biomarkers for clinical use. What is already known about this topic? The current treatment paradigm in psoriasis is reactive. There is a need to develop effective risk-stratified management approaches that can proactively attenuate the substantial burden of disease. Prognostic biomarkers of disease progression have therefore been the focus of intense research. What does this study add? This review is the first to scope, collate and catalogue research investigating biomarkers of disease progression in psoriasis. The review identifies potentially promising candidate biomarkers for further investigation and highlights common important limitations that should be considered when designing and conducting future studies in this area.

Differences in Clinical Features and Comorbid Burden between HLA-C∗06:02 Carrier Groups in >9,000 People with Psoriasis.

The identification of robust endotypes-disease subgroups of clinical relevance-is fundamental to stratified medicine. We hypothesized that HLA-C∗06:02 status, the major genetic determinant of psoriasis, defines a psoriasis endotype of clinical relevance. Using two United Kingdom-based cross-sectional datasets-an observational severe-psoriasis study (Biomarkers of Systemic Treatment Outcomes in Psoriasis; n = 3,767) and a large population-based bioresource (UK Biobank, including n = 5,519 individuals with psoriasis)-we compared demographic, environmental, and clinical variables of interest in HLA-C∗06:02-positive (one or two copies of the HLA-C∗06:02 allele) with those in HLA-C∗06:02‒negative (no copies) individuals of European ancestry. We used multivariable regression analyses to account for mediation effects established a priori. We confirm previous observations that HLA-C∗06:02-positive status is associated with earlier age of psoriasis onset and extend findings to reveal an association with disease expressivity in females (Biomarkers of Systemic Treatment Outcomes in Psoriasis: P = 2.7 × 10-14, UK Biobank: P = 1.0 × 10-8). We also show HLA-C∗06:02-negative status to be associated with characteristic clinical features (large plaque disease, OR for HLA-C∗06:02 = 0.73, P = 7.4 × 10-4; nail involvement, OR = 0.70, P = 2.4 × 10-6); higher central adiposity (Biomarkers of Systemic Treatment Outcomes in Psoriasis: waist circumference difference of 2.0 cm, P = 8.4 × 10-4; UK Biobank: waist circumference difference of 1.4 cm, P = 1.5 × 10-4), especially in women; and a higher prevalence of other cardiometabolic comorbidities. These findings extend the clinical phenotype delineated by HLA-C∗06:02 and highlight its potential as an important biomarker to consider in future multimarker stratified medicine approaches.