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Indirect excess morbidity in the COVID-19 pandemic may arise from public health risk-mitigation efforts such as stay-at-home orders and re-purposing of healthcare services1 . Increased mental health disorders and shortfalls in the care of long-term conditions are described.

Background The effectiveness and cost-effectiveness of biologic therapies for psoriasis are significantly compromised by variable treatment responses. Thus, more precise management of psoriasis is needed. Objectives We aim to identify subgroups of psoriasis patients treated with biologic therapies, based on changes in their disease activity over time, that may better inform patient management. Methods Here we apply latent class mixed modelling, to identify trajectory-based patient subgroups from longitudinal, routine clinical data on disease severity, as measured by the Psoriasis Area and Severity Index (PASI), from 3546 patients in the British Association of Dermatologists Biologics and Immunomodulators Register, as well as in an independent cohort of 2889 subjects pooled across four clinical trials. Results We discovered four, discrete classes of global response trajectories, each characterised in terms of time to response, size of effect and relapse. Each class was associated with differing clinical characteristics, e.g. Body Mass Index, baseline PASI, and prevalence of different manifestations. Our results were verified in a second cohort of clinical trials subjects, where similar trajectories following initiation of biologic therapy were identified. Further, we found differential associations of the genetic marker HLA-C*06:02 between our registry-identified trajectories. Conclusion These subgroups, defined by change in disease over time, may be indicative of distinct endotypes driven by different biological mechanisms and may help inform the management of patients with psoriasis. Future work will aim to further delineate these mechanisms by extensively characterising the subgroups with additional molecular and pharmacological data.

Ustekinumab is an effective treatment for psoriasis, but response varies between patients. The formation of anti-drug antibodies (ADAs) may explain part of this variation by reducing the free ustekinumab level. Currently, published analyses of the clinical impact of ADAs are incomplete. In this observational cross-sectional multicenter study of 340 patients, we evaluated the impact of ADAs on ustekinumab level and clinical response as assessed by the PASI. Circulating ADA levels were measured using two assays: a drug-sensitive radioimmunoassay and a drug-tolerant ELISA. Circulating ustekinumab levels were measured using an ELISA. ADAs were detected in 3.8% (95% confidence interval [CI] = 3.2–4.2) and in 10.6% (95% CI = 7.9–13.9) of patients using the radioimmunoassay and drug-tolerant ELISA, respectively. At least 85% of the ADAs were neutralizing. Compared with patients negative for ADAs, ADA positivity in the radioimmunoassay and drug-tolerant ELISA were associated with lower median ustekinumab levels (−0.62 μg/ml [95% CI = −1.190 to −0.30] and −0.74 μg/ml [95% CI = −1.09 to −0.47], respectively) and higher absolute PASI (6.6 [95% CI = 3.0–9.9] and 1.9 [95% CI = 0.4–4.0], respectively). Absence of detectable ustekinumab regardless of ADA status correlated with poor clinical outcome (median sample PASI 10.1, 6.5 [95% CI = 3.9–8.8] compared with patients positive for ustekinumab). In conclusion, substantially reduced drug exposure resulting from ADAs formation is associated with impaired clinical response.

Frontal fibrosing alopecia (FFA) is a variant of lichen planopilaris (LPP) characterised primarily by inflammation and irreversible hair loss affecting the frontotemporal scalp. Expert consensus now suggests that FFA incidence is increasing and this has led to increased interest in its aetiopathogenesis. As FFA disproportionately affects post-menopausal women, our group previously assessed genotype-phenotype correlation in FFA, phenotyping a large female FFA cohort and demonstrating a causal role for genetic variants implicated in xenobiotic metabolism and antigen presentation.

Frontal fibrosing alopecia (FFA) is a recently described inflammatory and scarring type of hair loss affecting almost exclusively women. Despite a dramatic recent increase in incidence the aetiopathogenesis of FFA remains unknown. We undertake genome-wide association studies in females from a UK cohort, comprising 844 cases and 3,760 controls, a Spanish cohort of 172 cases and 385 controls, and perform statistical meta-analysis. We observe genome-wide significant association with FFA at four genomic loci: 2p22.2, 6p21.1, 8q24.22 and 15q2.1. Within the 6p21.1 locus, fine-mapping indicates that the association is driven by the HLA-B*07:02 allele. At 2p22.1, we implicate a putative causal missense variant in CYP1B1, encoding the homonymous xenobiotic- and hormone-processing enzyme. Transcriptomic analysis of affected scalp tissue highlights overrepresentation of transcripts encoding components of innate and adaptive immune response pathways. These findings provide insight into disease pathogenesis and characterise FFA as a genetically predisposed immuno-inflammatory disorder driven by HLA-B*07:02., Frontal fibrosing alopecia (FFA) features lichenoid cutaneous inflammation and scarring hair loss. Here, Tziotzios et al. identify four genetic loci associated with FFA by GWAS followed by Bayesian fine-mapping, co-localisation and HLA imputation which highlights HLA-B*07:02 as a risk factor.

BackgroundIndirect excess morbidity has emerged as a major concern in the COVID-19 pandemic. People with psoriasis may be particularly vulnerable to this because of prevalent anxiety and depression, multimorbidity and therapeutic use of immunosuppression.ObjectiveCharacterise the factors associated with worsening psoriasis in the COVID-19 pandemic, using mental health status (anxiety and depression) as the main exposure of interest.MethodsGlobal cross-sectional study using a primary outcome of self-reported worsening of psoriasis. Individuals with psoriasis completed an online self-report questionnaire (PsoProtectMe; Psoriasis Patient Registry for Outcomes, Therapy and Epidemiology of COVID-19 Infection Me) between May 2020 and January 2021. Each individual completed a validated screen for anxiety (Generalized Anxiety Disorder-2) and depression (Patient Health Questionnaire-2). Odds ratios (OR) and 95% confidence intervals (CI) were estimated using multivariable logistic regression.Results4,043 people with psoriasis (without COVID-19) from 86 countries self-reported to PsoProtectMe (mean age 47.2 years [SD 15.1]; mean BMI 27.6kg/m2 [SD 6.0], 2,684 [66.4%] female and 3,016 [74.6%] of white European ethnicity). 1,728 (42.7%) participants (1322 [77%] female) reported worsening of their psoriasis in the pandemic. A positive screen for anxiety or depression associated with worsening psoriasis in age and gender adjusted (OR 2.04, 95% CI 1.77-2.36), and fully adjusted (OR 2.01, 95% CI 1.72-2.34) logistic regression models. Female sex, obesity, shielding behaviour and systemic immunosuppressant non-adherence also associated with worsening psoriasis. The commonest reason for non-adherence was concern regarding complications related to COVID-19.ConclusionsThese data indicate an association between poor mental health and worsening psoriasis in the pandemic. Access to holistic care including psychological support may mitigate potentially long-lasting effects of the pandemic on health outcomes in psoriasis. The study also highlights an urgent need to address patient concerns about immunosuppressant-related risks, which may be contributing to non-adherence.

Altres ajuts: Department of Health via the National Institute for Health Research (NIHR); St Thomas' NHS Foundation Trust; King's College London; NIHR Manchester Biomedical Research Centre; Psoriasis Association. Wellcome Senior Research Fellowship in Clinical Science (205039/Z/16/Z); Health Data Research UK (grant no. LOND1); Health Data Research UK (grant no. MR/S003126/1); UK MRC, Engineering and Physical Sciences Research Council; Economic and Social Research Council; Department of Health and Social Care (England); Chief Scientist Office of the Scottish Government Health; Social Care Directorates; Health and Social Care Research and Development Division (Welsh Government); Public Health Agency (Northern Ireland); British Heart Foundation; Wellcome Trust; NIHR Academic Clinical Lectureship through the University of Manchester; NIHR Emeritus Senior Investigator (MR/101 1808/1); NIHR Manchester Biomedical Research Centre. Background: Registry data suggest that people with immune-mediated inflammatory diseases (IMIDs) receiving targeted systemic therapies have fewer adverse coronavirus disease 2019 (COVID-19) outcomes compared with patients receiving no systemic treatments. Objectives: We used international patient survey data to explore the hypothesis that greater risk-mitigating behaviour in those receiving targeted therapies may account, at least in part, for this observation. Methods: Online surveys were completed by individuals with psoriasis (globally) or rheumatic and musculoskeletal diseases (RMDs) (UK only) between 4 May and 7 September 2020. We used multiple logistic regression to assess the association between treatment type and risk-mitigating behaviour, adjusting for clinical and demographic characteristics. We characterized international variation in a mixed-effects model. Results: Of 3720 participants (2869 psoriasis, 851 RMDs) from 74 countries, 2262 (60·8%) reported the most stringent risk-mitigating behaviour (classified here under the umbrella term 'shielding'). A greater proportion of those receiving targeted therapies (biologics and Janus Kinase inhibitors) reported shielding compared with those receiving no systemic therapy [adjusted odds ratio (OR) 1·63, 95% confidence interval (CI) 1·35-1·97]. The association between targeted therapy and shielding was preserved when standard systemic therapy was used as the reference group (OR 1·39, 95% CI 1·23-1·56). Shielding was associated with established risk factors for severe COVID-19 [male sex (OR 1·14, 95% CI 1·05-1·24), obesity (OR 1·37, 95% CI 1·23-1·54), comorbidity burden (OR 1·43, 95% CI 1·15-1·78)], a primary indication of RMDs (OR 1·37, 95% CI 1·27-1·48) and a positive anxiety or depression screen (OR 1·57, 95% CI 1·36-1·80). Modest differences in the proportion shielding were observed across nations. Conclusions: Greater risk-mitigating behaviour among people with IMIDs receiving targeted therapies may contribute to the reported lower risk of adverse COVID-19 outcomes. The behaviour variation across treatment groups, IMIDs and nations reinforces the need for clear evidence-based patient communication on risk-mitigation strategies and may help inform updated public health guidelines as the pandemic continues.

Background The multi-morbid burden and use of systemic immunosuppressants in people with psoriasis may confer greater risk of adverse COVID-19 outcomes but data are limited. Objective Characterize the course of COVID-19 in psoriasis and identify factors associated with hospitalization. Methods Clinicians reported psoriasis patients with confirmed/suspected COVID-19 via an international registry, PsoProtect. Multiple logistic regression assessed the association between clinical/demographic characteristics and hospitalization. A separate patient-facing registry characterized risk-mitigating behaviours. Results Of 374 clinician-reported patients from 25 countries, 71% were receiving a biologic, 18% a non-biologic and 10% no systemic treatment for psoriasis. 348 (93%) fully recovered from COVID-19, 77 (21%) were hospitalized and nine (2%) died. Increased hospitalization risk was associated with older age (multivariable-adjusted OR 1.59 per 10 years, 95% CI 1.19-2.13), male sex (OR 2.51, 95% CI 1.23-5.12), non-white ethnicity (OR 3.15, 95% CI 1.24-8.03) and comorbid chronic lung disease (OR 3.87, 95% CI 1.52-9.83). Hospitalization was more frequent in patients using non-biologic systemic therapy than biologics (OR 2.84, 95% CI 1.31-6.18). No significant differences were found between biologic classes. Independent patient-reported data (n=1,626 across 48 countries) suggested lower levels of social isolation in individuals receiving non-biologic systemic therapy compared to biologics (OR 0.68, 95% CI 0.50-0.94). Conclusion In this international moderate-severe psoriasis case series, biologics use was associated with lower risk of COVID-19-related hospitalization than non-biologic systemic therapies, however further investigation is warranted due to potential selection bias and unmeasured confounding. Established risk factors (being older, male, non-white ethnicity, comorbidities) were associated with higher hospitalization rates. Clinical Implications We identify risk factors for COVID-19-related hospitalization in psoriasis patients, including older age, male sex, non-white ethnicity and comorbidities. Use of biologics was associated with lower hospitalization risk than non-biologic systemic therapies., Capsule summary: In this global registry-based study, risk factors for COVID-19-related hospitalization in psoriasis patients were older age, male sex, non-white ethnicity and comorbidities. Use of biologics was associated with lower hospitalization risk than non-biologic systemic treatment.

ObjectivesRegistry data suggest that people with immune-mediated inflammatory diseases (IMIDs) receiving targeted systemic therapies have fewer adverse COVID-19 outcomes compared to patients receiving no systemic treatments. We used international patient survey data to explore the hypothesis that greater risk-mitigating behaviour in those receiving targeted therapies may account, at least in part, for this observation.MethodsOnline surveys were completed by individuals with Rheumatic and Musculoskeletal Diseases (RMD) (UK only) or psoriasis (globally) between 4th May and 7th September 2020. We used multiple logistic regression to assess the association between treatment type and risk-mitigating behaviour, adjusting for clinical and demographic characteristics. We characterised international variation in a mixed effects model.ResultsOf 3,720 participants (2,869 psoriasis, 851 RMD) from 74 countries, 2,262 (60.8%) reported the most stringent risk-mitigating behaviour (classified here under the umbrella term ‘shielding’). A greater proportion of those receiving targeted therapies (biologics and JAK inhibitors) reported shielding compared to those receiving no systemic therapy (adjusted odds ratio [OR] 1.63, 95% CI 1.35-1.97) and standard systemic agents (OR 1.39, 95% CI 1.22-1.56). Shielding was associated with established risk factors for severe COVID-19 (male sex [OR 1.14, 95% CI 1.05-1.24], obesity [OR 1.38, 95% CI 1.23-1.54], comorbidity burden [OR 1.43, 95% CI 1.15-1.78]), a primary indication of RMD (OR 1.37, 95% CI 1.27-1.48) and a positive anxiety or depression screen (OR 1.57, 95% CI 1.36-1.80). Modest differences in the proportion shielding were observed across nations.ConclusionsGreater risk-mitigating behaviour among people with IMIDs receiving targeted therapies may contribute to the reported lower risk of adverse COVID-19 outcomes. The behaviour variation across treatment groups, IMIDs and nations reinforces the need for clear evidence-based patient communication on risk mitigation strategies and may help inform updated public health guidelines as the pandemic continues.Key messagesWhat is already known about this subject?At the beginning of the COVID-19 pandemic, patients with immune mediated inflammatory diseases (IMIDs) on targeted systemic immunosuppressive therapy were considered to be at higher risk of severe COVID-19. Subsequent registry data suggest that this may not the case.What does this study add?Here we characterise shielding behaviour in patients with IMIDs from a global survey. We identified that targeted systemic therapy associates with increased shielding behaviour, as do demographic risk factors for severe COVID-19 including male gender and obesity.Shielding behaviour varies across nations, albeit modestly when case-mix is taken into account.How might this impact on clinical practice or future developments?Variable shielding behaviour amongst patients with IMIDs may be an important confounder when considering differential COVID-19 risk between therapy types, so should be accounted for in analyses where possible.

Key Points Question Are clinical and demographic factors associated with the severity of palmoplantar pustulosis? Findings In a cross-sectional study of 203 patients in the UK, the Palmoplantar Pustulosis Psoriasis Area Severity Index score was significantly higher in women compared with men and in current smokers vs former and never smokers. Both of these findings were replicated in an independently ascertained, Northern European cohort including 159 patients. Meaning The findings of this study suggest that smoking cessation interventions may be beneficial in patients with palmoplantar pustulosis and should be investigated in clinical studies., Importance Although palmoplantar pustulosis (PPP) can significantly impact quality of life, the factors underlying disease severity have not been studied. Objective To examine the factors associated with PPP severity. Design, Setting, and Participants An observational, cross-sectional study of 2 cohorts was conducted. A UK data set including 203 patients was obtained through the Anakinra in Pustular Psoriasis, Response in a Controlled Trial (2016-2019) and its sister research study Pustular Psoriasis, Elucidating Underlying Mechanisms (2016-2020). A Northern European cohort including 193 patients was independently ascertained by the European Rare and Severe Psoriasis Expert Network (2014-2017). Patients had been recruited in secondary or tertiary dermatology referral centers. All patients were of European descent. The PPP diagnosis was established by dermatologists, based on clinical examination and/or published consensus criteria. The present study was conducted from October 1, 2014, to March 15, 2020. Main Outcomes and Measures Demographic characteristics, comorbidities, smoking status, Palmoplantar Pustulosis Psoriasis Area Severity Index (PPPASI), measuring severity from 0 (no sign of disease) to 72 (very severe disease), or Physician Global Assessment (PGA), measuring severity as 0 (clear), 1 (almost clear), 2 (mild), 3 (moderate), and 4 (severe). Results Among the 203 UK patients (43 men [21%], 160 women [79%]; median age at onset, 48 [interquartile range (IQR), 38-59] years), the PPPASI was inversely correlated with age of onset (r = −0.18, P = .01). Similarly, in the 159 Northern European patients who were eligible for inclusion in this analysis (25 men [16%], 134 women [84%]; median age at onset, 45 [IQR, 34-53.3] years), the median age at onset was lower in individuals with a moderate to severe PGA score (41 years [IQR, 30.5-52 years]) compared with those with a clear to mild PGA score (46.5 years [IQR, 35-55 years]) (P = .04). In the UK sample, the median PPPASI score was higher in women (9.6 [IQR, 3.0-16.2]) vs men (4.0 [IQR, 1.0-11.7]) (P = .01). Likewise, moderate to severe PPP was more prevalent among Northern European women (57 of 134 [43%]) compared with men (5 of 25 [20%]) (P = .03). In the UK cohort, the median PPPASI score was increased in current smokers (10.7 [IQR, 4.2-17.5]) compared with former smokers (7 [IQR, 2.0-14.4]) and nonsmokers (2.2 [IQR, 1-6]) (P = .003). Comparable differences were observed in the Northern European data set, as the prevalence of moderate to severe PPP was higher in former and current smokers (51 of 130 [39%]) compared with nonsmokers (6 of 24 [25%]) (P = .14). Conclusions and Relevance The findings of this study suggest that PPP severity is associated with early-onset disease, female sex, and smoking status. Thus, smoking cessation intervention might be beneficial., This cross-sectional study examines factors that may contribute to the severity of symptoms in patients with palmoplantar pustulosis.

We wish to bring your attention to the PsoPROTECT (Psoriasis Patient Registry for Outcomes, Therapy and Epidemiology of Covid‐19 infecTion) and SECURE‐AD (Surveillance Epidemiology of Coronavirus Under Research Exclusion‐Atopic Dermatitis) registries; two urgent global initiatives that address an unmet need for delineating the determinants of COVID‐19 outcomes in the common cutaneous immune‐mediated inflammatory diseases (IMIDs) psoriasis and atopic dermatitis.

Key Points Question Is receipt of tumor necrosis factor (TNF) inhibitor monotherapy at the time of COVID-19 diagnosis associated with adverse COVID-19 outcomes compared with other treatment regimens among patients with immune-mediated inflammatory diseases (IMIDs)? Findings In this cohort study of 6077 patients with IMIDs and COVID-19, TNF inhibitors in combination with azathioprine/6-mercaptopurine therapy, methotrexate monotherapy, azathioprine/6-mercaptopurine monotherapy, or Janus kinase inhibitor monotherapy were each associated with significantly higher odds of hospitalization or death compared with TNF inhibitor monotherapy. Meaning This study’s findings support the continued use of TNF inhibitor monotherapy among individuals with IMIDs during the pandemic., Importance Although tumor necrosis factor (TNF) inhibitors are widely prescribed globally because of their ability to ameliorate shared immune pathways across immune-mediated inflammatory diseases (IMIDs), the impact of COVID-19 among individuals with IMIDs who are receiving TNF inhibitors remains insufficiently understood. Objective To examine the association between the receipt of TNF inhibitor monotherapy and the risk of COVID-19–associated hospitalization or death compared with other commonly prescribed immunomodulatory treatment regimens among adult patients with IMIDs. Design, Setting, and Participants This cohort study was a pooled analysis of data from 3 international COVID-19 registries comprising individuals with rheumatic diseases, inflammatory bowel disease, and psoriasis from March 12, 2020, to February 1, 2021. Clinicians directly reported COVID-19 outcomes as well as demographic and clinical characteristics of individuals with IMIDs and confirmed or suspected COVID-19 using online data entry portals. Adults (age ≥18 years) with a diagnosis of inflammatory arthritis, inflammatory bowel disease, or psoriasis were included. Exposures Treatment exposure categories included TNF inhibitor monotherapy (reference treatment), TNF inhibitors in combination with methotrexate therapy, TNF inhibitors in combination with azathioprine/6-mercaptopurine therapy, methotrexate monotherapy, azathioprine/6-mercaptopurine monotherapy, and Janus kinase (Jak) inhibitor monotherapy. Main Outcomes and Measures The main outcome was COVID-19–associated hospitalization or death. Registry-level analyses and a pooled analysis of data across the 3 registries were conducted using multilevel multivariable logistic regression models, adjusting for demographic and clinical characteristics and accounting for country, calendar month, and registry-level correlations. Results A total of 6077 patients from 74 countries were included in the analyses; of those, 3215 individuals (52.9%) were from Europe, 3563 individuals (58.6%) were female, and the mean (SD) age was 48.8 (16.5) years. The most common IMID diagnoses were rheumatoid arthritis (2146 patients [35.3%]) and Crohn disease (1537 patients [25.3%]). A total of 1297 patients (21.3%) were hospitalized, and 189 patients (3.1%) died. In the pooled analysis, compared with patients who received TNF inhibitor monotherapy, higher odds of hospitalization or death were observed among those who received a TNF inhibitor in combination with azathioprine/6-mercaptopurine therapy (odds ratio [OR], 1.74; 95% CI, 1.17-2.58; P = .006), azathioprine/6-mercaptopurine monotherapy (OR, 1.84; 95% CI, 1.30-2.61; P = .001), methotrexate monotherapy (OR, 2.00; 95% CI, 1.57-2.56; P, This cohort study uses data from 3 international registries to examine the association between the receipt of tumor necrosis factor monotherapy and the risk of COVID-19–associated hospitalization or death among adult patients with immune-mediated inflammatory diseases.

Psoriasis is a common inflammatory skin disease caused by the interplay between multiple genetic and environmental risk factors. This review summarises recent progress in elucidating the genetic basis of psoriasis, particularly through large genome-wide association studies. We illustrate the power of genetic analyses for disease stratification. Psoriasis can be stratified by phenotype (common plaque versus rare pustular variants), or by outcome (prognosis, comorbidities, response to treatment); recent progress has been made in delineating the genetic contribution in each of these areas. We also highlight how genetic data can directly inform the development of effective psoriasis treatments.

Importance: High-cost biologic therapies have transformed the management of immune-mediated inflammatory diseases. To optimize outcomes and reduce costs, dose adjustment informed by measurement of circulating drug levels has been shown to be effective in various settings. However, limited evidence exists for this approach with the interleukin 12 and interleukin 23 inhibitor ustekinumab.\ud \ud Objective: To evaluate clinical utility of therapeutic drug monitoring for ustekinumab in patients with psoriasis.\ud \ud Design, Setting, and Participants: A prospective observational cohort of 491 adults with psoriasis was recruited to the multicenter Biomarkers of Systemic Treatment Outcomes in Psoriasis study within the British Association of Dermatologists Biologic and Immunomodulators Register from June 2009 to December 2017; samples from some patients were taken between 2009 and 2011 as part of a pilot study with the same inclusion criteria.\ud \ud Exposure: Serum ustekinumab level measured at any point during the dosing cycle using an enzyme-linked immunosorbent assay.\ud \ud Main Outcomes and Measures: Disease activity measured using the Psoriasis Area and Severity Index (PASI) score. Treatment response outcomes were PASI75 (75% reduction in PASI score from baseline [primary outcome]), PASI90 (90% reduction of PASI score from baseline), and absolute PASI score of 1.5 or less.\ud \ud Results: A total of 491 patients (171 women and 320 men; mean [SD] age, 45.7 [12.8] years) had 1 or more serum samples (total, 853 samples obtained 0-56 weeks from start of treatment) and 1 or more PASI scores within the first year of treatment. Antidrug antibodies were detected in only 17 of 490 patients (3.5%). Early measured drug levels (1-12 weeks after starting treatment) were associated with PASI75 response 6 months after starting treatment (odds ratio, 1.38; 95% CI, 1.11-1.71) when adjusted for baseline PASI score, age, and ustekinumab dose. However, this finding was not consistent across the other PASI outcomes (PASI90 and PASI score of ≤1.5).\ud \ud Conclusions and Relevance: This real-world study provides evidence that measurement of early serum ustekinumab levels could be useful to direct the treatment strategy for psoriasis. Adequate drug exposure early in the treatment cycle may be particularly important in determining clinical outcome.

Background The 'treat to target' paradigm improves outcomes and reduces costs in chronic disease management but is not yet established in psoriasis. Objectives To identify treatment targets in psoriasis using two common measures of disease activity: Psoriasis Area and Severity Index (PASI) and Physician's Global Assessment (PGA). Methods Data from a multicentre longitudinal U.K. cohort of patients with psoriasis receiving systemic or biologic therapies (British Association of Dermatologists Biologics and Immunomodulators Register, BADBIR) were used to identify absolute PASI thresholds for 90% (PASI 90) and 75% (PASI 75) improvements in baseline disease activity, using receiver operating characteristic curves. The relationship between PGA (clear, almost clear, mild, moderate, moderate-severe, severe) and PASI (range 0-72) was described, and the concordance between absolute and relative definitions of response was determined. The same approach was used to establish treatment response and eligibility definitions based on PGA. Results Data from 13 422 patients were available (58% male, 91% white ethnicity, mean age 44·9 years), including over 23 000 longitudinal PASI and PGA scores. An absolute PASI ≤ 2 was concordant with PASI 90 and an absolute PASI ≤ 4 was concordant with PASI 75 in 90% and 88% of cases, respectively. These findings were robust to subgroups of timing of assessment, baseline disease severity and treatment modality. PASI and PGA were strongly correlated (Spearman's rank correlation coefficient 0·92). The median PASI increased from 0 (interquartile range 0-0, range 0-23) to 19 (interquartile range 15-25, range 0-64) for PGA clear to severe, respectively. PGA clear/almost clear was concordant with PASI ≤ 2 in 90% of cases, and PGA moderate-severe severe was concordant with the National Institute for Health and Care Excellence PASI eligibility criteria for biologics in 81% of cases. Conclusions An absolute PASI ≤ 2 and PGA clear/almost clear represent relevant disease end points to inform treat-to-target management strategies in psoriasis. What's already known about this topic? The most commonly used relative disease activity measure in psoriasis is ≥ 90% improvement in Psoriasis Area and Severity Index (PASI 90); however, it has several limitations including dependency on a baseline severity assessment. Defining an absolute target disease activity end point in psoriasis has the potential to improve patient outcomes and reduce costs, as demonstrated by treat-to-target approaches in other chronic diseases such as hypertension and diabetes. The Physician's Global Assessment (PGA) is a popular alternative measure of psoriasis severity in daily practice; however, its utility has not been formally assessed with respect to PASI. What does this study add? An absolute PASI ≤ 2 corresponds with PASI 90 response and is a relevant disease end point for treat-to-target approaches in psoriasis. There is a strong correlation between PASI and PGA. PGA moderate-severe/severe may serve as an alternative eligibility criterion for biologics to PASI-based definitions, and PGA clear/almost clear is an appropriate alternative absolute treatment end point. What are the clinical implications of this work? Absolute PASI ≤ 2 and PGA clear/almost clear represent relevant disease end points to inform treat-to-target management strategies in psoriasis.

Many immune diseases occur at different rates among people with schizophrenia compared to the general population. Here, we evaluated whether this phenomenon might be explained by shared genetic risk factors. We used data from large genome-wide association studies to compare the genetic architecture of schizophrenia to 19 immune diseases. First, we evaluated the association with schizophrenia of 581 variants previously reported to be associated with immune diseases at genome-wide significance. We identified five variants with potentially pleiotropic effects. While colocalization analyses were inconclusive, functional characterization of these variants provided the strongest evidence for a model in which genetic variation at rs1734907 modulates risk of schizophrenia and Crohn’s disease via altered methylation and expression of EPHB4—a gene whose protein product guides the migration of neuronal axons in the brain and the migration of lymphocytes towards infected cells in the immune system. Next, we investigated genome-wide sharing of common variants between schizophrenia and immune diseases using cross-trait LD score regression. Of the 11 immune diseases with available genome-wide summary statistics, we observed genetic correlation between six immune diseases and schizophrenia: inflammatory bowel disease (rg = 0.12 ± 0.03, P = 2.49 × 10−4), Crohn’s disease (rg = 0.097 ± 0.06, P = 3.27 × 10−3), ulcerative colitis (rg = 0.11 ± 0.04, P = 4.05 × 10–3), primary biliary cirrhosis (rg = 0.13 ± 0.05, P = 3.98 × 10−3), psoriasis (rg = 0.18 ± 0.07, P = 7.78 × 10–3) and systemic lupus erythematosus (rg = 0.13 ± 0.05, P = 3.76 × 10–3). With the exception of ulcerative colitis, the degree and direction of these genetic correlations were consistent with the expected phenotypic correlation based on epidemiological data. Our findings suggest shared genetic risk factors contribute to the epidemiological association of certain immune diseases and schizophrenia., This research was supported in part by a number of funding sources. This research uses resources provided by the Genetic Association Information Network (GAIN), obtained from the database of Genotypes and Phenotypes (dbGaP) found at http://www.ncbi.nlm.nih.gov/gap through dbGaP accession number phs000021.v3.p2; samples and associated phenotype data for this study were provided by the Molecular Genetics of Schizophrenia Collaboration (PI: Pablo V. Gejman, Evanston Northwestern Healthcare and Northwestern University, Evanston, IL, USA). Fulbright Canada, the Weston Foundation, and Brain Canada through the Canada Brain Research Fund—a public-private partnership established by the Government of Canada (to J.G.P.); the National Research Foundation of Korea (NRF) [grant 2016R1C1B2013126 to B.H.] and the Bio & Medical Technology Development Program of the NRF [grant 2017M3A9B6061852 to B.H.] funded by the Korean government, Ministry of Science and ICT; the Finnish Cultural Foundation and Academy of Finland [grant 309643 to H.M.O.]; the Spanish Ministry of Economy and Competitiveness and P12-BIO-1395 from Consejería de Innovación, Ciencia y Tecnología, Junta de Andalucía (Spain) [grant SAF2015-66761-P to J.M.]; the US National Institutes of Health (NIH) [grants R01AR045584, R01AR056292, X01HG007484 and P30AR057212 to Y.J., S.A.S. and R.S.]; the US NIH [grants N01AR02251 and R01AR05528 to M.D.M.]; the US NIH [grants 1R01AR063759, 1R01AR062886, 1UH2AR067677-01 and U19AI111224-01 to S.R.] and Doris Duke Charitable Foundation [grant 2013097 to S.R.]. Funding for the GAIN schizophrenia sample was provided by the US NIH [grants R01 MH67257, R01 MH59588, R01 MH59571, R01 MH59565, R01 MH59587, R01 MH60870, R01 MH59566, R01 MH59586, R01 MH61675, R01 MH60879, R01 MH81800, U01 MH46276, U01 MH46289, U01 MH46318, U01 MH79469 and U01 MH79470] and the genotyping of samples was provided through GAIN. The funding sources did not influence the study design, data analysis or writing of this manuscript.

Background Approximately 30% of patients with psoriasis develop a chronic inflammatory arthritis referred to as psoriatic arthritis (PsA). The ability to accurately predict which psoriasis patients will develop PsA would enable early intervention and help prevent disability. Both psoriasis and PsA have a substantial genetic risk component, however the utility of using genetic risk factors for the prediction of PsA is currently unknown. Alleles of the human leukocyte antigen (HLA) genes represent the largest genetic effects observed for both psoriasis and PsA (HLA-C*0602 and HLA-B*27 respectively); these genes are highly polymorphic with extensive linkage disequilibrium (LD) which will make variable (feature) selection using statistical models very challenging. Machine learning methods, such as information theoretic criteria, are well suited to this challenge and will find a subset of the original variables that enable more accurate prediction. Objectives To apply machine learning methods for feature selection of HLA alleles and evaluate the accuracy of these feature for the prediction of PsA. Methods Feature selection was performed using information theoretic criteria methods which are classifier independent methods that provide a ranking of genetic features that differentiate PsA from cutaneous-only psoriasis. Multiple methods were tested; mutual information maximisation (MIM), joint mutual information (JMI), minimal-Redundancy-Maximal-Relevance (mRMR) and conditional mutual information maximisation (CMIM). Two principal components (population stratification) and age of psoriasis onset were included as potential confounders. The Bagged Trees method was used for classification and the performance of the predictive models were assessed using area under the receiver operating characteristic curve. These methods were applied to a dataset of 1462 PsA cases and 1132 cutaneous-only psoriasis cases using 2-digit and 4-digit classical HLA alleles imputed using the SNP2HLA algorithm. Results The single most important features based on rank were identified as HLA-B*27 (2-digit) and HLA-B*2705 (4-digit) by the four different feature selection techniques; this is consistent with previous analyses of this data using regression based methods. However, the predictive accuracy of these single features was found to be poor (AUC 0.55 HLA-B*27). Sequentially adding additional HLA features based on rank substantially improved the performance of the classification model where 20 2-digit features selected by JMI demonstrated an average AUC of 0.84 based on 10 cross-fold validation (figure 1). Conclusions The results demonstrate that classification models constructed from multiple HLA alleles substantially outperform classification based solely on the previously reported PsA risk allele (HLA-B*27). Importantly, the study demonstrates that this additional information is efficiently captured using information theoretic criteria methods which capture correlations between markers. Disclosure of Interest None declared

Acne vulgaris is a highly heritable common, chronic inflammatory disease of the skin for which five genetic risk loci have so far been identified. Here, we perform a genome-wide association study of 3823 cases and 16,144 controls followed by meta-analysis with summary statistics from a previous study, with a total sample size of 26,722. We identify 20 independent association signals at 15 risk loci, 12 of which have not been previously implicated in the disease. Likely causal variants disrupt the coding region of WNT10A and a P63 transcription factor binding site in SEMA4B. Risk alleles at the 1q25 locus are associated with increased expression of LAMC2, in which biallelic loss-of-function mutations cause the blistering skin disease epidermolysis bullosa. These findings indicate that variation affecting the structure and maintenance of the skin, in particular the pilosebaceous unit, is a critical aspect of the genetic predisposition to severe acne. Acne vulgaris is a chronic inflammation of the skin, the genetic basis of which is incompletely understood. Here, Petridis et al. perform GWAS and meta-analysis for acne in 26,722 individuals and identify 12 novel risk loci that implicate structure and maintenance of the skin in severe acne risk.

Interleukin (IL)-36α, IL-36β, and IL-36γ are innate mediators of acute epithelial inflammation. We sought to demonstrate that these cytokines are also required for the pathogenesis of plaque psoriasis, a common and chronic skin disorder, caused by abnormal T helper 17 (TH17) cell activation. To investigate this possibility, we first defined the genes that are induced by IL-36 cytokines in primary human keratinocytes. This enabled us to demonstrate a significant IL-36 signature among the transcripts that are up-regulated in plaque psoriasis and the susceptibility loci associated with the disease in genome-wide studies. Next, we investigated the impact of in vivo and ex vivo IL-36 receptor blockade using a neutralizing antibody or a recombinant antagonist. Both inhibitors had marked anti-inflammatory effects on psoriatic skin, demonstrated by statistically significant reductions in IL-17 expression, keratinocyte activation, and leukocyte infiltration. Finally, we explored the potential safety profile associated with IL-36 blockade by phenotyping 12 individuals carrying knockout mutations of the IL-36 receptor gene. We found that normal immune function was broadly preserved in these individuals, suggesting that IL-36 signaling inhibition would not substantially compromise host defenses. These observations, which integrate the results of transcriptomics and model system analysis, pave the way for early-stage clinical trials of IL-36 antagonists.

Psoriasis is a complex disease of skin with a prevalence of about 2%. We conducted the largest meta-analysis of genome-wide association studies (GWAS) for psoriasis to date, including data from eight different Caucasian cohorts, with a combined effective sample size >39,000 individuals. We identified 16 additional psoriasis susceptibility loci achieving genome-wide significance, increasing the number of identified loci to 63 for European-origin individuals. Functional analysis highlighted the roles of interferon signalling and the NFκB cascade, and we showed that the psoriasis signals are enriched in regulatory elements from different T cells (CD8+ T-cells and CD4+ T-cells including TH0, TH1 and TH17). The identified loci explain ∼28% of the genetic heritability and generate a discriminatory genetic risk score (AUC=0.76 in our sample) that is significantly correlated with age at onset (p=2 × 10−89). This study provides a comprehensive layout for the genetic architecture of common variants for psoriasis., Psoriasis is an immune-mediated skin disease with a complex genetic architecture. Here, Elder and colleagues identify 16 novel psoriasis susceptibility loci using GWAS meta-analysis with a combined effective sample size of over 39,000 individuals.

Psoriasis is a chronic inflammatory disease with a complex genetic architecture. To date, the psoriasis heritability is only partially explained. However, there is increasing evidence that the missing heritability in psoriasis could be explained by multiple genetic variants of low effect size from common genetic pathways. The objective of this study was to identify new genetic variation associated with psoriasis risk at the pathway level. We genotyped 598,258 single nucleotide polymorphisms in a discovery cohort of 2,281 case-control individuals from Spain. We performed a genome-wide pathway analysis using 1,053 reference biological pathways. A total of 14 genetic pathways (PFDR ≤ 2.55 × 10(-2)) were found to be significantly associated with psoriasis risk. Using an independent validation cohort of 7,353 individuals from the UK, a total of 6 genetic pathways were significantly replicated (PFDR ≤ 3.46 × 10(-2)). We found genetic pathways that had not been previously associated with psoriasis risk such as retinol metabolism (Pcombined = 1.84 × 10(-4)), the transport of inorganic ions and amino acids (Pcombined = 1.57 × 10(-7)), and post-translational protein modification (Pcombined = 1.57 × 10(-7)). In the latter pathway, MGAT5 showed a strong network centrality, and its association with psoriasis risk was further validated in an additional case-control cohort of 3,429 individuals (P < 0.05). These findings provide insights into the biological mechanisms associated with psoriasis susceptibility. This study was funded by of the Spanish Ministry of Economy and Competitiveness, grant numbers: PSE-010000-2006-6 and IPT-010000-2010-36

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.