The response of psoriasis to antibodies targeting the interleukin (IL)-23/IL-17A pathway suggests a prominent role of T-helper type-17 (Th17) cells in this disease. We examined the clinical and immunological response patterns of 100 subjects with moderate-to-severe psoriasis receiving 3 different intravenous dosing regimens of the anti-IL-17A antibody secukinumab (1 × 3 mg/kg or 1 × 10 mg/kg on Day 1, or 3 × 10 mg/kg on Days 1, 15 and 29) or placebo in a phase 2 trial. Baseline biopsies revealed typical features of active psoriasis, including epidermal accumulation of neutrophils and formation of microabscesses in >60% of cases. Neutrophils were the numerically largest fraction of infiltrating cells containing IL-17 and may store the cytokine preformed, as IL-17A mRNA was not detectable in neutrophils isolated from active plaques. Significant clinical responses to secukinumab were observed 2 weeks after a single infusion, associated with extensive clearance of cutaneous neutrophils parallel to the normalization of keratinocyte abnormalities and reduction of IL-17-inducible neutrophil chemoattractants (e.g. CXCL1, CXCL8); effects on numbers of T cells and CD11c-positive dendritic cells were more delayed. Histological and immunological improvements were generally dose dependent and not observed in the placebo group. In the lowest-dose group, a recurrence of neutrophils was seen in some subjects at Week 12; these subjects relapsed faster than those without microabscesses. Our findings are indicative of a neutrophil–keratinocyte axis in psoriasis that may involve neutrophil-derived IL-17 and is an early target of IL-17A-directed therapies such as secukinumab.

Background: We report the study of an intensified dosing schedule of subcutaneous methotrexate (MTX) in patients with moderate-tosevere psoriasis. Methods: In this prospective, double-blind, multicentre phase 3 study (METOP) eligible patients were 18 years or older with a diagnosis of chronic plaque psoriasis at least 6 months before baseline, had a psoriasis area and severity index (PASI) of 10 or more or 10% or greater body-surface area involvement or a dermatology life quality index (DLQI) of 10 or more and were naïve to treatment with MTX. Participants were randomly assigned 3:1 by computer-generated random sequence integrated in the electronic data capture system to receive either MTX at a starting dose of 17.5 mg/week or placebo for the first 16 weeks, followed by openlabel MTX treatment of all patients up to 52 weeks (MTX/MTX and PLC/MTX groups, respectively). Dose escalation to 22.5 mg/week was allowed after 8 weeks of MTX therapy if patients failed to achieve an at least 50% improvement of their baseline PASI (PASI50); blinding was maintained by a corresponding volume increase of placebo injections. Treatment was combined with folic acid 5 mg/week. The primary efficacy endpoint was the proportion of patients achieving a PASI75 response at week 16 analysed by intention to treat with non-responder imputation. This study is registered with the European Medicines Agency, EudraCT number 2012-002716-10. Findings: Between February 2013 and May 2015 120 patients were randomly assigned to receive subcutaneous MTX (n=91) or placebo (n=29). The primary endpoint was met; the PASI75 response rate at week 16 was 41% (n=37) in the MTX group compared to 10% (n=3) in the placebo group [p=0.0026; effect size 30.3% (95% CI 15.3-45.3) MTX vs placebo]. Subcutaneous MTX was generally well tolerated; no cases of serious infections, malignancies, major adverse cardiovascular events or deaths were noted. Serious adverse events were observed in 3 patients started on MTX during the 52-week study period. Interpretation: The study documents a favourable 52-week benefit-risk profile of subcutaneous MTX in psoriasis. The route of administration and the intensified dosing schedule should be considered when using MTX in patients with psoriasis. Role of the funding source (see also below)The study was an investigator-initiated trial supported by a grant from Medac to K.R. Manuscript 2 SummaryBackground: We report the study of an intensified dosing schedule of subcutaneous methotrexate (MTX) in patients with moderate-to-severe psoriasis.

CL seems often to be misdiagnosed clinically in countries where it is not endemic. Histopathologically, CL may be misinterpreted as sarcoidosis, foreign body granuloma, lupoid rosacea and granuloma annulare, especially when Leishmania is not seen microscopically. We suggest that in Northern Europe, PCR for Leishmania-specific DNA should be performed routinely in any granulomatous dermatitis presenting as a single or few nodules on the extremities or face, even when a diagnosis of CL was not considered by the referring clinician.

Background Current clinico-pathological American Joint Committee on Cancer (AJCC) staging of primary cutaneous melanoma is limited in its ability to determine clinical outcome, and complementary biomarkers are not available for routine prognostic assessment. We therefore adapted a gene signature, previously identified in fresh-frozen (FF) melanomas and adjacent stroma, to formalin-fixed paraffin-embedded (FFPE) melanomas. The aim was to develop a gene expression profiling (GEP) score to define patient survival probability at the time of first diagnosis. Methods Expression of 11 FF melanoma signature genes was quantified by reverse transcription polymerase chain reaction in an FFPE melanoma training cohort (n = 125), corresponding to the combined FF melanoma training and validation cohorts. The resulting GEP score was validated technically and clinically in an independent FFPE melanoma cohort (n = 211). All statistical tests were two-sided. Results We identified a prognostic eight-gene signature in the tumor area (tumor and adjacent tissue) of AJCC stage I–III melanomas. A signature-based GEP score correlated with melanoma-specific survival (MSS; Kaplan-Meier analysis: P < .0001) was independent of tumor stage (multivariable regression analysis: P = .0032) and stroma content (<5%–90%) and complemented conventional AJCC staging (receiver operating characteristic curve analysis: area under the curve = 0.91). In the clinical validation cohort, the GEP score remained statistically significant (P = .0131) in a multivariable analysis accounting for conventional staging. The GEP score was technically robust (reproducibility: 93%; n = 84) and clinically useful, as a binary as well as a continuous score, in predicting stage-specific patient MSS. Conclusions The GEP score is a clinically significant prognostic tool, contributes additional information regarding the MSS of melanoma patients, and complements conventional staging.

These recommendations are suitable for standardizing the histopathological diagnosis of malignant melanoma and for providing a common basis for clinical decisions and scientific research.