H.B. Thio

Loss-of-Function Mutations in the Filaggrin Gene Lead to Reduced Level of Natural Moisturizing Factor in the Stratum Corneum

TO THE EDITOR Filaggrin is a key protein required for the formation of the stratum corneum (SC) barrier. Filaggrin is also essential for SC hydration, as it acts as a source of hygroscopic amino acids and their derivatives, known as natural moisturizing factor (NMF). The human gene encoding filaggrin (FLG) is highly polymorphic and to date, 15 null mutations have been detected of which four (R501X, 2282del4, R2447X, and S3247X) are prevalent at varying frequencies in the white European population (Sandilands et al., 2007). Homozygous or compound heterozygous FLG mutations underlie the common skin-keratinizing disorder ichthyosis vulgaris, and have been shown to be a major genetic predisposing factor for atopic dermatitis (AD) (Sandilands et al., 2006). Diminished filaggrin expression has been demonstrated in both ichthyosis vulgaris and AD skin (Seguchi et al., 1996; Sugiura et al., 2005; Smith et al., 2006). As filaggrin is the precursor protein for the amino-acid-derived components of the NMF, we hypothesized that carriers of FLG-null mutations have reduced level of NMF in the SC. To measure NMF in the SC of the palm (thenar eminence) and forearm skin, we used confocal Raman microspectroscopy (3510 Skin Composition Analyzer; River Diagnostics, Rotterdam, The Netherlands). The principles of this method and the procedure have extensively been described elsewhere (Caspers et al., 2001, 2003). The reference spectrum of NMF was constructed from a superposition of the spectra of pyrrolidone-5-carboxylic acid, ornithine, serine, proline, glycine, histidine, and alanine. In addition to NMF, skin barrier function as measured by transepidermal water loss was assessed on the volar forearm (Tewameter 210; Courage and Khazaka Electronic GmbH, Cologne, Germany). One hundred and forty-nine volunteers recruited by public advertisement, as well as 10 AD patients, were screened for four FLG mutations (R501X, 2282del4 R2447X, and S3247X). All subjects filled in a questionnaire on the history of skin diseases and allergies, and the Erlangen atopy questionnaire that also included a question on skin dryness. Signs of active disease (erythema, crusting, weeping, and lichenification) were assessed by a dermatologist. Having visible skin changes on the forearm was the exclusion criterion. Written informed consent was obtained from all subjects. The experimental protocol followed the Declaration of Helsinki Principles and was approved by the Ethical Committee of the Academic Medical Centre. Genomic DNA was extracted from buccal swab samples (Puregene DNA isolation kit; Gentra Systems, Minneapolis, MN). Polymorphisms were genotyped as reported previously (Sandilands et al., 2007). To compare data from two groups, we used twotailed Student’s t-test for unpaired samples. Sixteen carriers (12 female) of an FLG mutation and 23 individuals (15 female) wild type with respect to these mutations were included in the study. Of the 16 carriers, five were heterozygous for R501X, eight were heterozygous for 2282del4, and one was heterozygous for R2447X. One individual was homozygous for Abbreviations: AD, atopic dermatitis; FLG, human filaggrin-encoding gene; NMF, natural moisturizing factor; SC, stratum corneum

Long-term safety aspects of systemic therapy with fumaric acid esters in severe psoriasis

Summary  Background Therapy with fumaric acid esters (FAE) has been shown to be safe and effective in patients with severe psoriasis in several clinical studies with limited follow‐up periods. In view of the chronic character of psoriasis, long‐term safety aspects are of major importance in determining the suitability of a drug during prolonged periods of treatment.

E-health in caring for patients with atopic dermatitis: A randomized controlled cost-effectiveness study of internet-guided monitoring and online self-management training

Background  The Dermatology Department of the University Medical Centre Utrecht, the Netherlands, developed an e‐health portal for patients with atopic dermatitis (AD), consisting of e‐consultation, a patient‐tailored website, monitoring and self‐management training.

Fumarates vs. methotrexate in moderate to severe chronic plaque psoriasis: a multicentre prospective randomized controlled clinical trial

Background  Methotrexate and fumarates are effective systemic therapies for moderate to severe psoriasis according to the European S3 guidelines.

Effects of monomethylfumarate on dendritic cell differentiation

Background  Fumaric acid esters (FAE) are effective against psoriasis vulgaris and monomethylfumarate (MMF) is believed to be the most bioactive metabolite of this medication. Earlier we found that the beneficial effects of FAE medication are accompanied by a downregulation of type 1 cytokine production by T‐helper (Th) lymphocytes, which are important as they maintain a type 1 cytokine [interferon (IFN)‐γ, interleukin (IL)‐2] environment in the skin lesions of psoriasis vulgaris patients and once maximal beneficial effects are obtained type 2 cytokine production is also decreased. In vitro MMF selectively induced type 2 cytokine production by primed Th lymphocytes, whereas type 1 cytokine production by and profileration of T lymphocytes were unaffected.

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

Summary 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.

Evaluation of the reimbursement criteria for biological therapies for psoriasis in the Netherlands

testosterone levels returned to normal ranges. Hypertrichosis is an uncommon and distressing reaction to drugs. Its mechanisms are poorly understood, but hair growth usually reverts back to normal after discontinuation of the drug. The disorder starts on the upper limbs or the face and spreads to the back and lower limbs, but spares the elbows, knees and gluteal area, as in our patient. Efalizumab has not been associated with hypertrichosis but the increased levels of free testosterone in our patient might have been caused by an androgen-dependent mechanism induced by the drug. A reversible increase in the circulating lymphocyte count was also observed and it is a matter of further investigation to determine whether or not this is associated with efalizumab’s systemic (or extensive?) adverse reactions. Efalizumab-induced hypertrichosis represents a new adverse reaction. It is not necessary to terminate efalizumab therapy and hypertrichosis may be treated with various methods of hair removal. Physicians should be aware of this and inform their patients accordingly.

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.

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.

Prevalence of cutaneous adverse events associated with long-term disease-modifying therapy and their impact on health-related quality of life in patients with multiple sclerosis: A cross-sectional study

BackgroundGlatiramer acetate (GA) and interferon-beta (IFN-β) are disease-modifying therapies (DMTs) for multiple sclerosis that are administered through subcutaneous (SC) or intramuscular (IM) injections. Skin reactions associated with DMTs are common and may influence patient’s health-related quality of life (QoL). We aimed to determine the prevalence of cutaneous adverse events associated with long-term DMT use, and to assess the impact of cutaneous adverse events on QoL.MethodsA cross-sectional study among patients with multiple sclerosis who had been treated with their first DMT for at least 2 years. Cutaneous events were assessed from photographs of injection-sites by dermatologists blinded for DMT. Generic and dermatology-specific health-related QoL were assessed using validated patient-reported questionnaires.ResultsA total of 229 patients were enrolled, of whom 156 (68%) had at least one skin reaction. The prevalence of cutaneous adverse events was higher for SC DMTs (75-82%) compared to IM DMT (41%) (P < 0.001). Erythema and lipoatrophy were the most common skin reactions, observed in 156 (68%) and 45 (20%) patients, respectively. Dermatology-specific, but not generic, QoL was significantly lower among patients with skin reactions compared to those without.ConclusionsThe prevalence of cutaneous adverse events was high in long-term DMT-treatment. Patients with cutaneous adverse events had a lower perceived dermatology-specific QoL.

Drug-induced Fanconi syndrome associated with fumaric acid esters treatment for psoriasis: a case series

Background Fumaric acid esters (FAEs), an oral immunomodulating treatment for psoriasis and multiple sclerosis, have been anecdotally associated with proximal renal tubular dysfunction due to a drug-induced Fanconi syndrome. Few data are available on clinical outcomes of FAE-induced Fanconi syndrome. Methods Descriptive case series with two cases of Fanconi syndrome associated with FAE treatment diagnosed at two Dutch university nephrology departments, three cases reported at the Dutch and German national pharmacovigilance databases and six previously reported cases. Results All 11 cases involved female patients with psoriasis. The median age at the time of onset was 38 years [interquartile range (IQR) 37–46]. Patients received long-term FAEs treatment with a median treatment duration of 60 months (IQR 28–111). Laboratory tests were typically significant for low serum levels of phosphate and uric acid, while urinalysis showed glycosuria and proteinuria. Eight (73%) patients had developed a hypophosphataemic osteomalacia and three (27%) had pathological bone fractures. All patients discontinued FAEs, while four (36%) patients were treated with supplementation of phosphate and/or vitamin D. Five (45%) patients had persisting symptoms despite FAEs discontinuation. Conclusions FAEs treatment can cause drug-induced Fanconi syndrome, but the association has been reported infrequently. Female patients with psoriasis treated long term with FAEs seem to be particularly at risk. Physicians treating patients with FAEs should be vigilant and monitor for the potential occurrence of Fanconi syndrome. Measurement of the urinary albumin:total protein ratio is a suggested screening tool for tubular proteinuria in Fanconi syndrome.