Definitions of remission in psoriasis: a systematic literature review from the National Psoriasis Foundation.

Psoriasis studies increasingly employ outcomes that indicate complete disease resolution, yet remission and cure are poorly defined for psoriasis. We conducted a systematic literature review to identify definitions of psoriasis remission and cure reported in the literature. Medline, EMBASE, and The Cochrane Central Register of Controlled Trials databases were searched on July 22, 2020, for full-text studies providing definitions for psoriasis remission/cure. Definitions were analysed descriptively for endpoint, time-frame, on/off treatment, patient-reported outcomes, and disease domains. We identified 106 studies that provided 41 unique remission definitions. Most definitions included endpoints based on Psoriasis Area and Severity Index (PASI), such as PASI75 (n = 16 studies), PASI90 (n = 10), PASI100 (n = 10), and PASI of 0 (n = 3), and descriptive endpoints related to 'skin clearance' (n = 18). Few definitions specified time-frame, on/off treatment or other psoriasis-related disease domains. One small consensus-initiative defined drug-free remission for plaque psoriasis by BSA of 0 without any therapy for at least 12 months. While there is no cure for psoriasis, seven studies defined psoriasis cure using similar endpoints to those used to define remission. We identified a variety of definitions of psoriasis remission. These results will inform the development of consensus-based definitions for psoriasis remission to support efforts to improve research and clinical outcomes.

Towards personalized treatment in atopic dermatitis.

INTRODUCTION: For many years, oral immunosuppressive drugs such as cyclosporine A, azathioprine, mycophenolic acid, and methotrexate were the only treatment options, in addition to topical treatment, in patients with severe atopic dermatitis (AD). Dupilumab, a monoclonal antibody targeting the IL-4 receptor alpha, is the first antibody-based treatment commercially available for the treatment of AD. In the near future, more antibody-based treatments and small molecules will become available in the treatment of severe AD. AREAS COVERED: This review gives an overview of current and future therapies for severe AD, outlines options to optimize treatment with oral immunosuppressive drugs and gives an insight into the future of personalized treatment in AD. EXPERT OPINION: Due to the heterogeneous character of AD, it is unlikely that all patients will respond equally to these newly tested drugs. We believe that biomarkers will lead to better identification of patients that will benefit from these highly specific, but expensive new treatments. In addition to a role for biomarkers in new treatments, the use of pharmacogenomic biomarkers can improve the efficacy of currently used oral immunosuppressive drugs in AD, which will still be needed for the treatment of moderate to severe AD in the coming years.

Progressive multifocal leukoencephalopathy associated with fumaric acid esters treatment in psoriasis patients.

BACKGROUND: Fumaric acid esters (FAEs) are a systemic treatment for psoriasis considered to have a favourable long-term safety profile without an increased risk for immunosuppression. However, progressive multifocal leukoencephalopathy (PML), a rare, opportunistic viral infection of the central nervous system, has been linked anecdotally to FAE treatment. OBJECTIVE: To assess clinical features and outcomes of FAE-associated PML cases. METHODS: Systematic literature search in multiple databases up to 25th February 2016 for reports of PML in psoriasis patients treated with FAEs. RESULTS: Eight cases (four male, four female) of FAE-associated PML were identified. Median age was 64 years (range 42-74 years); median FAE treatment duration was 3 years (range 1.5-5 years). Six patients were treated with a formulation containing dimethyl fumarate (DMF) and monoethyl fumarates, and two patients with a DMF formulation. Patients exhibited neurological symptoms, such as aphasia, hemiparesis and dysarthria. PML diagnosis was based on MRI findings and presence of JC virus in cerebrospinal fluid and/or brain tissue. All cases were linked to moderate-to-severe reductions in absolute lymphocyte counts, with nadirs ranging from 200 to 792 cells per mm3 . Median exposure to lymphocytopenia was 2 years (range 1-5 years). In all cases, FAE treatment was discontinued; PML was treated with mefloquine plus mirtazapine. Three patients improved, two had stable disease, two had residual symptoms, and one patient died to an immune reconstitution inflammatory syndrome. CONCLUSION: Progressive multifocal leukoencephalopathy is infrequently linked to FAE treatment, but underreporting cannot be excluded. Physicians treating patients with FAEs should be vigilant for the occurrence of PML, and both clinicians and patients should be alert for onset of new neurological symptoms. Periodic monitoring of lymphocyte counts and FAE discontinuation in case of moderate-to-severe lymphocytopenia is recommended to minimize the risk for PML.

Efficacy, effectiveness and safety of fumaric acid esters in the treatment of psoriasis: a systematic review of randomized and observational studies.

Fumaric acid esters (FAEs) are increasingly used as a systemic treatment for psoriasis, but there are still uncertainties regarding their suitability. The objective of this systematic review was to assess the evidence for the efficacy and safety of FAEs in psoriasis treatment. A systematic literature search was performed in seven databases up to 17 August 2015. Inclusion criteria were studies that reported clinical effects of FAEs in patients with psoriasis without restrictions in study design, language or publication date. Methodological quality of randomized controlled trials (RCTs) and overall level of quality were assessed using the Cochrane risk of bias tool and the Grading of Recommendation, Assessment, Development and Evaluation approach, respectively. A total of 68 articles were included. There were seven RCTs (total 449 patients) that had an unclear risk of bias and were too clinically heterogeneous to allow a meta-analysis. Overall, mean Psoriasis Area and Severity Index decreased by 42-65% following 12-16 weeks of treatment. There were 37 observational studies (a total of 3457 patients) that supported the RCT findings, but most were uncontrolled with a high risk of bias. Commonly reported adverse events included gastrointestinal complaints and flushing, leading to treatment withdrawal in 6-40% of patients. Several case-reports described rare adverse events, such as renal Fanconi syndrome and progressive multifocal leukoencephalopathy. There was a lack of studies focusing on long-term use and comparisons with other treatments. This review concluded that there is low-quality evidence to recommend the use of oral FAEs to treat plaque psoriasis in adult patients. Studies focusing on long-term safety and comparison with systemic psoriasis treatments could lead to a better understanding of the role of FAEs as a treatment for psoriasis.

Addition of an oral histamine antagonist to reduce adverse events associated with fumaric acid esters in the treatment of psoriasis: a randomized double-blind placebo-controlled trial.

BACKGROUND: Fumaric acid esters (FAEs) are considered an effective and safe long-term treatment for psoriasis. However, 30-40% of patients need to discontinue FAE treatment due to intolerable adverse events. OBJECTIVES: To assess whether the addition of cetirizine, an oral histamine-1 receptor antagonist, to FAEs would reduce the incidence of adverse events. METHODS: In a randomized, double-blind, placebo-controlled trial, patients with psoriasis with a Psoriasis Area and Severity Index ≥ 10 starting an FAE up to a dose of dimethylfumarate 720 mg per day were randomized 1 : 1 to receive either additional cetirizine 10 mg once daily (n = 25) or placebo (n = 25) for 12 weeks. Randomization and treatment allocation were done at our hospital trial pharmacy. Primary outcomes were the incidence of adverse events and the proportion of patients discontinuing treatment. RESULTS: Fifty patients (33 male, 17 female; median age 44 years) were enrolled. Addition of cetirizine did not reduce the incidence of adverse events compared with placebo (84% vs. 84%, P = 1·00). The types of adverse events were not different between the cetirizine and placebo groups, the most common being gastrointestinal complaints (68% vs. 64%) and flushes (60% vs. 48%). The proportion of patients discontinuing treatment was not statistically different between the cetirizine and placebo groups (24% vs. 32%, P = 0·53). CONCLUSIONS: Addition of oral cetirizine 10 mg once daily to FAE treatment did not reduce adverse events in patients with psoriasis during the first 12 weeks of treatment. The mechanisms underlying FAE-induced gastrointestinal and flushing symptoms likely involve mediators other than histamine.

Regulated genes in psoriatic skin during treatment with fumaric acid esters.

BACKGROUND: Fumaric acid esters (FAEs) are widely used in Europe for the treatment of psoriasis because of their clinical efficacy and favourable safety profile. However, the mechanisms of action by which FAEs improve psoriasis remain largely unknown. OBJECTIVES: To identify pathways and mechanisms affected by FAE treatment and to compare these with pathways affected by treatment with the antitumour necrosis factor (anti-TNF)-α biologic etanercept. METHODS: In a prospective cohort study, 50 patients with plaque psoriasis were treated with FAEs for 20 weeks. Nine patients were randomly selected for gene expression profiling of plaque biopsies from week 0 and week 12. The groups consisted of FAE responders [> Psoriasis Area and Severity Index (PASI)-75 improvement] and nonresponders (< PASI-50 improvement). Changes in gene expression profiles were analysed using Ingenuity Pathway Analysis (IPA) and the outcome was compared with gene expression affected by etanercept. RESULTS: Response to FAE treatment was associated with a ≥ 2-fold change (P < 0.05) in the expression of 458 genes. In FAE responders the role of interleukin-17A in the psoriasis pathway was most significantly activated. Glutathione and Nrf2 pathway molecules were specifically induced by FAE treatment and not by etanercept treatment, representing an FAE-specific effect in psoriatic skin. In addition, FAE treatment specifically induced the transcription factors PTTG1, NR3C1, GATA3 and NFκBIZ in responding patients. CONCLUSIONS: FAE treatment induces glutathione and Nrf2 pathway genes in lesional skin of patients with psoriasis. In responders, FAEs specifically regulate the transcription factors PTTG1, NR3C1, GATA3 and NFκBIZ, which are important in normal cutaneous development, and the T-helper (Th)2 and Th17 pathways, respectively.

Treatment of psoriasis with non-registered fumaric acid esters in The Netherlands: a nationwide survey among Dutch dermatologists.

BACKGROUND: Psoriasis vulgaris is a T-cell mediated disease that affects 2-3% of the worldwide white-skinned population. Fumaric acid esters are mentioned as an effective therapy for moderate-to-severe psoriasis vulgaris in adult patients in the new guidelines for psoriasis treatment. OBJECTIVES: To obtain an insight into the use of fumaric acid esters by Dutch dermatologists in the Netherlands. METHODS: This was a cross-sectional postal survey. An anonymous survey was posted to all Dutch dermatologists. In this survey, data were collected on the extent of fumaric acid esters use, the reasons for use, the reasons for non- or limited use of fumaric acid esters, the perception of fumaric acid esters as a mono-therapy with regards to the effectiveness, the safety, the adverse events and the overall satisfaction of fumaric acid esters as a mono-therapy. RESULTS: Sixty-three per cent of the 300 responders indicated to prescribe fumaric acid esters for the treatment of psoriasis. About 37% of the dermatologists indicated (almost) never to prescribe it. Biologicals were considered as the most effective therapy. Fumaric acid esters were regarded as the safest therapy. They were generally well-tolerated by the patients similar to that for methotrexate according to the respondents. CONCLUSION: A large proportion of the dermatologists in our survey indicated to prescribe fumaric acid esters. It is considered to be effective, safe and without adverse events profile that is favourable in the practice, also as compared with other systemic therapies such as methotrexate and biologicals.

Effectiveness and safety of fumaric acid esters in children with psoriasis: a retrospective analysis of 14 patients from The Netherlands.

BACKGROUND: Fumaric acid esters (FAE) are used as an effective and safe oral treatment for plaque psoriasis in adult patients, but little is known about their efficacy and safety in children with psoriasis. OBJECTIVES: To assess the effectiveness and safety of FAE in the treatment of paediatric psoriasis. METHODS: This is a retrospective analysis of 14 paediatric patients with psoriasis (age <18 years) treated with FAE between 2004 and 2012 at several Dutch university and regional clinics. Patients were identified through databases or registries. RESULTS: The median age at the start of FAE treatment was 15 years (range 8-17 years). The median duration of FAE treatment was 10 months (range 1-80 months), and the median maintenance dosage per day was 360 mg dimethylfumarate (range 240-600 mg). Five patients (36%) achieved a complete clearance of their psoriasis, one patient (7%) had a good improvement, three patients (21%) had a partial response and five patients (36%) were nonresponders. FAE treatment was well tolerated, but two patients (14%) discontinued FAE, one with severe diarrhoea and one with flushes. Five patients (36%) had transient, slightly abnormal laboratory values of liver-function tests or leucocytes that did not necessitate FAE dosage reduction or treatment discontinuation. No serious adverse events occurred. CONCLUSIONS: In this retrospective case series FAE seemed to be an effective and safe treatment for children with psoriasis. FAE may be an attractive therapeutic alternative to the currently used systemic immunosuppressive agents for paediatric patients with psoriasis. Further studies are needed to evaluate the suitability of FAE in paediatric psoriasis.

Prenatal diagnosis for haemophilia: a nationwide survey among female carriers in the Netherlands.

Carriers of haemophilia face difficult choices regarding prenatal diagnosis, but little is known about the determinants that influence their decisions. The aim of this study was to assess the incidence of prenatal diagnosis and potential determinants affecting the choice for prenatal diagnosis. A nationwide survey was performed among all women who underwent carriership testing for haemophilia in the Netherlands between 1992 and 2004. Prenatal diagnosis was assessed in 207 carriers of haemophilia A or B who had been pregnant. Prenatal diagnosis was categorized into early first trimester (Y-PCR testing or chorionic villus sampling) often intended to prevent the birth of a child with haemophilia, and into late prenatal diagnosis (amniocentesis or ultrasound assessment) aimed at obstetrical management. Of 207 carriers 112 (54%) underwent prenatal diagnosis. Forty-eight women underwent early prenatal diagnosis and 64 women underwent late prenatal diagnosis. In 26 pregnancies early prenatal diagnosis was positive for haemophilia, and in 18 of these pregnancies termination was opted for. The choice for early prenatal diagnosis was associated with a liberal view towards termination of pregnancy (relative risk (RR) 12.5; 95% confidence interval (CI) 3.1-51.2), severe haemophilia in the family (RR 20.2; CI 2.7-153.6), absence of a religion (RR 1.9; CI 1.1-3.1) and older age (RR 2.0; CI 1.0-3.9). The choice for late prenatal diagnosis was associated with birth year after 1970 (RR 2.3; CI 1.5-3.5) and a previous child with haemophilia (RR 2.2; CI 1.4-3.4). More than half of all Dutch haemophilia carriers underwent prenatal diagnosis. Several determinants were strongly associated with prenatal diagnosis.

Lactoferrin-conjugated dendritic nanoconstructs for lung targeting of methotrexate.

The present investigation was aimed at developing and exploring the potential of lactoferrin (Lf)-conjugated dendritic nanocomposite for lung targeting of methotrexate (MTX). The 5.0 G poly(propylene imine) (PPI) dendrimer and Lf-conjugated 5.0 G PPI dendrimer were synthesized and characterized by Fourier-transform infrared spectroscopy, nuclear magnetic resonance, and transmission electron microscopy. The entrapment efficiency, in vitro release, and hemolytic toxicity were assessed. Pharmacokinetic and organ distribution studies were carried out to evaluate in vivo targeting potential of developed system. The pharmacokinetic studies showed that elimination half-life of MTX-loaded plain PPI dendrimer (10.41 ± 2.12 h, p < 0.05) and MTX-loaded Lf-conjugated PPI dendrimer (12.23 ± 1.53 h, p < 0.01) was significantly higher than the free drug (5.85 ± 1.19 h). Organ distribution assessment of different formulations displayed significant (p <0.05) higher accumulation of drug in lungs by MTX-Lf-PPI (1329 ± 26.7 ng/g of tissue) as compared with MTX-PPI (721 ± 23.4 ng/g of tissue) and free MTX (575 ± 19.7 ng/g of tissue) after 6 h of administration. The result suggested that Lf-conjugated 5.0 G PPI dendrimer-based formulations to be approximately 1.5 times and 2.5 times superior to plain 5.0 G PPI dendrimer as well as pure MTX, respectively, for lung targeting of anticancer drugs.

Micro- and nanocarrier-mediated lung targeting.

IMPORTANCE OF THE FIELD: Drug delivery to lungs appears to be an attractive proposition on account of the large surface area of the alveolar region; it provides tremendous opportunities to improve drug therapies both systemically and locally using new drug delivery systems. Administration of drugs directly to the lungs is the most appropriate route in the treatment of asthma and other pulmonary diseases such as tuberculosis, chronic obstructive pulmonary disease and lung cancer. AREAS COVERED IN THIS REVIEW: This review focuses on the utilization of nano- and microcarriers such as microspheres, nanoparticles, liposomes, niosomes and dendrimers for targeted delivery of bioactive molecules to lungs. WHAT THE READER WILL GAIN: This review sheds light on the current status of nano- and microcarrier-mediated lung targeting of bioactive compounds. TAKE HOME MESSAGE: The literature review shows that carriers could supplement sustained drug delivery to the lungs, extended duration of action, reduced therapeutic dose, improved patient compliance, and reduced adverse effects of highly toxic drugs. There is still a need to identify more specific receptors that are present exclusively in the lungs. The identification of such receptors may also facilitate drug targeting to further specific parts of the lungs, such as bronchioles and alveoli.