Long-Term Treatment with Dimethyl Fumarate for Plaque Psoriasis in Routine Practice: Good Overall Effectiveness and Positive Effect on Impactful Areas.

INTRODUCTION: Dimethyl fumarate (DMF) is an oral compound to treat plaque psoriasis. Data on the treatment of patients with psoriasis affecting impactful areas are scarce. In this interim analysis of the prospective, noninterventional SKILL study, we summarized results of DMF treatment regarding effectiveness (overall and in impactful areas) and safety. METHODS: Data from 676 patients suffering from moderate-to-severe plaque psoriasis were analyzed after 52 weeks of DMF treatment. Of these, 257 had data available after 52 weeks. The considered impactful areas were nails, palms, soles, and scalp. Data analysis included observed cases (OC) and last observation carried forward (LOCF). RESULTS: All effectiveness parameters improved after 52 weeks. The Psoriasis Area and Severity Index score was reduced by 79.5% (OC) and 65.7% (LOCF). Compared with baseline, improvements were shown for 70.2% of the patients in their nail psoriasis [nail-Physician Global Assessment (PGA)] and for 57.3% in palmoplantar disease (palmoplantar-PGA). The proportion of patients with scalp-PGA 0/1 (clear/almost clear) increased significantly to 79.8% (OC) and 69.3% (LOCF, both p < 0.001) (versus 37.5% and 36.6% at baseline, respectively). Significant reduction of pruritus (p < 0.001) was also observed. No unexpected adverse drug reactions were observed. CONCLUSION: Long-term treatment with DMF in routine practice showed good overall effectiveness and safety, and a positive effect on plaque-psoriasis-affected impactful areas.

IL-23 blockade with guselkumab potentially modifies psoriasis pathogenesis: rationale and study protocol of a phase 3b, randomised, double-blind, multicentre study in participants with moderate-to-severe plaque-type psoriasis (GUIDE).

BACKGROUND: Guselkumab 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 ANALYSIS: Here 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 DISSEMINATION: Approval obtained from ethics committee Medical Council Hamburg, Germany (PVN5925). GUIDE is compliant with the Declaration of Helsinki. TRIAL REGISTRATION NUMBER: Registered 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.

Immunotherapy in psoriasis.

Over the past two decades, significant progress has been achieved in the treatment of psoriasis by targeting the human cytokine network. At present, 11 biologicals - antibodies, and a soluble receptor - are used to neutralize key inflammatory cytokines. Based on their targets, they can be grouped into the following four classes: TNF-α-, IL-12/23-, IL-17- and IL-23-inhibitors. The range of available substances, as well as their different modes of action can be challenging when selecting the right drug for an individual patient. In this article, we provide an overview of the approved biologicals for the treatment of psoriasis, including their advantages and limitations, and summarize criteria for therapy selection.

Cytokines of the IL-17 family in psoriasis.

Various immune cells and their messenger substances influence the development of psoriasis. Cytokines of the IL-17 family are of particular importance. In addition to IL-17A, which plays a central role in the pathogenesis of psoriasis, other subtypes of the IL-17 family also have a proinflammatory effect. This review provides an up-to-date overview of the immunopathogenesis of psoriasis with regard to the six IL-17 subtypes, in particular their physiological and pathogenic properties, as well as their significance for psoriasis therapy.

Dimethyl fumarate (DMF) vs. monoethyl fumarate (MEF) salts for the treatment of plaque psoriasis: a review of clinical data.

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.

Biomarkers and personalized medicine: current status and further perspectives with special focus on dermatology.

Biomarkers are of increasingly high importance in medicine, particularly in the realm of 'personalized medicine'. They are valuable for predicting prognosis and dose selection. Moreover, they may be helpful in detecting therapeutic and adverse responses and in patient stratification based on efficacy or safety prediction. Thus, biomarkers are essential tools for the selection of appropriate patients for treatment with certain drugs to and enable personalized medicine, that is 'providing the right treatment to the right patient, at the right dose at the right time'. Currently, there are six drugs approved for dermatological indications with recommended or mandatory biomarker testing. Most of them are used to treat melanoma and human immunodeficiency virus infection. In contrast to the few fully validated biomarkers, many exploratory biomarkers and biomarker candidates have potential applications. Prognostic biomarkers are of particular significance for malignant conditions. Similarly, diagnostic biomarkers are important in autoimmune diseases. Disease severity biomarkers are helpful tools in the treatment for inflammatory skin diseases. Identification, qualification and implementation of the different kinds of biomarkers are challenging and frequently necessitate collaborative efforts. This is particularly true for stratification biomarkers that require a companion diagnostic marker that is co-developed with a certain drug. In this article general definitions and requirements for biomarkers as well as for the impact of biomarkers in dermatology are reviewed and opportunities and challenges are discussed.

Industry-academia collaborations for biomarkers.

Several types of collaboration are being pursued to identify, validate and apply new biomarkers. Here, we highlight examples of such initiatives and discuss the challenges, approaches to address these challenges and key factors for success.

IL-19 is a component of the pathogenetic IL-23/IL-17 cascade in psoriasis.

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-1ß, 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 ß-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.

A call for transparent reporting to optimize the predictive value of preclinical research.

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.

What makes a good drug target?

Novel therapeutics in areas with a high unmet medical need are based on innovative drug targets. Although 'biologicals' have enlarged the space of druggable molecules, the number of appropriate drug targets is still limited. Discovering and assessing the potential therapeutic benefit of a drug target is based not only on experimental, mechanistic and pharmacological studies but also on a theoretical molecular druggability assessment, an early evaluation of potential side effects and considerations regarding opportunities for commercialization. This article defines key properties of a good drug target from the perspective of a pharmaceutical company.

Test systems for the determination of glucocorticoid receptor ligand induced skin atrophy.

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.

Willingness to Donate Human Samples for Establishing a Dermatology Research Biobank: Results of a Survey.

There is a rising need for biomaterial in dermatological research with regard to both quality and quantity. Research biobanks as organized collections of biological material with associated personal and clinical data are of increasing importance. Besides technological/methodological and legal aspects, the willingness to donate samples by patients and healthy volunteers is a key success factor. To analyze the theoretical willingness to donate blood and skin samples, we developed and distributed a questionnaire. Six hundred nineteen questionnaires were returned and analyzed. The willingness to donate samples of blood (82.5%) and skin (58.7%) is high among the population analyzed and seems to be largely independent of any expense allowance. People working in the healthcare system, dermatological patients, and higher qualified individuals seem to be in particular willing to donate material. An adequate patient insurance as well as an extensive education about risks and benefits is requested. In summary, there is a high willingness to donate biological samples for dermatological research. This theoretical awareness fits well with our own experiences in establishing such a biobank.

What makes a good drug target?

Novel therapeutics in areas with a high unmet medical need are based on innovative drug targets. Although 'biologicals' have enlarged the space of druggable molecules, the number of appropriate drug targets is still limited. Discovering and assessing the potential therapeutic benefit of a drug target is based not only on experimental, mechanistic and pharmacological studies but also on a theoretical molecular druggability assessment, an early evaluation of potential side effects and considerations regarding opportunities for commercialization. This article defines key properties of a good drug target from the perspective of a pharmaceutical company.

Shortened treatment duration of glucocorticoid-induced skin atrophy in rats.

Glucocorticoids (GCs) belong to the most widely used anti-inflammatory drugs at all. However, their topical use is limited by their side effect potential, with skin atrophy being the most prominent one. Thus, determining the atrophogenic potential of novel compounds is of importance for drug development. Currently, the most frequently performed model in the base and pharmaceutical research is the hr/hr rat model of GC-induced skin atrophy that lasts for 19 days. In this study, we analysed statistically skin atrophy experiments retrospectively to ascertain (i) the earliest time-point, at which skin atrophy is significantly induced; and (ii) whether the differences between the GC treatment groups change until the end of the experiment. We show here that the treatment duration of rat skin atrophy models might be reduced to 5 days for economical and ethical reasons.