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.

ABSTRACT. The framework for analyzing sustainability of social-ecological systems (SES) framework of Elinor Ostrom is a multitier collection of concepts and variables that have proven to be relevant for understanding outcomes in diverse SES. The first tier of this framework includes the concepts resource system (RS) and resource units (RU), which are then further characterized through lower tier variables such as clarity of system boundaries and mobility. The long-term goal of framework development is to derive conclusions about which combinations of variables explain outcomes across diverse types of SES. This will only be possible if the concepts and variables of the framework can be made operational unambiguously for the different types of SES, which, however, remains a challenge. Reasons for this are that case studies examine other types of RS than those for which the framework has been developed or consider RS for which different actors obtain different kinds of RU. We explore these difficulties and relate them to antecedent work on commonpool resources and public goods. We propose a diagnostic procedure which resolves some of these difficulties by establishing a sequence of questions that facilitate the step-wise and unambiguous application of the SES framework to a given case. The questions relate to the actors benefiting from the SES, the collective goods involved in the generation of those benefits, and the action situations in which the collective goods are provided and appropriated. We illustrate the diagnostic procedure for four case studies in the context of irrigated agriculture in New Mexico, common property meadows in the Swiss Alps, recreational fishery in Germany, and energy regions in Austria. We conclude that the current SES framework has limitations when applied to complex, multiuse SES, because it does not sufficiently capture the actor interdependencies introduced through RS and RU characteristics and dynamics.

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.

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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.

B-cell and T-cell pseudoclones are not uncommonly encountered in moderately dense pseudolymphomatous infiltrates (23% and 13%, respectively). B-cell clonality is seen occasionally in pseudolymphomatous infiltrates (13%), especially when they are sparse in B lymphocytes. Therefore, rearrangement studies cannot be interpreted without correlation with morphological patterns and immunophenotyping of infiltrates and they need to be confirmed by duplicate or triplicate tests in order to prevent overinterpretation.

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In biopsy specimens taken from herpes virus infections, involvement of follicular units is more commonly encountered in VZV infections compared with HSV infections. Early in the course, herpes folliculitis presents as lymphocytic folliculitis devoid of epithelial changes considered to be diagnostic of herpes virus infections. Exclusive involvement of follicles is rather typical of zoster.