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Background: The TREatment of ATopic eczema (TREAT) Registry Taskforce is a collaborative international network of registries collecting data of atopic eczema (AE) patients receiving systemic and phototherapy with the common goal to provide long-term real-world data on the effectiveness, safety and cost-effectiveness of therapies. A core dataset, consisting of domains and domain items with corresponding measurement instruments, has been developed to harmonize data collection. Objectives: We aimed to give an overview of the status and characteristics of the eight established TREAT registries, and to perform a mapping exercise to examine the degree of overlap and pooling ability between the national registry datasets. This will allow us to determine which research questions can be answered in the future by pooling data. Methods: All eight registries were asked to share their dataset and information on the current status and characteristics. The overlap between the core dataset and each registry dataset was identified (according to the domains, domain items and measurement instruments of the TREAT core dataset). Results and conclusions: A total of 4702 participants have been recruited in the eight registries as of 1st of May 2022. Of the 69 core dataset domain items, data pooling was possible for 69 domain item outcomes in TREAT NL (the Netherlands), 61 items in A-STAR (UK and Ireland), 38 items in TREATgermany (Germany), 36 items in FIRST (France), 33 items in AtopyReg (Italy), 29 items in Biobadatop (Spain), 28 items in SCRATCH (Denmark) and 20 items in SwedAD (Sweden). Pooled analyses across all registries can be performed on multiple important domain items, covering the main aims of analysing data on the (cost-)effectiveness and safety of AE therapies. These results will facilitate future comparative or joint analyses.

BackgroundThe population prevalence of multimorbidity (the existence of at least 2 or more long-term conditions (LTCs) in an individual) is increasing among young adults, particularly in minority ethnic groups and individuals living in socioeconomically deprived areas. In this study, we applied a data-driven approach to identify clusters of individuals who had an early onset multimorbidity in an ethnically and socioeconomically diverse population. We identified associations between clusters and a range of health outcomes.Methods and findingsWe analysed the electronic health records from 837,869 individuals in England with early onset multimorbidity (aged between 16 and 39 years old when the second LTC was recorded) using linked primary and secondary care data between 2010 and 2020 from the Clinical Practice Research Datalink GOLD (CPRD GOLD). A total of 204 LTCs were included. Latent class analysis stratified by ethnicity unveiled 4 clusters of multimorbidity in White groups and 3 clusters in South Asian and Black groups. We found that early onset multimorbidity is the most common form of multimorbidity among minority ethnic (59% and 56%, in the South Asian and Black populations, respectively) in the UK compared to the White population (42%). At the end of the study, 4% of the White early onset multimorbidity population had died compared to 2% of the South Asian and Black populations, however, the latter groups died younger and lost more years of life. The three ethnic groups displayed a cluster of individuals with increased rates of primary care consultations, hospitalisations, long-term prescribing, and odds of mortality. These presented a combination of physical and mental health conditions that are common across all groups (hypertension, depression and painful conditions being the leading conditions). However, they also presented exclusive LTCs and had different sociodemographic profiles: Whites were mostly men (54%), South Asian and Black groups were more socioeconomically deprived than White groups, with a consistent deprivation gradient across all multimorbidity clusters. In White groups, the highest risk cluster was more socioeconomically deprived than the lowest risk cluster.ConclusionsThese findings emphasise the need to identify, prevent and manage multimorbidity early in the life course. Our work provides additional insights into the need to ensure healthcare improvements are equitable and reach those from socioeconomically deprived and diverse groups who are disproportionately and more severely affected by multimorbidity.

Psoriasis is an incurable chronic inflammatory skin disease characterised by immune cytokine-stimulated epidermal hyperproliferation. This results in the skin becoming red with scaly plaques that can appear anywhere on the body, decreasing the quality of life for patients. Previous modelling studies of psoriasis have been limited to 2D models and lacked cell-cell interactions. We have developed a 3D agent-based model of epidermal cell dynamics to gain insights into how immune cytokine stimuli induces hyperproliferation in psoriasis to better understand disease formation and structural changes. Three main keratinocytes, stem, transit-amplifying (TA), differentiated and T cells, are modelled with proliferation and division governed by various nutrients and immune cytokines. Each cell has a set of attributes (growth rate, division probability, position, etc) whose values are governed by processes such as monod-based cellular growth model, probability-based division based on calcium and cytokine concentration and various forces to form the epidermal layers. The model has 2 steady states, healthy (non-lesional) and psoriatic (lesional) skin. Transition from healthy to psoriatic state is triggered by a temporary cytokine stimulus which causes hyperproliferation to occur, a hallmark of psoriasis. This results in the deepening of rete ridges and thickening of the epidermal structure. Model outputs has been validated against population ratios of stem, TA, differentiated, and T cells, cell cycle and turnover times in vivo. The model simulates the structural properties of epidermis, including layer stratification, formation of wave-like rete ridges, change in epidermal height and length of rete ridges from healthy to psoriasis. This has provided some insights on the complex spatio-temporal changes when transitioning between the 2 steady states and how a shot of temporary cytokine stimulus can induce different severity of psoriasis and alters proliferation between healthy and psoriatic skin in line with known literature. This provides the basis to study different cytokine simulation variations of psoriasis development and tracking of cell proliferation in the lab. It also provides a baseline to model the effects of psoriasis treatments such as narrowband-ultraviolet B (NB-UVB) or biologics and predict potential treatment outcomes for patients.

Background: few data exist on differences in treatment effectiveness and safety in atopic dermatitis patients of different skin types.Objective: to investigate treatment outcomes of dupilumab, methotrexate, and ciclosporin, and morphological phenotypes in atopic dermatitis patients, stratified by Fitzpatrick skin type.Methods: in an observational prospective cohort study, pooling data from the Dutch TREAT (TREatment of ATopic eczema) NL (treatregister.nl) and UK-Irish A-STAR (Atopic eczema Systemic TherApy Register; astar-register.org) registries, data on morphological phenotypes and treatment outcomes were investigated.Results: a total of 235 patients were included (light skin types [LST]: Fitzpatrick skin type 1-3, n = 156 [Ethnicity, White: 94.2%]; dark skin types [DST]: skin type 4-6, n = 68 [Black African/Afro-Caribbean: 25%, South-Asian: 26.5%, and Hispanics: 0%]). DST were younger (19.5 vs 29.0 years; P < .001), more often had follicular eczema (22.1% vs 2.6%; P < .001), higher baseline Eczema Area and Severity Index (EASI) scores (20.1 vs 14.9; P = .009), less allergic contact dermatitis (30.9% vs 47.4%; P = .03), and less previous phototherapy use (39.7% vs 59.0%; P = .008). When comparing DST and LST corrected for covariates including baseline EASI, DST showed greater mean EASI reduction between baseline and 6 months with only dupilumab (16.7 vs 9.7; adjusted P = .032). No differences were found for adverse events for any treatments (P > .05).Limitations: unblinded, non-randomized.Conclusions: atopic dermatitis differs in several characteristics between LST and DST. Skin type may influence treatment effectiveness of dupilumab.

Background Remission duration and treatment response following phototherapy for psoriasis are highly variable and factors influencing these are poorly understood. Objectives Our primary outcome was to investigate whether selected clinical/serum biomarkers were associated with remission duration, and secondly with psoriasis clearance at the end of phototherapy. In addition, we looked at whether early trajectory of UVB clearance was associated with final clearance outcome. Methods We performed a prospective cohort study of 100 psoriasis patients, routinely prescribed Narrowband UVB and measured selected clinical and biochemical biomarkers, including weekly PASI (psoriasis area and severity index) scores. Patients were followed up for 18 months. Results The median time to relapse was 6 months (95% CI 5-18) if PASI90 was achieved, and 4 months (95% CI 3-9) if less than PASI90 was achieved. Achieving PASI100 did not result in prolonged remission. On UVB completion, the median final PASI (n = 96) was 1.0 (IQR 0.5, 1.6) with 78 (81%) achieving PASI75 and 39 (41%) achieving PASI90. Improved PASI90 response was significantly associated with lower BMI, higher baseline PASI, non-smoking status and lower cumulative NbUVB. Serum levels of C-reactive protein (CRP) and vitamin D were not associated with clearance or remission duration. Early treatment response from weeks 2-3 was predictive of final outcome. For example, achieving PASI30 at week 3 was significantly associated with PASI90 at the end of the course [36/77 (51%) vs. 2/24 (8%), P Conclusions Raised BMI and positive smoking status predicted poorer phototherapy response. For the first time, we have shown that PASI clearance trajectory over the first 2-3 weeks of UVB, can predict psoriasis clearance. This is an important new step towards developing psoriasis personalized prescribing, which can now be formally tested in clinical trials. These simple clinical measures can be used to inform patient treatment expectations; allowing treatment modifications and/or switching to alternative therapies.

A stratified medicine approach for the treatment of psoriasis promises greater certainty of clinical decision making through prediction of response on the basis of clinical, pharmacological, and -omics data from an individual patient. As yet, there is no predictive model for treatment response in routine clinical use for psoriasis. The Psoriasis Stratification to Optimise Relevant Therapy (PSORT) Consortium is a United Kingdom Medical Research Council‒funded, academic‒industrial stratified medicine consortium established with the objective of discovering the predictors and stratifiers of response of psoriasis to biologic therapies. A showcase meeting was convened and attended by 80 stakeholders at the Royal College of Physicians, London, United Kingdom on 18 November 2019. The purpose was to disseminate the research findings from the PSORT consortium discovered thus far. This report summarizes the presentations made on the day and the significant advances made by PSORT toward a stratified medicine approach to the management of psoriasis.

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.

Background Immunosuppressive treatments inhibit vaccine-induced immunity against SARS-CoV-2. We evaluated whether a 2-week interruption of methotrexate treatment immediately after the COVID-19 vaccine booster improved antibody responses against the S1 receptor-binding domain (S1-RBD) of the SARS-CoV-2 spike protein compared with uninterrupted treatment in patients with immune-mediated inflammatory diseases. Methods We did an open-label, prospective, two-arm, parallel-group, multicentre, randomised, controlled, superiority trial in 26 hospitals in the UK. We recruited adults from rheumatology and dermatology clinics who had been diagnosed with an immune-mediated inflammatory disease (eg, rheumatoid arthritis, psoriasis with or without arthritis, axial spondyloarthritis, atopic dermatitis, polymyalgia rheumatica, and systemic lupus erythematosus) and who were taking low-dose weekly methotrexate (≤25 mg per week) for at least 3 months. Participants also had to have received two primary vaccine doses from the UK COVID-19 vaccination programme. We randomly assigned the participants (1:1), using a centralised validated computer randomisation program, to suspend methotrexate treatment for 2 weeks immediately after their COVID-19 booster (suspend methotrexate group) or to continue treatment as usual (continue methotrexate group). Participants, investigators, clinical research staff, and data analysts were unmasked, while researchers doing the laboratory analyses were masked to group assignment. The primary outcome was S1-RBD antibody titres 4 weeks after receiving the COVID-19 booster vaccine dose, assessed in the intention-to-treat population. This trial is registered with ISRCT, ISRCTN11442263; following the pre-planned interim analysis, recruitment was stopped early. Findings Between Sept 30, 2021 and March 3, 2022, we recruited 340 participants, of whom 254 were included in the interim analysis and had been randomly assigned to one of the two groups: 127 in the continue methotrexate group and 127 in the suspend methotrexate group. Their mean age was 59·1 years, 155 (61%) were female, 130 (51%) had rheumatoid arthritis, and 86 (34%) had psoriasis with or without arthritis. After 4 weeks, the geometric mean S1-RBD antibody titre was 22 750 U/mL (95% CI 19 314–26 796) in the suspend methotrexate group and 10 798 U/mL (8970–12 997) in the continue methotrexate group, with a geometric mean ratio (GMR) of 2·19 (95% CI 1·57–3·04; p Interpretation A 2-week interruption of methotrexate treatment for people with immune-mediated inflammatory diseases resulted in enhanced boosting of antibody responses after COVID-19 vaccination. This intervention is simple, low-cost, and easy to implement, and could potentially translate to increased vaccine efficacy and duration of protection for susceptible groups. Funding National Institute for Health and Care Research.

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.

Current management approaches for the treatment of psoriasis and psoriatic arthritis (PsA) are imprecise and depend largely on clinical assessment. A more precise approach, which takes into account an individual patient's variations in genes, proteins, environment, and lifestyle, is beginning to receive attention with the most advanced progress seen in the treatment of cancer. Herein, the methodological approaches required for this precision medicine approach to be adopted in psoriatic disease, as well as their advantages, are reviewed. In addition, advances that are being made to address areas of unmet need in PsA, notably the use of proteomic approaches, are presented with suggestions that combine genetic and protein data (proteogenomics). Finally, progress that is being made in 2 large-scale, multipartner studies focused on the development of a precision medicine approach to the treatment of skin psoriasis is presented and discussed.

The application of artificial intelligence (AI) to whole slide images has the potential to improve research reliability and ultimately diagnostic efficiency and service capacity. Image annotation plays a key role in AI and digital pathology. However, the work-streams required for tissue-specific (skin) and immunostain-specific annotation has not been extensively studied compared with the development of AI algorithms.The objective of this study is to develop a common workflow for annotating whole slide images of biopsies from inflammatory skin disease immunostained with a variety of epidermal and dermal markers prior to the development of the AI-assisted analysis pipeline.A total of 45 slides containing 3-5 sections each were scanned using Aperio AT2 slide scanner (Leica Biosystems). These slides were annotated by hand using a commonly used image analysis tool which resulted in more than 4000 images blocks. We used deep learning (DL) methodology to first sequentially segment (epidermis and upper dermis), with the exclusion of common artefacts and second to quantify the immunostained signal in those two compartments of skin biopsies and the ratio of positive cells.We validated two DL models using 10-fold validation runs and by comparing to ground truth manually annotated data. The models achieved an average (global) accuracy of 95.0% for the segmentation of epidermis and dermis and 86.1% for the segmentation of positive/negative cells.The application of two DL models in sequence facilitates accurate segmentation of epidermal and dermal structures, exclusion of common artefacts and enables the quantitative analysis of the immunostained signal. However, inaccurate annotation of the slides for training the DL model can decrease the accuracy of the output. Our open source code will facilitate further external validation across different immunostaining platforms and slide scanners.

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.We sought to investigate the immune pathways that underlie the pathogenesis of PPP.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 TPPP 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.

Despite increased understanding about psoriasis pathophysiology, currently there is a lack of predictive computational models. We developed a personalisable ordinary differential equations model of human epidermis and psoriasis that incorporates immune cells and cytokine stimuli to regulate the transition between two stable steady states of clinically healthy (non-lesional) and disease (lesional psoriasis, plaque) skin. In line with experimental data, an immune stimulus initiated transition from healthy skin to psoriasis and apoptosis of immune and epidermal cells induced by UVB phototherapy returned the epidermis back to the healthy state. Notably, our model was able to distinguish disease flares. The flexibility of our model permitted the development of a patient-specific “UVB sensitivity” parameter that reflected subject-specific sensitivity to apoptosis and enabled simulation of individual patients’ clinical response trajectory. In a prospective clinical study of 94 patients, serial individual UVB doses and clinical response (Psoriasis Area Severity Index) values collected over the first three weeks of UVB therapy informed estimation of the “UVB sensitivity” parameter and the prediction of individual patient outcome at the end of phototherapy. An important advance of our model is its potential for direct clinical application through early assessment of response to UVB therapy, and for individualised optimisation of phototherapy regimes to improve clinical outcome. Additionally by incorporating the complex interaction of immune cells and epidermal keratinocytes, our model provides a basis to study and predict outcomes to biologic therapies in psoriasis.Author SummaryWe present a new computer model for psoriasis, an immune-mediated disabling skin disease which presents with red, raised scaly plaques that can appear over the whole body. Psoriasis affects millions of people in the UK alone and causes significant impairment to quality of life, and currently has no cure. Only a few treatments (including UVB phototherapy) can induce temporary remission. Despite our increased understanding about psoriasis, treatments are still given on a ‘trial and error’ basis and there are no reliable computer models that can a) elucidate the mechanisms behind psoriasis onset or flare and b) predict a patient’s response to a course of treatment (e.g., phototherapy) and the likelihood of inducing a period of remission. Our computer model addresses both these needs. First, it explicitly describes the interaction between the immune system and skin cells. Second, our model captures response to therapy at the individual patient level and enables personalised prediction of clinical outcomes. Notably, our model also supports prediction of amending individual UVB phototherapy regimes based on the patient’s initial response that include for example personalised delivery schedules (i.e., 3x weekly vs. 5x weekly phototherapy). Therefore, our work is a crucial step towards precision medicine for psoriasis treatment.

Wounding induces a calcium wave and disrupts the calcium gradient across the epidermis but mechanisms mediating calcium and downstream signalling, and longer-term wound healing responses are incompletely understood. As expected, live-cell confocal imaging of Fluo-4-loaded normal human keratinocytes showed an immediate increase in [Ca2+ ]i at the wound edge that spread as a calcium wave (8.3 µm/s) away from the wound edge with gradually diminishing rate of rise and amplitude. The amplitude and area under the curve of [Ca2+ ]i flux was increased in high (1.2 mM) [Ca2+ ]o media. 18α-glycyrrhetinic acid (18αGA), a gap-junction inhibitor or hexokinase, an ATP scavenger, blocked the wound-induced calcium wave, dependent in part on [Ca2+ ]o . Wounding in a high [Ca2+ ]o increased nuclear factor of activated T-cells (NFAT) but not NFkB activation, assessed by dual-luciferase receptor assays compared to unwounded cells. Treatment with 18αGA or the store-operated channel blocker GSK-7975A inhibited wound-induced NFAT activation, whereas treatment with hexokinase did not. Real-time cell migration analysis, measuring wound closure rates over 24 h, revealed that 18αGA essentially blocked wound closure whereas hexokinase and GSK-7975A showed relatively minimal effects. Together these data indicate that while both gap-junction communication and ATP release from damaged cells are important in regulating the wound-induced calcium wave, long-term transcriptional and functional responses are dominantly regulated by gap-junction communication.

Ultraviolet B radiation (UVB) exerts pleiotropic effects on human skin. DNA damage response and repair pathways are activated by UVB; if damage cannot be repaired, apoptosis ensues. Although cumulative UVB exposure predisposes to skin cancer, UVB phototherapy is widely used as an effective treatment for psoriasis. Previous studies defined the therapeutic action spectrum of UVB and showed that psoriasis is resistant to apoptosis. This study aimed to investigate early molecular responses within psoriasis plaques following irradiation with single equi-erythemogenic doses of clinically-effective (311 nm, narrow-band) compared to clinically-ineffective (290 nm) UVB. Forty-eight micro-dissected epidermal samples from 20 psoriatic patients were analyzed using microarrays. Our bioinformatic analysis compared gene expression between 311 nm irradiated, 290 nm irradiated and control psoriasis epidermis to specifically identify 311 nm UVB differentially expressed genes (DEGs) and their upstream regulatory pathways. Key DEGs and pathways were validated by immunohistochemical analysis. There was a dynamic induction and repression of 311 nm UVB DEGs between 6 h and 18 h, only a limited number of DEGs maintained their designated expression status between time-points. Key disease and function pathways included apoptosis, cell death, cell migration and leucocyte chemotaxis. DNA damage response pathways, NRF2-mediated oxidative stress response and P53 signalling were key nodes, interconnecting apoptosis and cell cycle arrest. Interferon signalling, dendritic cell maturation, granulocyte adhesion and atherosclerotic pathways were also differentially regulated. Consistent with these findings, top transcriptional regulators of 311 nm UVB DEGs related to: a) apoptosis, DNA damage response and cell cycle control; b) innate/acquired immune regulation and inflammation; c) hypoxia/redox response and angiogenesis; d) circadian rhythmicity; f) EGR/AP1 signalling and keratinocyte differentiation; and g) mitochondrial biogenesis. This research provides important insights into the molecular targets of 311 nm UVB, underscoring key roles for apoptosis and cell death. These and the other key pathways delineated may be central to the therapeutic effects of 311 nm in psoriasis., Graphical abstract Schematic representation of study to delineate pathways activated by therapeutic wavelengths of UVB in psoriasis.Image 1

There are concerns that immunomodulatory therapies may increase the risks of developing basal cell carcinoma (BCC) and cutaneous squamous cell carcinoma (SCC) in patients with moderate-severe psoriasis. A systematic review showed that psoriasis patients were significantly more likely to develop SCC than the general population, though included studies lacked adequate comparator cohorts and adjustment for relevant confounding factors including heterogeneity between BCC and SCC in association with phototherapy and immunomodulatory therapies and lacked data on newer biologic therapies. We therefore followed-up a large prospective patient cohort to determine whether the risks of developing BCC and SCC are increased in patients with psoriasis receiving biologic therapy compared with those treated with non-biologic systemic therapies only.

Cellular beauty is skin deep Human skin works as barrier, preventing the entry of pathogens, among other functions. Reynolds et al. used single-cell sequencing to generate an atlas of the human skin from both developing and adult sources, identifying differences and similarities across heterogeneous populations of skin cells. In this atlas, gene expression in the two disease states studied—atopic dermatitis and psoriasis—varied from that in a healthy adult, suggesting that a fetal skin signature is expressed in adult inflamed skin. Furthermore, differences in immune cell composition between healthy fetal and adult skin and that of individuals suffering from disease were observed. Science , this issue p. eaba6500

Autophagy is required for normal skin homeostasis and its disordered regulation is implicated in a range of cutaneous diseases. Several well-characterized biomarkers of autophagy are used experimentally to quantify autophagic activity or clinically to correlate autophagy with disease progression. This article discusses the advantages and limitations of different approaches for measuring autophagy as well as the techniques for modulating autophagy. These include analysis of endogenous LC3, a central autophagy regulatory protein, and measurement of LC3 flux using a dual-fluorescent reporter, which provides a quantitative readout of autophagy in cell culture systems in vitro and animal models in vivo. Degradation of SQSTM1/p62 during autophagy is proposed as an alternative biomarker allowing the analysis of autophagy both experimentally and clinically. However, the complex regulation of individual autophagy proteins and their involvement in multiple pathways means that several proteins must be analyzed together, preferably over a time course to accurately interpret changes in autophagic activity. Genetic modification of autophagy proteins can be used to better understand basic autophagic mechanisms contributing to health and disease, whereas small molecule inhibitors of autophagy regulatory proteins, lysosomal inhibitors, or activators of cytotoxic autophagy have been explored as potential treatments for skin disorders where autophagy is defective. [Abstract copyright: Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.]

Importance Treatments for psoriasis may be less effective in everyday practice than in clinical trials. Emulating a target trial using data from the British Association of Dermatologists Biologics and Immunomodulators Register (BADBIR) can provide treatment effect estimates that are robust and can inform both clinicians and regulatory bodies. Objectives To assess the comparative effectiveness of ustekinumab and secukinumab in patients with psoriasis, and to test whether the relative effectiveness estimate of the CLEAR trial, a randomized clinical trial that compared secukinumab with ustekinumab for psoriasis, can be replicated. Design, Setting, and Participants This comparative effectiveness research study used a target trial emulation approach and was performed between November 2007 and August 2019. Data were obtained from BADBIR, a multicenter longitudinal pharmacovigilance register of patients with moderate to severe psoriasis in the United Kingdom and Republic of Ireland. Participants had chronic plaque psoriasis, were 18 years or older, and had at least 1 record of a Psoriasis Area and Severity Index (PASI) of 12 or higher before their initiation to secukinumab or ustekinumab. Propensity score (PS) 1:1 matched analysis and inverse probability treatment weighted analysis were performed. Main Outcomes and Measures The primary outcomes were the risk ratio (RR) and the risk difference (RD) for achieving PASI of 2 or lower after 12 months of therapy for secukinumab compared with ustekinumab. Methods to account for missing outcome data were complete case analysis, nonresponder imputation, last observation carried forward, inverse probability of censoring weighting, and multiple imputation. Regulatory and estimate agreement metrics were used to benchmark the effect estimates in this study against those in the CLEAR trial. Results A total of 1231 patients were included in the analysis, with 917 receiving ustekinumab and 314 receiving secukinumab. Secukinumab was superior to ustekinumab in all analyses, except under the nonresponder imputation method, in the proportion of participants achieving a PASI of 2 or lower (PS-weighted complete case analysis: RR, 1.28 [95% CI, 1.06-1.55]; RD, 11.9% [1.6-22.1]). All analyses, except for nonresponder imputation, reached regulatory agreement in both PS-matching and PS-weighted analyses. Conclusions and Relevance This comparative effectiveness study found that secukinumab resulted in more patients achieving a PASI of 2 or lower after 12 months of therapy compared with ustekinumab in patients with psoriasis. Target trial emulation in this study resulted in regulatory and estimate agreement with the CLEAR randomized clinical trial; further such studies may help fill the evidence gap when comparing other systemic therapies for psoriasis.

The human skin confers biophysical and immunological protection through a complex cellular network that is established early in development. We profiled ~500,000 single cells using RNA-sequencing from healthy adult and developing skin, and skin from patients with atopic dermatitis and psoriasis. Our findings reveal a predominance of innate lymphoid cells and macrophages in developing skin in contrast to T cells and migratory dendritic cells in adult skin. We demonstrate dual keratinocyte differentiation trajectories and activated cellular circuits comprising vascular endothelial cells mediating immune cell trafficking, disease-specific clonally expanded IL13/IL22 and IL17A/F-expressing lymphocytes, epidermal IL23-expressing dendritic cells and inflammatory keratinocytes in disease. Our findings provide key insights into the dynamic cellular landscape of human skin in health and disease.One Sentence SummarySingle cell atlas of human skin reveals cell circuits which are quantitatively and qualitatively reconfigured in inflammatory skin disease.

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.

BACKGROUND: Real-world biologic drug survival is an important proxy measure for effectiveness. Predictors of drug survival may help patients with psoriasis choose between biologic therapies.\ud \ud OBJECTIVES: (i) To assess the relative drug survival of adalimumab, ustekinumab and secukinumab in patients with psoriasis. (ii) To investigate predictors of biologic drug survival. \ud \ud METHODS: A prospective cohort study was performed in the British Association of Dermatologists Biologics and Immunomodulators Register (BADBIR) between November 2007 and August 2019. We performed survival analysis and fitted a flexible parametric survival model for biologic discontinuation due to ineffectiveness. \ud \ud RESULTS: In total 9652 patients were included: 5543 starting on adalimumab (57·4%), 991 on secukinumab (10·3%) and 3118 on ustekinumab (32·3%). The overall drug survivals of adalimumab, secukinumab and ustekinumab in year 1 were 0·78 [95% confidence interval (CI) 0·77-0·79], 0·88 (95% CI 0·86-0·91) and 0·88 (95% CI 0·87-0·89), respectively. The adjusted hazard ratios (adjHRs) for discontinuation of adalimumab and secukinumab compared with ustekinumab were 2·11 (95% CI 1·76-2·54) and 0·67 (95% CI 0·40-1·11), respectively. The presence of psoriatic arthritis predicted for survival in the adalimumab and secukinumab cohorts (adjHR 0·67, 95% CI 0·51-0·88 and 0·70, 95% CI 0·40-1·24, respectively), but for discontinuation in the ustekinumab cohort (adjHR 1·42, 95% CI 1·12-1·81). Previous exposure to biologic therapies predicted for discontinuation in the ustekinumab and secukinumab cohorts (adjHR 1·54, 95% CI 1·26-1·89 and 1·49, 95% CI 0·91-2·45, respectively) and for survival in the adalimumab cohort (adjHR 0·71, 95% CI 0·55-0·92). \ud \ud CONCLUSIONS: Secukinumab and ustekinumab have similar sustained drug survival, while adalimumab has a lower drug survival in patients with psoriasis. Psoriatic arthritis and previous biologic experience were predictors with differential effects between the biologic therapies. What is already known about this topic? There is conflicting evidence over the real-world drug survival of secukinumab in patients with psoriasis. Data from registries to date suggest that secukinumab has a lower drug survival than that reported from clinical trials. What does this study add? This study found that secukinumab and ustekinumab had similar sustained drug survival in the real world, while the drug survival of adalimumab was lower, suggesting that the real-world drug survival of secukinumab is higher than previously reported. We found that psoriatic arthritis and previous biologic experience had differential effects on drug discontinuation in the three biologic cohorts. These predictors may help patients and clinicians choose the most appropriate biologic therapy.

The identification of disease alleles underlying human autoinflammatory diseases can provide important insights into the mechanisms that maintain neutrophil homeostasis. Here, we focused on generalized pustular psoriasis (GPP), a potentially life-threatening disorder presenting with cutaneous and systemic neutrophilia. Following the whole exome sequencing of 19 unrelated cases, we identified one affected individual harbouring a homozygous splice-site mutation (c.2031-2A>C) in MPO. The same homozygous change was subsequently identified in a further subject suffering from acral pustular psoriasis, a disease phenotypically related to GPP.MPO encodes myeloperoxidase, an essential component of neutrophil azurophil granules. Of interest, the c.2031-2A>C allele was previously described as a genetic determinant of myeloperoxidase deficiency (MPOD), a condition which can causes recurrent infections. Here, a systematic literature review identified four individuals suffering from MPOD and pustular skin disease, further strengthening the link between MPO and pustular inflammation.A subsequent analysis of the UK Biobank cohort demonstrated that the c.2031-2A>C allele was associated with increased neutrophil abundance in the general population (P=5.1×10−6). The same applied to three further MPOD mutations for which genotype data was available, with two alleles generating p-values −10. Finally, treatment of healthy neutrophils with an MPO inhibitor reduced cell apoptosis, highlighting a mechanism whereby MPO mutations affect granulocyte numbers.These findings identify MPO mutations as genetic determinants of pustular skin disease and neutrophil abundance. Given the recent interest in the development of MPO antagonists for the treatment of neurodegenerative disease, our results also suggest that the pro-inflammatory effects of these agents should be closely monitored.

Summary Background Epidemiological studies indicate that gene–environment interactions play a role in atopic dermatitis (AD). Objectives To review the evidence for gene–environment interactions in AD aetiology, focusing on filaggrin (FLG) loss‐of‐function mutations. Methods A systematic search from inception to September 2018 in Embase, MEDLINE and BIOSIS was performed. Search terms included all synonyms for AD and filaggrin/FLG; any genetic or epidemiological study design using any statistical methods were included. Quality assessment using criteria modified from guidance (ROBINS‐I and Human Genome Epidemiology Network) for nonrandomized and genetic studies was completed, including consideration of power. Heterogeneity of study design and analyses precluded the use of meta‐analysis. Results Of 1817 papers identified, 12 studies fulfilled the inclusion criteria required and performed formal interaction testing. There was some evidence for FLG–environment interactions in six of the studies (P‐value for interaction ≤ 0·05), including early‐life cat ownership, older siblings, water hardness, phthalate exposure, higher urinary phthalate metabolite levels (which all increased AD risk additional to FLG null genotype) and prolonged breastfeeding (which decreased AD risk in the context of FLG null genotype). Major limitations of published studies were the low numbers of individuals (ranging from five to 94) with AD and FLG loss‐of‐function mutations and exposure to specific environmental factors, and variation in exposure definitions. Conclusions Evidence on FLG–environment interactions in AD aetiology is limited. However, many of the studies lacked large enough sample sizes to assess these interactions fully. Further research is needed with larger sample sizes and clearly defined exposure assessment. Linked Comment: Park and Seo. Br J Dermatol 2020; 183:411., What's already known about this topic? Gene–environment interactions are considered important in the aetiology of atopic dermatitis.Loss‐of-function mutations in the gene coding filaggrin (FLG) are the most consistently reported genetic variants for atopic dermatitis.Studies have reported evidence for gene–environment interaction involving FLG and a range of different environmental exposures. What does this study add? There is some evidence for FLG–environment interactions in the aetiology of atopic dermatitis; however, the evidence is limited.Studies lack large enough sample sizes to achieve adequate power in order to assess these interactions fully. Linked Comment: Park and Seo. Br J Dermatol 2020; 183:411. Plain language summary available online

Psoriasis is associated with the metabolic syndrome, an interconnected group of conditions characterized by significant morbidity and mortality, although the causal mechanisms are still under investigation. Ikumi et al. provide evidence of a link-involving IL-17-between psoriasis and hyperglycemia in humans and mice.

Summary Background Evidence of the comparative effectiveness of biological therapies for psoriasis on health‐related quality of life (HRQoL) in routine clinical practice is limited. Objectives To examine the comparative effectiveness of adalimumab, etanercept and ustekinumab on HRQoL in patients with psoriasis, and to identify potential predictors for improved HRQoL. Methods This was a prospective cohort study in which changes in HRQoL were assessed using the Dermatology Life Quality Index (DLQI) and EuroQoL‐5D (EQ‐5D) at 6 and 12 months. Multivariable regression models were developed to identify factors associated with achieving a DLQI of 0/1 and improvements in the EQ‐5D utility score. Results In total, 2152 patients with psoriasis were included, with 1239 patients on adalimumab, 517 on etanercept and 396 on ustekinumab; 81% were biologic naïve. For the entire cohort, the median (interquartile range) DLQI and EQ‐5D improved from 18 (13–24) and 0·73 (0·69–0·80) at baseline to 2 (0–7) and 0·85 (0·69–1·00) at 6 months, respectively (P < 0·001). Similar improvements were achieved at 12 months. At 12 months, multivariable regression modelling showed that female sex, multiple comorbidities, smoking and a higher DLQI or a lower EQ‐5D utility score at baseline predicted a lower likelihood of achieving a DLQI of 0/1 or improvement in the EQ‐5D. Compared with adalimumab, patients receiving etanercept, but not ustekinumab, were less likely to achieve a DLQI of 0/1. There was no significant difference between the biological therapies in EQ‐5D improvement. Conclusions In routine clinical practice biological therapies produce marked improvement in HRQoL, which is influenced by the choice of biological therapy, baseline impairment in HRQoL, lifestyle characteristics and comorbidities. These findings should help inform selection of optimal biological therapy for patients related to improvements in HRQoL., What's already known about this topic? Evidence of the comparative effectiveness of biological therapies for psoriasis on health‐related quality of life (HRQoL) in routine clinical practice is limited.Earlier observational studies were either cross‐sectional, thereby limiting the ability to compare changes in HRQoL, or cohort studies that have not taken into account important clinical factors that could influence treatment response, such as alterations in dosing regimens of biological therapies and the concomitant use of conventional systemic treatments for psoriasis. What does this study add? This large prospective cohort study found that in routine clinical practice, the use of biological therapies for psoriasis was associated with marked improvements in HRQoL over 12 months.These improvements were influenced by the choice of biological therapy, baseline impairment in HRQoL, lifestyle characteristics and comorbidities.Compared with adalimumab, patients receiving etanercept were less likely to achieve a DLQI of 0/1, but there was no significant difference between ustekinumab and adalimumab in the proportion of patients achieving a DLQI of 0/1.There was no significant difference between the three biological therapies in level of improvement in the EQ‐5D. Linked Comment: Finlay. Br J Dermatol 2017; 177:1164–1165.

Psoriasis is a common inflammatory skin disorder for which multiple genetic susceptibility loci have been identified, but few resolved to specific functional variants. In this study, we sought to identify common and rare psoriasis-associated gene-centric variation. Using exome arrays we genotyped four independent cohorts, totalling 11 861 psoriasis cases and 28 610 controls, aggregating the dataset through statistical meta-analysis. Single variant analysis detected a previously unreported risk locus at TNFSF15 (rs6478108; P = 1.50 x 10(-8), OR = 1.10), and association of common protein-altering variants at 11 loci previously implicated in psoriasis susceptibility. We validate previous reports of protective low-frequency protein-altering variants within IFIH1 (encoding an innate antiviral receptor) and TYK2 (encoding a Janus kinase), in each case establishing a further series of protective rare variants (minor allele frequency amp;lt; 0.01) via gene-wide aggregation testing (IFIH1: p(burden) = 2.53 x 10(-7), OR = 0.707; TYK2: p(burden) = 6.17 x 10(-4), OR = 0.744). Both genes play significant roles in type I interferon (IFN) production and signalling. Several of the protective rare and low-frequency variants in IFIH1 and TYK2 disrupt conserved protein domains, highlighting potential mechanisms through which their effect may be exerted. Funding Agencies|Medical Research Council (MRC) Stratified Medicine award [MR/L011808/1]; Psoriasis Association [RG2/10]; MRC Clinical Training Fellowship [MR/L001543/1]; NIHR Biomedical Research Centre based at Guys and St Thomas NHS Foundation Trust; Kings College London; NIHR Biomedical Research Centre at South London; Maudsley NHS Foundation Trust; Maudsley Charity [980]; Guys and St Thomass Charity [STR130505]; MRC grant [G0000934]; Wellcome Trust grant [068545/Z/02]; German Federal Ministry of Education and Research (BMBF) [01ZX1306A]; PopGen Biobank (Kiel, Germany) [01EY1103]; Helmholtz Zentrum Munchen - German Research Center for Environmental Health; BMBF; State of Bavaria; Munich Center of Health Sciences (MC Health); Ludwig-Maximilians-Universitat, of LMUinnovativ; BMBF [01ZZ9603, 01ZZ0103, 01ZZ0403, 03152061A, 03Z1CN22]; Ministry of Cultural Affairs; Social Ministry of the Federal State of Mecklenburg -West Pomerania; network Greifswald Approach to Individualized Medicine (GANI MED); Federal State of Mecklenburg West Pomerania; BMBF Metarthros grant [01EC1407A]; National Institutes of Health [R01AR042742, R01AR050511, R01AR054966, R01AR063611, R01AR065183]; GAIN award from the Foundation for the National Institutes of Health; Ann Arbor Veterans Affairs Hospital; Taubman Medical Research Institute; International Psoriasis Council

Group 2 innate lymphoid cells (ILC-2s) regulate immune responses to pathogens and maintain tissue homeostasis in response to cytokines. Positive regulation of ILC-2s through ICOS has been recently elucidated. We demonstrate here that PD-1 is an important negative regulator of KLRG1+ ILC-2 function in both mice and humans. Increase in KLRG1+ ILC-2 cell numbers was attributed to an intrinsic defect in PD-1 signaling, which resulted in enhanced STAT5 activation. During Nippostrongylus brasiliensis infection, a significant expansion of KLRG1+ ILC-2 subsets occurred in Pdcd1−/− mice and, upon adoptive transfer, Pdcd1−/− KLRG1+ ILC-2s significantly reduced worm burden. Furthermore, blocking PD-1 with an antibody increased KLRG1+ ILC-2 cell number and reduced disease burden. Therefore, PD-1 is required for maintaining the number, and hence function, of KLRG1+ ILC-2s.

BACKGROUND: Treatment modifications, including dose-escalations, dose-reductions, switches, discontinuations and restarts of biologics may be necessary in the management of psoriasis but the patterns of usage are incompletely defined.OBJECTIVES: To examine the treatment utilisation patterns of adalimumab, etanercept and ustekinumab among biologic-naïve and non-naïve psoriasis patients enrolled in the British Association of Dermatologists Biologic Interventions Register (BADBIR).METHOD: The cohort study included adults with chronic plaque psoriasis who were followed-up for ≥12-months.Treatment modifications were assessed during the first year of therapy. The time-trend method, comparing the cumulative dose (CD) patients received to the recommended cumulative dose (RCD), was used to assess dosing patterns. Concomitant use of other systemic treatments was also examined.RESULTS: In total, 2980 patients (adalimumab:1675; etanercept:996; ustekinumab:309) were included; 79.2% were biologic-naïve. Over 12-months, 77.4% of patients continued the biologic, 2.6% restarted therapy after a break of ≥90-days, 2.5% discontinued, and 17.5% switched biologic therapy. Most patients (85.7%) received the RCD of the biologic, although 8.1% were exposed to a higher CD. In total, 749(25.1%) patients used conventional systemic therapies concomitantly with a biologic at some stage; methotrexate was used most commonly (458;61.2%). Of those using combination therapy, 454(60.6%) continued the use of the conventional systemic therapy for >120 days after the start of the biologic.CONCLUSION: More than one-third of patients experienced treatment modifications within the first year of initiating a biologic. Conventional systemic therapies, particularly methotrexate, were commonly used concurrently which should be considered when evaluating treatment response and adverse events to biologics in real-world observational studies. This article is protected by copyright. All rights reserved.

Atopic dermatitis comorbidities extend well beyond the march to allergic conditions (food allergy, asthma, allergic rhinitis, allergic conjunctivitis, and eosinophilic esophagitis), suggesting both cutaneous and systemic immune activation. In reviewing atopic dermatitis comorbidities, Councilors of the International Eczema Council found a strong pattern of immune activation in peripheral blood and the propensity to both skin and systemic infections. Associations with cardiovascular, neuropsychiatric, and malignant diseases were increasingly reported, but confirmation of their link with atopic dermatitis requires longitudinal studies. Given the possibility of atopic dermatitis-related systemic immune activation, future investigations of new interventions should concurrently examine the impact on these comorbidities.

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.