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Deficiencies in methods reporting in animal experimentation lead to difficulties in reproducing experiments; the authors propose a set of reporting standards to improve scientific communication and study design. Making the most of animal studies Animal studies have contributed immensely to our understanding of diseases and assist the development of new therapies, but inadequate experimental reporting can sometimes render such studies difficult to reproduce and to translate into the clinic. This year, a US National Institute of Neurological Disorders and Stroke workshop addressed this issue, and its conclusions are discussed in a Perspective piece in this issue of Nature . The main workshop recommendation is that at a minimum, studies should report on randomization, blinding, sample-size estimation and how the data were handled. The US National Institute of Neurological Disorders and Stroke convened major stakeholders in June 2012 to discuss how to improve the methodological reporting of animal studies in grant applications and publications. The main workshop recommendation is that at a minimum studies should report on sample-size estimation, whether and how animals were randomized, whether investigators were blind to the treatment, and the handling of data. We recognize that achieving a meaningful improvement in the quality of reporting will require a concerted effort by investigators, reviewers, funding agencies and journal editors. Requiring better reporting of animal studies will raise awareness of the importance of rigorous study design to accelerate scientific progress.

BackgroundGuselkumab is an interleukin (IL)-23 pathway blocker with proven efficacy in patients with moderate-to-severe plaque psoriasis. Early intervention with guselkumab may result in changes to the clinical disease course versus later intervention.Methods and analysisHere we present the rationale and design of a phase 3b, randomised, double-blind, multicentre study (GUIDE), comparing treatment effects of guselkumab in patients with short (≤2 years) or longer (>2 years) duration of plaque-type psoriasis, measured from first appearance of psoriatic plaques. Participants achieving skin clearance (Psoriasis Area and Severity Index (PASI)=0) by week 20 and maintaining complete clearance at week 28 visit (‘super-responders’ (SRe)) will be randomised to continue approved maintenance dosing every 8 weeks (q8w) versus an investigational maintenance dosing interval of 16 weeks (q16w) until week 68. Primary endpoint: proportion of participants in the q8w vs q16w arms with absolute PASI <3 at week 68. Participants with PASI <3 at week 68 will be withdrawn from guselkumab treatment for up to 48 weeks. Participants not achieving SRe criteria (non-SRe) will remain in the study with q8w guselkumab dosing through week 68. Additional to serum samples obtained from all patients, skin biopsies and whole-blood samples will be taken from SRe and non-SRe participants at various time points in optional substudies. Analyses include: genetics; immunophenotyping (fluorescence-activated cell sorting); gene and protein expression profiling; immunohistology. By merging clinical endpoints with mechanistic findings, this study aims to elucidate how IL-23 blockade with guselkumab can modify the disease course by altering molecular and cellular drivers that cause relapse after treatment withdrawal, particularly among SRe.Ethics and disseminationApproval obtained from ethics committee Medical Council Hamburg, Germany (PVN5925). GUIDE is compliant with the Declaration of Helsinki.Trial registration numberRegistered at ClinicalTrials.gov (NCT03818035). All primary endpoint results (prespecified analyses) will be submitted to peer-reviewed, international journals within 18 months after primary completion date.

Psoriasis is a common chronic inflammatory disease with characteristic skin alterations and functions as a model of immune-mediated disorders. Cytokines have a key role in psoriasis pathogenesis. Here, we demonstrated that out of 30 individually quantified cytokines, IL-19 showed the strongest differential expression between psoriatic lesions and healthy skin. Cutaneous IL-19 overproduction was reflected by elevated IL-19 blood levels that correlated with psoriasis severity. Accordingly, anti-psoriatic therapies substantially reduced both cutaneous and systemic IL-19 levels. IL-19 production was induced in keratinocytes by IL-17A and was further amplified by tumor necrosis factor-α and IL-22. Among skin cells, keratinocytes were found to be important targets of IL-19. IL-19 alone, however, regulated only a few keratinocyte functions. While increasing the production of S100A7/8/9 and, to a moderate extent, also IL-1β, IL-20, chemokine C-X-C motif ligand 8, and matrix metalloproteinase 1, IL-19 had no clear influence on the differentiation, proliferation, or migration of these cells. Importantly, IL-19 amplified many IL-17A effects on keratinocytes, including the induction of β-defensins, IL-19, IL-23p19, and T helper type 17-cell- and neutrophil-attracting chemokines. In summary, IL-19 as a component of the IL-23/IL-17 axis strengthens the IL-17A action and might be a biomarker for the activity of this axis in chronic inflammatory disorders.

Background Patients with psoriasis often suffer from obesity. However, only limited data are available on the efficacy of brodalumab 210 mg, a fully human monoclonal immunoglobulin IgG2 antibody binding to the human interleukin 17 receptor subunit A, in obese patients in daily practice, to date. Objectives A subgroup analysis from the LIBERO study was conducted to compare the effectiveness of brodalumab in patients weighing ≤100 and >100 kg after ~12 weeks (W) and ~52 W. Methods LIBERO is a large prospective, multicenter, non‐interventional, real‐world‐evidence study including adult patients with plaque psoriasis treated with brodalumab 210 mg. Results Four hundred and sixty‐one patients with a body weight up to 100 kg (nonobese) and 161 patients with >100 kg body weight (obese) were included in this subgroup analysis. At baseline, the majority of patients in both groups had very severe (12.6%; 15.7%) or severe (49.4%; 55.0%) psoriasis, as assessed by Physician Global Assessment (PGA). As of W2, a significant reduction of the mean PASI could be achieved in both groups. In patients weighing ≤100 kg mean PASI decreased from 16.9 to 9.0 and further improved to 2.6 at ~W12 (p < 0.001). In the patient group >100 kg, the PASI decreased from 17.9 to 10.2 at ~W2 (p < 0.001) and improved further to 3.9 at ~W12 (p < 0.001). However, at ~W12 absolute PASI0‐3 rates were lower in patients >100 kg than in patients ≤100 kg (68.4% vs. 80.5%, p = 0.006); there was no statistically significant difference between the groups at ~W52/last visit any more in any of the effectiveness parameters with, for example, a PGA0/1 response of 82.3% versus 86.5% (p = 0.6089), respectively. Conclusions This subgroup analysis of LIBERO confirmed, that in daily practice brodalumab can be equally beneficial patients with >100 and ≤100 kg in the long‐term management of psoriasis.

Glucocorticoids (GCs) are the most commonly used antiinflammatory and immunosuppressive drugs. Their outstanding therapeutic effects, however, are often accompanied by severe and sometimes irreversible side effects. For this reason, one goal of research in the GC field is the development of new drugs, which show a reduced side-effect profile while maintaining the antiinflammatory and immunosuppressive properties of classical GCs. GCs affect gene expression by both transactivation and transrepression mechanisms. The antiinflammatory effects are mediated to a major extent via transrepression, while many side effects are due to transactivation. Our aim has been to identify ligands of the GC receptor (GR), which preferentially induce transrepression with little or no transactivating activity. Here we describe a nonsteroidal selective GR-agonist, ZK 216348, which shows a significant dissociation between transrepression and transactivation both in vitro and in vivo. In a murine model of skin inflammation, ZK 216348 showed antiinflammatory activity comparable to prednisolone for both systemic and topical application. A markedly superior side-effect profile was found with regard to increases in blood glucose, spleen involution, and, to a lesser extent, skin atrophy; however, adrenocorticotropic hormone suppression was similar for both compounds. Based on these findings, ZK 216348 should have a lower risk, e.g., for induction of diabetes mellitus. The selective GR agonists therefore represent a promising previously undescribed class of drug candidates with an improved therapeutic index compared to classical GCs. Moreover, they are useful tool compounds for further investigating the mechanisms of GR-mediated effects.

Hidradenitis suppurativa (HS) is a painful and disfiguring chronic inflammatory skin disease. Despite many efforts over the past decade to improve the care of patients with HS, their satisfaction with medical care remains limited. The aim of this study was to assess the perceived involvement of patients with HS and, for comparison, patients with psoriasis, in treatment decision-making and to identify areas associated with positive perception. A prospective, cross-sectional, questionnaire-based survey was conducted between May 2023 and July 2024 in different types of dermatological care facilities in Germany. Patients rated their therapy decision involvement and treatment satisfaction on a 0-10 scale. Data were stratified by demographic, clinical, and healthcare-related variables. 124 HS patients and 133 psoriasis patients completed the questionnaires. The percentage of HS patients rating their therapy decision involvement as low (values of 0-5) was 27.2%, while the percentage of psoriasis patients who gave the same assessment was 11.9% ( < 0.01). Moreover, the average degree of perceived therapy decision involvement was significantly lower for patients with HS compared to psoriasis patients (mean ± SD: 7.0 ± 2.9 vs. 8.4 ± 2.1; < 0.001). Greater involvement in therapy decisions was linked to higher satisfaction of patients with the therapies received ( < 0.01). Younger HS patients (18-40 years) reported lower involvement scores ( < 0.01), while gender, education level, disease duration, disease severity, number of comorbidities, type of healthcare facility, and type of therapies undergone had no influence. Extended consultation times with the dermatologist (≥20 min; < 0.05) and more than one quarterly visit to the dermatologist ( < 0.01) were marginally associated with greater patient involvement in decision-making, but did not explain the difference between patients with HS and psoriasis in this regard. Waiting time until first visit to a dermatologist (negative association, < 0.01) and, more strongly, satisfaction with information provided by the dermatologist about patient's skin disease (positive association, < 0.001) were associated with patient involvement in therapy decision and were significantly different in patients with HS vs. psoriasis. This study shows limited involvement of HS patients in the therapy decision-making process, which was associated with low treatment satisfaction. Improvement may be achieved by training dermatologists in disease mechanisms and patient communication.

The mechanism of immunodepression after brain injury is not yet clear. Here we demonstrate rapid systemic release of the immunoinhibitory cytokine interleukin-10, monocytic deactivation and a high incidence of infection in patients with ‘sympathetic storm’ due to acute accidental or iatrogenic brain trauma. In vitro studies showed that within minutes catecholamines trigger the secretion of interleukin-10 from unstimulated monocytes through a β-adrenoreceptor-mediated, cAMP/protein kinase A-dependent pathway. We found that in a rat model of acute brain injury, the βreceptor antagonist propranolol prevented the increase of interleukin-10 plasma levels. Rapid monocytic interleukin-10 release after sympathetic activation may represent a common pathway for immunodepression induced by stress and injury.

Topical glucocorticoids are highly anti-inflammatory effective but limited by their side effect potential, with skin atrophy being the most prominent one. Thus, determining the atrophogenic potential of novel compounds targeting the glucocorticoid receptor is important. Significant progress in the understanding of glucocorticoid receptor mediated molecular action has been made providing the basis for novel glucocorticoid receptor ligands with a potentially superior effect/side effect profile. Such compounds, however, need to be tested. The present gold standard for the reliable prediction of glucocorticoid induced skin atrophy are still in vivo models, however, in vitro models may replace them to some extent in the future. Indeed, advances in technologies to determine the atrophogenic potential of compounds in vitro has been made recently and promising novel test models like the human full thickness skin models are emerging. Their full predictive value, however, needs to be further evaluated. Currently, a screening approach starting with a combination of several in vitro test systems followed by subsequent testing of the most promising compounds in rodent models is recommended prior entering clinical studies with selected development compounds.

Fumarates (fumaric acid esters, FAEs) are orally administered systemic agents used for the treatment of psoriasis and multiple sclerosis. In 1994, a proprietary combination of FAEs was licensed for psoriasis by the German Drug Administration for use within Germany. Since then, fumarates have been established as one of the most commonly used treatments for moderate-to-severe psoriasis in Germany and other countries. The licensed FAE formulation contains dimethyl fumarate (DMF), as well as calcium, zinc, and magnesium salts of monoethyl fumarate (MEF). While the clinical efficacy of this FAE mixture is well established, the combination of esters on which it is based, and its dosing regimen, was determined empirically. Since the mid-1990s, the modes of action and contribution of the different FAEs to their overall therapeutic effect in psoriasis, as well as their adverse event profile, have been investigated in more detail. In this article, the available clinical data for DMF are reviewed and compared with data for the other FAEs. The current evidence substantiates that DMF is the main active compound, via its metabolic transformation to monomethyl fumarate (MMF). A recent phase III randomized and placebo-controlled trial including more than 700 patients demonstrated therapeutic equivalence when comparing the licensed FAE combination with DMF alone, in terms of psoriasis clearance according to the Psoriasis Area and Severity Index (PASI) and Physician’s Global Assessment (PGA). Thus, DMF as monotherapy for the treatment of psoriasis is as efficacious as in combination with MEF, making the addition of such fumarate derivatives unnecessary.