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Interleukins 12 and 23 have important roles in the pathophysiology of psoriasis. We assessed ustekinumab, a human monoclonal antibody directed against these cytokines, for the treatment of psoriasis. In this phase III, parallel, double-blind, placebo-controlled study, 766 patients with moderate-to-severe psoriasis were randomly assigned to receive ustekinumab 45 mg (n=255) or 90 mg (n=256) at weeks 0 and 4 and then every 12 weeks; or placebo (n=255) at weeks 0 and 4, with subsequent crossover to ustekinumab at week 12. Patients who were initially randomised to receive ustekinumab at week 0 who achieved long-term response (at least 75% improvement in psoriasis area and severity index [PASI 75] at weeks 28 and 40) were re-randomised at week 40 to maintenance ustekinumab or withdrawal from treatment until loss of response. Both randomisations were done with a minimisation method via a centralised interactive voice response system. The primary endpoint was the proportion of patients achieving PASI 75 at week 12. Analyses were by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00267969. All randomised patients were included in the efficacy analysis. 171 (67·1%) patients receiving ustekinumab 45 mg, 170 (66·4%) receiving ustekinumab 90 mg, and eight (3·1%) receiving placebo achieved PASI 75 at week 12 (difference in response rate vs placebo 63·9%, 95% CI 57·8–70·1, p<0·0001 for 45 mg and 63·3%, 57·1–69·4, p<0·0001 for 90 mg). At week 40, long-term response had been achieved by 150 patients in the 45 mg group and 172 patients in the 90 mg group. Of these, 162 patients were randomly assigned to maintenance ustekinumab and 160 to withdrawal. PASI 75 response was better maintained to at least 1 year in those receiving maintenance ustekinumab than in those withdrawn from treatment at week 40 (p<0·0001 by log-rank test). During the placebo-controlled phase, adverse events occurred in 278 (54·5%) of the 510 patients receiving ustekinumab and 123 (48·2%) of the 255 receiving placebo. Serious adverse events occurred in six (1·2%) of 510 patients receiving ustekinumab and in two (0·8%) of 255 receiving placebo in this phase. The pattern of adverse events was much the same in the placebo crossover and randomised withdrawal phases as it was in the placebo-controlled phase. Ustekinumab seems to be efficacious for the treatment of moderate-to-severe psoriasis; dosing every 12 weeks maintains efficacy for at least a year in most patients. Centocor Inc.

Innovative, online models of specialty-care delivery are critical to improving patient access and outcomes. To determine whether an online, collaborative connected-health model results in equivalent clinical improvements in psoriasis compared with in-person care. The Patient-Centered Outcomes Research Institute Psoriasis Teledermatology Trial is a 12-month, pragmatic, randomized clinical equivalency trial to evaluate the effect of an online model for psoriasis compared with in-person care. Participant recruitment and study visits took place at multicenter ambulatory clinics from February 2, 2015, to August 18, 2017. Participants were adults with psoriasis in Northern California, Southern California, and Colorado. The eligibility criteria were an age of 18 years or older, having physician-diagnosed psoriasis, access to the internet and a digital camera or mobile phone with a camera, and having a primary care physician. Analyses were on an intention-to-treat basis. Participants were randomized 1:1 to receive online or in-person care (148 randomized to online care and 148 randomized to in-person care). The online model enabled patients and primary care physicians to access dermatologists online asynchronously. The dermatologists provided assessments, recommendations, education, and prescriptions online. The in-person group sought care in person. The frequency of online or in-person visits was determined by medical necessity. All participants were exposed to their respective interventions for 12 months. The prespecified primary outcome was the difference in improvement in the self-administered Psoriasis Area and Severity Index (PASI) score between the online and in-person groups. Prespecified secondary outcomes included body surface area (BSA) affected by psoriasis and the patient global assessment score. Of the 296 randomized participants, 147 were women, 149 were men, 187 were white, and the mean (SD) age was 49 (14) years. The adjusted difference between the online and in-person groups in the mean change in the self-administered PASI score during the 12-month study period was -0.27 (95% CI, -0.85 to 0.31). The difference in the mean change in BSA affected by psoriasis between the 2 groups was -0.05% (95% CI, -1.58% to 1.48%). Between-group differences in the PASI score and BSA were within prespecified equivalence margins, which demonstrated equivalence between the 2 interventions. The difference in the mean change in the patient global assessment score between the 2 groups was -0.11 (95% CI, -0.32 to 0.10), which exceeded the equivalence margin, with the online group displaying greater improvement. The online, collaborative connected-health model was as effective as in-person management in improving clinical outcomes among patients with psoriasis. Innovative telehealth delivery models that emphasize collaboration, quality, and efficiency can be transformative to improving patient-centered outcomes in chronic diseases. ClinicalTrials.gov Identifier: NCT02358135.

Psoriasis is a common, chronic papulosquamous skin disease occurring worldwide, presenting at any age, and leading to a substantial burden for individuals and society. It is associated with several important medical conditions, including depression, psoriatic arthritis, and cardiometabolic syndrome. Its most common form, chronic plaque or psoriasis vulgaris, is a consequence of genetic susceptibility, particularly in the presence of the HLA-C*06:02 risk allele, and of environmental triggers such as streptococcal infection, stress, smoking, obesity, and alcohol consumption. There are several phenotypes and research has separated pustular from chronic plaque forms. Immunological and genetic studies have identified IL-17 and IL-23 as key drivers of psoriasis pathogenesis. Immune targeting of these cytokines and of TNFα by biological therapies has revolutionised the care of severe chronic plaque disease. Psoriasis cannot currently be cured, but management should aim to minimise physical and psychological harm by treating patients early in the disease process, identifying and preventing associated multimorbidity, instilling lifestyle modifications, and employing a personalised approach to treatment.

Purpose The Physician Global Assessment (PGA) is a key measure of psoriasis frequently used in clinical trials. A psychometric validation of a three-item (erythema, induration, and scaling) PGA scale was performed using Phase 2 data. Methods Confirmatory factor analysis (CFA) tested the PGA measurement model and appropriateness of equal weighting of the items. PGA test–retest reliability was assessed by estimating the intraclass correlation coefficient (ICC). Internal consistency reliability was gauged by calculating Cronbach’s coefficient α (CCα). Clinically important difference (CID) was defined using the repeated measures model to estimate the relationship between PGA and Patient Global Assessment (PtGA). Known-group, convergent, and divergent validity for the PGA were also assessed. Results 197 patients with psoriasis were randomized to tofacitinib 2, 5, 15 mg twice daily, or placebo. CFA demonstrated that the PGA measurement model fitted the data using equal weighting of the PGA items. The PGA scale demonstrated good test–retest reliability (ICC > 0.7) and internal consistency reliability (CCα > 0.8). The CID for PGA was estimated at 0.52 (95 % confidence interval: 0.47, 0.56). A robust monotonic relationship between PGA and Psoriasis Area and Severity Index (PASI) data substantiated known-group validity. Relatively high correlations of PGA with PASI and PtGA data (all correlations >0.5 except at baseline) supported convergent validity; relatively low correlations of PGA with the Pain/Discomfort Assessment and the Ocular Comfort Index supported divergent validity. Conclusions The three-item PGA scale has sound psychometric properties with respect to reliability and validity, with equal weighting of the items being appropriate.

Psoriasis is the result of uncontrolled keratinocyte proliferation, and its pathogenesis involves the dysregulation of the immune system. The interplay among cytokines released by dendritic, Th1, Th2, and Th17 cells leads to the phenotypical manifestations seen in psoriasis. Biological therapies target the cytokine-mediated pathogenesis of psoriasis and have improved patient quality of life. This review will describe the underlying molecular pathophysiology and biologics used to treat psoriasis. A review of the literature was conducted using the PubMed and Google Scholar repositories to investigate the molecular pathogenesis, clinical presentation, and current therapeutics in psoriasis. Plaque psoriasis’, the most prevalent subtype of psoriasis, pathogenesis primarily involves cytokines TNF-α, IL-17, and IL-23. Pustular psoriasis’, an uncommon variant, pathogenesis involves a mutation in IL-36RN. Currently, biological therapeutics targeted at TNF-α, IL-12/IL-23, IL-17, and IL-23/IL-39 are approved for the treatment of moderate to severe psoriasis. More studies need to be performed to elucidate the precise molecular pathology and assess efficacy between biological therapies for psoriasis. Psoriasis is a heterogenous, chronic, systemic inflammatory disease that presents in the skin with multiple types. Recognizing and understanding the underlying molecular pathways and biological therapeutics to treat psoriasis is important in treating this common disease.

Angiogenesis, the growth of new blood vessels from preexisting vessels, is associated with inflammation in various pathological conditions. Well-known angiogenetic factors include vascular endothelial growth factor (VEGF), angiopoietins, platelet-derived growth factor, transforming growth factor-β, and basic fibroblast growth factor. Yes-associated protein 1 (YAP) and transcriptional co-activator with PDZ-binding motif (TAZ) have recently been added to an important angiogenic factor. Accumulating evidence indicates associations between angiogenesis and chronic inflammatory skin diseases. Angiogenesis is deeply involved in the pathogenesis of psoriasis. VEGF, angiopoietins, tumor necrosis factor-a, interleukin-8, and interleukin-17 are unregulated in psoriasis and induce angiogenesis. Angiogenesis may be involved in the pathogenesis of atopic dermatitis, and in particular, mast cells are a major source of VEGF expression. Angiogenesis is an essential process in rosacea, which is induced by LL-37 from a signal cascade by microorganisms, VEGF, and MMP-3 from mast cells. In addition, angiogenesis by increased VEGF has been reported in chronic urticaria and hidradenitis suppurativa. The finding that VEGF is expressed in inflammatory skin lesions indicates that inhibition of angiogenesis is a useful strategy for treatment of chronic, inflammatory skin disorders.

Psoriasis is a chronic inflammatory condition that is polygenic and multisystemic, impacting approximately 2–3% of the global population. The onset of this disease is influenced by an intricate interplay of genetic and environmental factors, predisposing individuals to the psoriasis phenotype. The complex pathogenesis of psoriasis contains certain key aspects found in other autoinflammatory and autoimmune dermatological diseases. Among these, vitiligo, alopecia areata, hidradenitis suppurativa, vitiligo, connective tissue diseases, bullous dermatoses, and atopic dermatitis are conditions that share overlapping immune system dysfunction, making their relationship with psoriasis particularly significant. For our research, we explored various terms including “shared”, “concomitant”, “coincident”, “overlap”, “coexist”, and “concurrent”, in relation to conditions such as “psoriasis”, “alopecia areata”, “hidradenitis suppurativa”, “atopic dermatitis”, “vitiligo”, “bullous pemphigoid”, “pemphigus vulgaris”, “lupus erythematosus”, “dermatomyositis”, and “systemic sclerosis.” Additionally, we used specific search queries like “atopic dermatitis overlapping syndrome” and “psoriasis and vitiligo concomitant disease” in the PubMed and Web of Science databases. While distinct in their clinical presentation, the skin diseases related to psoriasis may become associated, complicating diagnosis and treatment. In this narrative review, the complex pathophysiology of psoriasis is described, along with its close relationship to other skin conditions. This review provides an exhaustive description of both immunological and non-immunological pathways contributing to their development. Understanding the intricate interconnection between psoriasis and these conditions is of interest to scientists in developing novel research directions and to clinicians in providing holistic care, as managing one condition may influence the course of others.

Psoriasis is a chronic scaling and inflammatory skin disease that can affect patients' quality of life and daily functioning. We studied the scores of 85 patients suffering from moderate to severe plaque-type psoriasis, participating in a randomized controlled trial. We compared their scores on a generic quality-of-life instrument with data from two reference populations. We examined associations between clinical severity, as measured by the components of the Psoriasis Area and Severity Index (PASI), and the respective quality-of-life subdimensions, measured by the Medical Outcome Survey Short Form 36 (SF-36), to find out what elements of disease activity are related with impaired quality of life. Compared to the reference population, quality of life was impaired in terms of bodily pain and social functioning. There were no significant correlations between overall disease severity, as measured by PASI, and the SF-36 subdimensions. When examining the PASI components, we found significant correlations between desquamation on the upper limbs and mental health and bodily pain (r=-0.23 and r=-0.28, respectively) and between desquamation on the scalp and mental health (r=-0.29). In conclusion, we found that psoriasis patients had a lower quality of life than a reference population, without a significant relation between disease severity or disease area and quality of life. Yet psoriasis lesions located on visible body parts are significantly correlated with aspects of quality of life.

Generalized pustular psoriasis (GPP) is a rare, severe form of pustular psoriasis characterized by widespread, recurrent episodes of neutrophil-rich pustule formation in the epidermis, which can be accompanied by fever and systemic inflammation. Recent clinical, histologic, and genetic evidence indicates that GPP is a distinct entity from plaque psoriasis, with different cytokine pathways predominant in the manifestation of each disease. The interleukin-36 (IL-36) signaling cascade plays a key role in regulating the innate immune system, and its dysregulation appears central to the pathogenesis of GPP. The altered expression of various IL-36 pathway constituents has been shown to cause a positive feedback loop of uncontrolled signaling and excess production of inflammatory cytokines, which in turn leads to chemokine induction and neutrophil recruitment in the epidermis. Given the potentially life-threatening nature of GPP episodes, drug interventions that rapidly achieve disease resolution are required. Early phase data indicate that treatments targeting various components of the IL-36 inflammatory cascade represent promising areas of research. However, there are currently no therapeutic agents specifically approved for GPP in the USA or Europe. Understanding the inflammatory pathways, associated risk factors, and role of neutrophils in the manifestation and perpetuation of GPP flares remains a key goal in developing effective therapeutics. In this article, we summarize the current understanding of GPP, describe novel therapeutic opportunities, and detail how the unique pathophysiology of the disease may inform future treatment strategies.

Plaque psoriasis is a chronic, immune-mediated inflammatory skin disease that has considerable effects on patients’ physical, psychological and social well-being. It is strongly influenced by genetic predisposition, with HLA-C*06:02 showing the strongest association, particularly in those with early-onset disease. Additional susceptibility loci, including IL23A , IL12B and IL17RA , are linked to dysregulation of the IL-23–T helper 17 axis, which contributes to chronic inflammation and keratinocyte hyperproliferation. Plaque psoriasis is frequently associated with psoriatic arthritis and other comorbidities, such as cardiovascular disease, metabolic syndrome and psychiatric disorders, all of which contribute to increased morbidity and mortality. Management strategies are tailored to disease severity and the presence of comorbidities. For mild disease, topical therapies remain the first-line treatment, including corticosteroids, vitamin D analogues and topical calcineurin inhibitors. New non-steroidal agents, such as topical PDE4 and aryl hydrocarbon receptor agonists, offer additional options. In moderate-to-severe disease, oral systemic therapies, such as methotrexate, ciclosporin, acitretin, apremilast and deucravacitinib, provide a range of immunomodulatory effects. Biologic therapies targeting TNF, IL-17, IL-23 and IL-12/23 have demonstrated high efficacy in improving both cutaneous and systemic inflammation. Current research on systemic therapies is focused on the development of additional inhibitors of the Tyk2 pathway and inhibitors to IL-23 receptor, IL-17, and TNF. Early screening for psoriatic arthritis, proactive cardiovascular risk reduction and multidisciplinary care are crucial to optimizing long-term outcomes. Ongoing research continues to advance precision medicine approaches, with the goal of enhancing treatment durability and improving quality of life for individuals living with psoriasis. Psoriasis is a chronic inflammatory disease characterized by cutaneous manifestations, which can also have systemic effects on joints, the cardiovascular system and metabolism. In this Primer, Armstrong et al. review the epidemiology, pathophysiology, diagnosis and management of psoriasis, and highlight the quality of life of patients and future research areas.