Development of a clinical algorithm to predict phenotypic switches between atopic dermatitis and psoriasis (the "Flip-Flop" phenomenon).

BACKGROUND: Atopic dermatitis (AD) and psoriasis vulgaris (PV) are almost mutually exclusive diseases with different immune polarizations, mechanisms and therapeutic targets. Switches to the other disease ("Flip-Flop" [FF] phenomenon) can occur with or without systemic treatment and are often referred to as paradoxical reactions under biological therapy. METHODS: The objective was to develop a diagnostic algorithm by combining clinical criteria of AD and PV to identify FF patients. The algorithm was prospectively validated in patients enrolled in the CK-CARE registry in Bonn, Germany. Afterward, algorithm refinements were implemented based on machine learning. RESULTS: Three hundred adult Caucasian patients were included in the validation study (n = 238 with AD, n = 49 with PV, n = 13 with FF; mean age 41.2 years; n = 161 [53.7%] female). The total FF scores of the PV and AD groups differed significantly from the FF group in the validation data (p < .001). The predictive mean generalized Youden-Index of the initial model was 78.9% [95% confidence interval 72.0%-85.6%] and the accuracy was 89.7%. Disease group-specific sensitivity was 100% (FF), 95.0% (AD), and 61.2% (PV). The specificity was 89.2% (FF), 100% (AD), and 100% (PV), respectively. CONCLUSION: The FF algorithm represents the first validated tool to identify FF patients.

Myeloperoxidase Modulates Inflammation in Generalized Pustular Psoriasis and Additional Rare Pustular Skin Diseases.

Generalized pustular psoriasis (GPP) is a severe multi-systemic inflammatory disease characterized by neutrophilic pustulosis and triggered by pro-inflammatory IL-36 cytokines in skin. While 19%-41% of affected individuals harbor bi-allelic mutations in IL36RN, the genetic cause is not known in most cases. To identify and characterize new pathways involved in the pathogenesis of GPP, we performed whole-exome sequencing in 31 individuals with GPP and demonstrated effects of mutations in MPO encoding the neutrophilic enzyme myeloperoxidase (MPO). We discovered eight MPO mutations resulting in MPO -deficiency in neutrophils and monocytes. MPO mutations, primarily those resulting in complete MPO deficiency, cumulatively associated with GPP (p = 1.85E-08; OR = 6.47). The number of mutant MPO alleles significantly differed between 82 affected individuals and >4,900 control subjects (p = 1.04E-09); this effect was stronger when including IL36RN mutations (1.48E-13) and correlated with a younger age of onset (p = 0.0018). The activity of four proteases, previously implicated as activating enzymes of IL-36 precursors, correlated with MPO deficiency. Phorbol-myristate-acetate-induced formation of neutrophil extracellular traps (NETs) was reduced in affected cells (p = 0.015), and phagocytosis assays in MPO-deficient mice and human cells revealed altered neutrophil function and impaired clearance of neutrophils by monocytes (efferocytosis) allowing prolonged neutrophil persistence in inflammatory skin. MPO mutations contribute significantly to GPP's pathogenesis. We implicate MPO as an inflammatory modulator in humans that regulates protease activity and NET formation and modifies efferocytosis. Our findings indicate possible implications for the application of MPO inhibitors in cardiovascular diseases. MPO and affected pathways represent attractive targets for inducing resolution of inflammation in neutrophil-mediated skin diseases.

Prospective double-blind study on the value of musculoskeletal ultrasound by dermatologists as a screening instrument for psoriatic arthritis.

OBJECTIVES: This study evaluated musculoskeletal ultrasound (MSUS) use by dermatologists previously trained on a novel handheld, chip-based ultrasound device (HHUD) to screen for early PsA. METHODS: Twelve dermatologists were recruited to screen psoriasis patients for PsA using the novel HHUD in one major hospital in Bonn (Germany) and six private practices in surrounding regions. Patient screening was based on medical history, clinical examination, and the GEPARD questionnaire paired with an MSUS examination of up to three painful joints. All screened patients were then referred to rheumatologists, who determined the final diagnosis. The screening effect of MSUS was assessed according to its sensitivity and specificity before and after its application. RESULTS: Between 1 October 2020 and 26 May 2021, a total of 140 psoriasis patients with arthralgia participated in this study. PsA was diagnosed in 19 (13.6%) cases. Before applying MSUS, dermatologists' screening sensitivity and specificity were recorded as 88.2% and 54.4%, respectively, while after applying MSUS the sensitivity and specificity changed to 70.6% and 90.4%, respectively. MSUS led to a change of PsA suspicion in 46 cases, with PsA no longer being suspected in 45 of them. CONCLUSION: This study was able to demonstrate that PsA screening using MSUS by previously trained dermatologists can lead to more precise PsA detection and potentially decreased rheumatologist referral rates.

Interleukin-19 Levels Are Increased in Palmoplantar Pustulosis and Reduced following Apremilast Treatment.

Palmoplantar pustulosis (PPP) is a chronic inflammatory skin disease characterised by neutrophilic granulocyte (neutrophil)-filled pustules on the palms and soles. The pathogenesis of PPP is poorly understood. This study conducted an identification of the immune mediators associated with PPP and an exploration of apremilast treatment effects on them. We screened for immune mediators elevated in blood taken from 68 patients with PPP versus control participants and included the most promising parameters in the protocol of phase the 2, multicentre study of apremilast (PDE4 inhibitor) in 21 patients with moderate-to-severe PPP (APLANTUS; EudraCT 2016-005122-11) for respective analysis of blood and skin samples of study patients. We investigated stimulated neutrophils and three-dimensional reconstituted epidermis cultures. Interleukin (IL)-19 was found to be the most upregulated immune mediator in the blood of PPP patients. IL-19 serum levels were independent of patients' age, gender, and BMI but were associated with strongly upregulated cutaneous IL-19 expression and correlated with the number of palmoplantar pustules. In patients participating in the APLANTUS study, apremilast reduced pustules more effectively than erythema and scaling. Moreover, this treatment significantly reduced IL-19 blood and skin levels. The reduction in IL-19 blood levels at week 4 correlated with the reduction in pustule counts at week 20 (end of treatment). IL-19 was expressed by neutrophils activated in vitro and induced CXCL6, a neutrophil-attracting chemokine, in epidermis models. This work demonstrates elevated IL-19 levels in the blood and skin of PPP patients and suggests a relevant role of this cytokine in the appearance of pustules in this disorder. It also suggests the suitability of IL-19 blood levels as a predictive biomarker for the treatment response of PPP patients, which should be validated in further studies.

Current developments and perspectives in psoriasis.

The study of psoriasis has yielded fundamental new insights into immunologic regulation and innovative therapies in a way that few other diseases have. In this review, we summarize the main features of current psoriasis research with emphasis on pathophysiological processes and the milestones in the approval of various biologics and small molecule drugs. Thus, through psoriasis research, we are gaining a better understanding of the interplay between the components of the innate and adaptive immune systems. New therapeutics interfere with crucial regulatory networks. Based on current knowledge, we outline what we believe to be some of the most important future research directions and therapeutic and clinical developments in psoriasis. These span multiple areas, ranging from the study of genetic, epigenetic, cellular, and immunological mechanisms to studies of particular clinical forms of psoriasis, individual systemic effects of the disease and its treatment, and the incorporation of large connected data sets and artificial intelligence. The goal is to understand psoriasis holistically, from the molecular to the organismic and societal levels, in order to develop individualized prevention and treatment strategies. Despite impressive progress, psoriasis research must continue to evolve at both the smallest and largest scales to comprehensively address the needs of both physicians and patients.

Absolute Psoriasis Area and Severity Index as a valuable marker to determine initial treatment response in psoriasis patients treated with guselkumab in routine clinical care.

Guselkumab is an anti-interleukin-23p19 monoclonal antibody approved as a first-line medication in patients with moderate-to-severe plaque-type psoriasis and second-line in active psoriatic arthritis. In the clinic, patients who have shown a lack of previous treatment efficacy and/or tolerability are often prescribed guselkumab. These patients generally have less severe psoriasis compared to clinical trial cohorts, reflected in lower Psoriasis Area and Severity Index (PASI). To evaluate treatment response in a real-world setting, we conducted a multicenter-retrospective chart review in three specialized dermatological centers. Seventy-four patients who received guselkumab treatment were included in the study and baseline characteristics were described. The mean PASI at baseline was 13.0 (± 6.7). After 12 weeks of treatment 40 patients could be followed up at the participating centers and efficacy was assessed: 72.5% of these patients achieved an absolute PASI ≤5 (55.0% ≤3; 42.5% ≤2) whereas only 57.5% of patients were able to gain a delta PASI reduction of at least 75%. Using the absolute PASI as a treatment goal rather than response rate revealed that guselkumab was highly effective in this real-world setting. In conclusion, the absolute PASI proved to be a more valuable tool to measure treatment outcome.

Therapy of psoriasis during pregnancy and breast-feeding.

There have been multiple systemic drugs approved for the therapy of psoriasis vulgaris and psoriasis arthritis (PsA) in the last decade. However, treatment decisions are difficult to make in women planning a pregnancy and in pregnant and lactating women due to the paucity of data for such cases. The strongest evidence for psoriasis therapy during pregnancy exists for topical corticosteroids. Medically controlled use of UVB-therapy is also considered safe. The best evidence regarding systemic therapy during pregnancy and lactation is available for the group of TNF-alpha inhibitors, which is also reflected in the respective medical product information. This is especially important in cases of psoriatic arthritis. Among traditional systemic therapeutics, the largest clinical experience exists for ciclosporin, which, if medically necessary, may be continued during gestation. However, TNF-alpha inhibitors, especially the pegylated form, should be preferred in case of pregnancy. Furthermore, an elective pregnancy termination is not necessary due to systemic therapy of psoriasis with many further substances during the first pregnancy weeks. The current work provides a comprehensive review of the scientific literature on treatment of psoriasis during pregnancy and lactation. Based on the available scientific information, severity of psoriasis and patient's comorbidities, the best possible therapeutic approach can be found in consensus with the patient.

Generalized pustular psoriasis: overview of the status quo and results of a panel discussion.

Generalized pustular psoriasis (GPP) is a rare, severe, potentially life-threatening, autoinflammatory, neutrophilic skin disease that may be accompanied by fever and leukocytosis. This paper describes the current state of knowledge on GPP in terms of classification, (differential) diagnosis and prevalence. We present a comparison of the genetics and pathoimmunology of GPP and psoriasis vulgaris with the central mechanisms of autoimmunology and autoinflammation. The currently available therapeutic options, expert recommendations for therapy, and data from early clinical trials investigating targeted therapies will be summarized. We present the results of our discussion with 13 experts for psoriasis vulgaris and GPP and give an integrated overview of indication and therapy based on our personal experience and present an outlook on further research questions. Collectively, this article highlights the high unmet need in GPP, as there exists no satisfactory method of diagnosis or treatment to date and new treatment options will be of great therapeutic benefit to those affected.

Drug survival in the treatment of generalized pustular psoriasis: A retrospective multicenter study.

Generalized pustular psoriasis (GPP) is a rare, potentially life-threatening inflammatory skin disease. Our aim was to assess patient and disease characteristics and analyze drug survival rates in the treatment of GPP in a real-life setting. In this retrospective study, 201 treatment series of 86 patients with GPP treated at five University Medical Centers were analyzed. Overall, excellent response was reached in 41.3% of all treatment courses, partial response in 31.4%, and nonresponse in 27.3%. Biological treatment was significantly more effective than non-biological therapies (excellent response: 47.4% vs 35.9%; P = .02). Overall, the median drug survival was 14.0 months (biologicals: 36.0 months vs nonbiologicals: 6.0 months; P < .001). The crude probability of survival was highest for secukinumab (hazard ratio [HR] of drug discontinuation compared with acitretin: 0.22), followed by ixekizumab and ustekinumab (HR: 0.38 each), adalimumab (HR: 0.59), etanercept (HR: 0.62), infliximab (HR: 0.69), cyclosporine (HR: 1.00), acitretin (reference for HR), fumaric acid esters (HR: 1.06), methotrexate (HR: 1.26), and apremilast (HR: 3.44); no drug discontinuation with guselkumab. Our results reveal high efficacy and drug survival, particularly for IL-17 and IL-(12)/23 antagonists. Thus, these biologics may be considered early in the therapeutic algorithm of GPP.

[Treatment of psoriasis with secukinumab : Practical guidance]. / Behandlung der Psoriasis mit Secukinumab : Praxisrelevante Hinweise.

BACKGROUND: Moderate to severe plaque psoriasis can be treated effectively with immunomodulating biologicals such as the interleukin-17A inhibitor secukinumab. In practice, however, questions often arise as to how to proceed in special situations, such as infections, comorbidity, pregnancy, or surgery. OBJECTIVES: To address frequent questions about the treatment of plaque psoriasis with secukinumab in a consensus document of German psoriasis experts that supplements current guidelines. METHODS: In a virtual expert meeting in May 2020, practical aspects of the treatment of psoriasis were discussed based on the experience of the participants and on current literature. The results of this discussion were summarized in the present consensus document. RESULTS: This article provides practical guidance on case history, documentation of previous therapies, severity of psoriasis, and comorbidities before starting therapy with secukinumab. For patients treated with secukinumab, the course of action in case of vaccinations, chronic or acute infections, surgical interventions, special manifestations of psoriasis, and comorbidities including history of cancer and autoimmune disorders is discussed. Questions regarding family planning and health policy regulations are also addressed. DISCUSSION: The recommendations for the treatment of psoriasis with secukinumab summarized in this consensus document may contribute to achieve optimal therapy for patients and to improve their quality of life.

Screening for depression in psoriasis patients during a dermatological consultation: A first step towards treatment.

BACKGROUND AND OBJECTIVES: Depression is a highly prevalent comorbidity in psoriatic patients. The aim of this prospective study was to follow up psoriasis patients at risk for depression and to evaluate individual pathways to mental health care and the efficacy of depression screening in a real-life setting. PATIENTS AND METHODS: In this prospective multicenter study, 355 patients with psoriasis were screened for depressive symptoms with the revised Beck Depression Inventory (BDI-II). General practitioners of patients at risk for depression were asked for further evaluation. One year later, information on mental health care provision was gathered. RESULTS: 130 patients were screened positive for depressive symptoms, and 71 patients were followed-up (follow-up rate: 54.6 %). Psychiatric treatment was recommended for 28.2 % and accepted by 23.9 % of patients. Parameters of disease activity of psoriasis (PASI: 3.1, ∆: -1.7, P = 0.018), quality of life (Dermatology Life Quality Index [DLQI]: 6.5, ∆: -2.8, P = 0.005), and depressive symptoms (BDI-II: 13.2, ∆: -8.3, P < 0.001) improved significantly. Decrease of the BDI-II score was more pronounced in patients with higher PASI decrease. CONCLUSIONS: Screening for depressive symptoms led to increased utilization of mental health care and improvement of psoriasis, depressive symptoms, and quality of life. Thus, such screening should be implemented in routine care to optimize patient management.

Establishment and validation of a didactic musculoskeletal ultrasound course for dermatologists using an innovative handheld ultrasound system - the MUDE study (Musculoskeletal Ultrasound in Dermatology).

BACKGROUND: In the early detection of arthritis, such as psoriatic arthritis, musculoskeletal ultrasound (MSUS) of painful joints plays an important role in diagnosis. Pathological findings can be missed during clinical examination, especially if conducted by physicians who are not trained. The objective of this study was to examine a pilot MSUS course designed specifically for dermatologists, the MUDE protocol. METHODS: To assess the degree of MSUS expertise of the participants, a questionnaire using SurveyMonkey® was completed before the course. The course concept covered only the most important ultrasound sections of all joints and focused on the detection of joint effusion and hyperperfusion. The course consisted of three modules and was carried out over six months. The portable Butterfly IQ® system in combination with an Apple iPad was provided to enable practice between the courses. The final teaching evaluation was carried out as an objective structured clinical examination (OSCE). RESULTS: Twelve dermatologists participated. The survey revealed no prior knowledge of MSUS. The overall score of all participants in the OSCE was 21.86 (87.44 %) out of a total of 25 points, which corresponded to the school grade good. CONCLUSION: The innovative MUDE protocol is thus particularly suitable for the training of dermatologists in MSUS, irrespective of prior knowledge.

Etablierung und Validierung eines didaktischen muskuloskelettalen Ultraschallkurses für Dermatologen unter Verwendung eines innovativen Hand-Ultraschallsystems - die MUDE-Studie (Muskuloskelettaler Ultraschall für Dermatologen).

HINTERGRUND: Der muskuloskelettale Ultraschall (MSUS) schmerzhafter Gelenke spielt bei der Früherkennung der Arthritis, wie zum Beispiel der Psoriasisarthritis, eine wichtige Rolle. Pathologische Befunde können bei der klinischen Untersuchung übersehen werden, insbesondere wenn sie von Ärzten durchgeführt werden, die nicht in der Durchführung geschult sind. Das Ziel dieser Studie war die Untersuchung eines Pilot-MSUS-Kurses anhand des MUDE-Protokolls, welches speziell für Dermatologen entwickelt wurde. METHODIK: Um den Grad der MSUS-Expertise der Teilnehmer zu ermitteln, wurde vor dem Kurs eine Umfrage mittels SurveyMonkey® durchgeführt. Das Kurskonzept umfasste nur die wichtigsten Ultraschallschnitte aller Gelenke und konzentrierte sich auf die Erkennung von Gelenkergüssen und Hyperperfusion der Synovia. Der Kurs bestand aus drei Modulen und wurde über sechs Monate durchgeführt. Das tragbare Butterfly IQ® System in Kombination mit einem Apple iPad wurde allen Teilnehmern zur Verfügung gestellt, um das Üben zwischen den Kursen zu ermöglichen. Die abschließende Lehrevaluation wurde als objective structured clinical examination (OSCE) durchgeführt. ERGEBNISSE: Zwölf Dermatologen nahmen teil. Die Umfrage ergab keine Vorkenntnisse des MSUS. Die Gesamtpunktzahl aller Teilnehmer in der OSCE betrug 21,86 (87,44 %) von insgesamt 25 Punkten, was der Schulnote "gut" entsprach. SCHLUSSFOLGERUNG: Das innovative Lehrkonzept MUDE eignet sich somit, unabhängig von Vorkenntnissen, in besonderer Weise für die Ausbildung von Dermatologen im MSUS.

Documentation of psoriasis in routine care - expert consensus on a German data set.

BACKGROUND AND OBJECTIVES: Documenting patient data in psoriasis clinical practice can improve care, but standardized and transparent documentation is rare. The current project aimed to develop a data set for the documentation of psoriasis in daily practice. MATERIAL AND METHODS: In four online Delphi rounds and one in-person meeting, 27 psoriasis experts allocated variables to a standard, an optimal and an optional data set. Most of the questions were standardized. Open questions were included to allow for the provision of reasons and to enlarge the data sets. Furthermore, in the in-person meeting we considered a) patients' attitudes and b) dermatologists' information on the current usage and acceptability in Germany. RESULTS: The consensus approach resulted in a data set with 69 variables. The standard data set includes 20, the optimal data set 31 and the optional data set 18 variables. In summary, the data set can mainly be grouped into master data, general status and medical history data, medical history of psoriasis, status of psoriasis, diagnostics and comorbidity, therapies and patient-reported outcomes. CONCLUSIONS: The consensus recommendation of a standard, an optimal and an optional data set for routine care of psoriasis intends to be a decision-making aid and an orientation for both daily practice and further development of documentation systems.

Two questions may be enough - screening for depression in patients with psoriasis: a multicenter study.

BACKGROUND: Depression is frequently underdiagnosed and insufficiently treated in psoriatic patients in their daily routine. The aim of this study was to screen and analyze the impact of patient and disease characteristics on depression scores. PATIENTS AND METHODS: In this cross-sectional multicenter cohort study, adult psoriasis patients were screened for depression with two validated tools: the Whooley questions and the revised Beck Depression Inventory (BDI-II). RESULTS: Overall, 538 patients (median PASI 3.0, mean DLQI 5.3) were screened for depressive symptoms (mean BDI-II score 8.3). 24.2 % of all participants reached a BDI-II score ≥ 13, suggesting a depression that was at least mild. The results of the Whooley questions were positive for 28.2 % of the patients. There was a strong correlation between the two tools (p < 0.001). In the subgroup with a BDI-II score ≥ 13, disease activity (median PASI 3.8 vs. 2.8, p = 0.06) and DLQI scores (mean 10.1 vs. 3.7, p < 0.0001) were higher, and psoriatic arthritis and diabetes were more prevalent (52.6 % vs. 37.8 %, p = 0.002, and 16.2 % vs. 10.0 %, p = 0.04, respectively) than in the subgroup with a BDI-II score < 13. CONCLUSIONS: In specialized psoriatic outpatient clinics, a BDI-II score ≥ 13 was present in almost every fourth patient despite a low median PASI. The Whooley questions might be easy to use as a screening tool for depression in psoriasis patients.

Diagnosis and treatment of xerosis cutis - a position paper.

BACKGROUND AND RATIONALE: Xerosis cutis (also referred to as xeroderma, dry skin, asteatosis) affects more than 10 million individuals in Germany. It is among the most common dermatological diagnoses and a cardinal symptom of many dermatological, internal and neurological diseases. Even though it has been established that basic skin care plays a significant role in the management of patients with xerosis cutis, there are as yet no evidence-based algorithms for diagnosis and treatment. OBJECTIVE: The present position paper provides physicians across all specialties with a practical, symptom-based approach to the prevention, diagnosis and treatment of xerosis cutis. METHODS: Within a structured decision-making process, a panel of experienced dermatologists first defined questions relevant to everyday clinical practice, which were then addressed by a systematic review of the literature. Based on the evidence available as well as expert consensus, diagnostic and treatment algorithms were subsequently developed and agreed upon. RESULTS: Xerosis cutis is generally diagnosed on clinical grounds. Possible trigger factors must be avoided, and comorbidities should be adequately and specifically treated. Suitable skin care products should be chosen with a view to improving skin hydration and restoring its barrier function. They should therefore contain both rehydrating and lipid-replenishing components. The "drier" the skin appears, the greater the lipid content should be (preferably using water-in-oil formulations). The choice of ingredients is based on a patient's individual symptoms, such as scaling (e.g., urea), fissures/rhagades (e.g., urea or dexpanthenol), erythema (e.g., licochalcone A) and pruritus (e.g., polidocanol). Other factors to be considered include the site affected and patient age. Ingredients or rather combinations thereof for which there is good clinical evidence should be preferentially used. The best evidence by far is available for urea, whose efficacy in the treatment of xerosis is further enhanced by combining it with other natural moisturizing components and ceramides. The "xerosimeter" is a tool developed in an effort to facilitate patient management and for training purposes. It not only includes practical tools for diagnosis and follow-up but also a classification of ingredients and a structured treatment algorithm. CONCLUSION: The structured symptom- and evidence-based approach proposed herein contains a road map for diagnosis and treatment of xerosis cutis. It aims to raise awareness in terms of prevention and early treatment of this condition and may thus improve quality of life and prevent potential sequelae.

Drug survival and reasons for drug discontinuation in palmoplantar pustulosis: a retrospective multicenter study.

BACKGROUND: Palmoplantar pustulosis (PPP) is a chronic inflammatory skin disease-related to psoriasis. Its treatment is challenging, and little is known about the sustainability of different medications. The aim of this study was to analyze drug survival rates and drug discontinuation in the treatment of PPP under real-world conditions. PATIENTS AND METHODS: Patients with PPP treated in the dermatology departments of five German university medical centers between 01/2005 and 08/2017 were included in our retrospective study. Drug survival of systemic therapies was assessed with Kaplan-Meier analysis and multivariate regression. RESULTS: Overall, 347 patients with 935 treatment courses were identified. Within the group of non-biologic systemic agents, apremilast showed the highest median drug survival (15 months), followed by cyclosporine (12 months), the combination of acitretin and topical PUVA (9 months), MTX (8 months), acitretin monotherapy (6 months), alitretinoin (5 months), and fumaric acid esters (3 months). Among biologicals, the highest maintenance rate was detected for certolizumab pegol (restricted mean: 47.4 months), followed by infliximab (median: 26 months), golimumab (22 months), ustekinumab (21 months), adalimumab (18 months), secukinumab (9 months), and etanercept (8 months). CONCLUSIONS: Biologicals and apremilast may serve as second-line options for treatment of PPP and should be further evaluated.

An intensified dosing schedule of subcutaneous methotrexate in patients with moderate to severe plaque-type psoriasis (METOP): a 52 week, multicentre, randomised, double-blind, placebo-controlled, phase 3 trial.

BACKGROUND: Methotrexate is one of the most commonly used systemic drugs for the treatment of moderate to severe psoriasis; however, high-quality evidence for its use is sparse and limited to use of oral dosing. We aimed to assess the effect of an intensified dosing schedule of subcutaneous methotrexate in patients with moderate to severe plaque-type psoriasis. METHODS: We did this prospective, multicentre, randomised, double-blind, placebo-controlled, phase 3 trial (METOP) at 16 sites in Germany, France, the Netherlands, and the UK. Eligible patients were aged 18 years or older, had a diagnosis of chronic plaque psoriasis for at least 6 months before baseline, had currently moderate to severe disease, and were methotrexate treatment-naive. Participants were randomly assigned (3:1), via a computer-generated random number sequence integrated into an electronic data capture system, to receive either methotrexate at a starting dose of 17·5 mg/week or placebo for the first 16 weeks, followed by methotrexate treatment of all patients up to 52 weeks (methotrexate-methotrexate vs placebo-methotrexate groups). Dose escalation to 22·5 mg/week was allowed after 8 weeks of methotrexate treatment if patients had not achieved at least a 50% reduction in baseline Psoriasis Area and Severity Index score (PASI), with corresponding volume increases in placebo injections. Treatment was combined with folic acid 5 mg/week. Group allocation was concealed from participants and investigators from the time of randomisation until an interim database lock at week 16, and was open label from week 16 onwards, with no masking of participants or investigators. The primary efficacy endpoint was a 75% reduction in PASI score (PASI 75) from baseline to week 16. We did analysis by modified intention to treat, with non-responder imputation. This study is registered with EudraCT, number 2012-002716-10. FINDINGS: Between Feb 22, 2013, and May 13, 2015, we randomly assigned 120 patients to receive methotrexate (n=91) or placebo (n=29). At week 16, a PASI 75 response was achieved in 37 (41%) patients in the methotrexate group compared with three (10%) patients in the placebo group (relative risk 3·93, 95% CI 1·31-11·81; p=0·0026). Subcutaneous methotrexate was generally well tolerated; no patients died or had serious infections, malignancies, or major adverse cardiovascular events. Serious adverse events were recorded in three (3%) patients who received methotrexate for the full 52 week treatment period. INTERPRETATION: Our findings show a favourable 52 week risk-benefit profile of subcutaneous methotrexate in patients with psoriasis. The route of administration and the intensified dosing schedule should be considered when methotrexate is used in this patient group. FUNDING: Medac.