Reduced stratum corneum acylceramides in autosomal recessive congenital ichthyosis with a NIPAL4 mutation.

BACKGROUND: NIPAL4, encoding the NIPA-like domain containing 4 protein (NIPAL4), is one of the causative genes of autosomal recessive congenital ichthyosis (ARCI). The physiological role of NIPAL4 and the pathogenetic mechanisms of ARCI caused by NIPAL4 mutations remain unclear. OBJECTIVE: To clarify the changes of ceramide components in the lesional stratum corneum (SC) and the gene expression profile in the lesional skin of an ARCI patient with a novel frameshift mutation in NIPAL4. METHODS: We performed ultrastructural and immunohistochemical analyses of the skin. We used RNA sequencing to determine the mRNA expression in the skin of the patient and healthy individuals. We investigated ceramide components using tape stripped SC samples from the patient. RESULTS: mRNA expression profiling in the patient's skin showed significant upregulation of IL-17/TNFα-related genes (IL17C, IL36A, IL36G, S100A7A, S100A9) and psoriasis hallmark genes (VNN3, LCE3D, PLA2G4D), and significant downregulation of lipid-associated genes (GAL, HAO2, FABP7). Ceramide analysis in the patient's SC revealed amounts of CER[NS] with carbon chain-length (C) 32-52 were increased, while amounts of most acylceramide with C66:2 - C72:2 were reduced relatively to those in healthy individuals. After the retinoid treatment, CER[NS] with carbon chains C46-54, CER[EOH] and CER[EOP] increased. CONCLUSION: IL-17C and IL-36 family cytokines might be involved in the pathogenetic process of ARCI with NIPAL4 mutations. Reduced amounts of the acylceramides in the SC are associated with the skin phenotype due to NIPAL4 mutations. Efficacy of the oral retinoid treatment might be due to restored amounts of CER[EOH] and CER[EOP] in the SC.

Infantile generalized pustular psoriasis: successful disease control with intermittent etretinate.

Infantile generalized pustular psoriasis is a rare form of psoriasis and the best treatment is controversial. We experienced a 2-year-old female with erythema on her neck and axilla starting at 3 months of age. She presented with recurrent annular and geographic scaly erythema with a few pustules on the neck, precordium and axilla, but no fever. The histopathology revealed subcorneal neutrophilic infiltration and microabscesses without Kogoj's spongiform pustules. The initial diagnosis was subcorneal pustular dermatosis. However, she developed widespread geographic erythema and numerous pustules over her entire body with a fever when she got a cold. A second skin biopsy revealed monolocular pustules and Kogoj's spongiform pustules in the subcorneal layer. Etretinate was administrated after a diagnosis of pustular psoriasis was made and her condition improved gradually. The choice of treatment depends on patient age, general condition and the disease severity.

Acitretin prescribing patterns in women of childbearing potential.

BACKGROUND: Acitretin is indicated for severe psoriasis, but it is also a potent teratogen whose use should be avoided in women of childbearing potential. Topical medications, phototherapy, cyclosporine A, and new biologic agents provide safer alternatives for women of childbearing age with moderate to severe psoriasis. PURPOSE: To determine the demographics of acitretin prescribing patterns as an assessment of acitretin use in women of child-bearing potential. METHODS: We examined National Ambulatory Medical Care Survey (NAMCS) data from the years 1990-2009 to determine demographic data on patients who were prescribed etretinate or acitretin. We used age under 50 as a proxy for childbearing potential. RESULTS: From 1996-2009, there were an estimated 29 million office visits for psoriasis. Females accounted for 14.3 million of these visits, and 6.5 million (45.6%) of them were under the age of 50. The NAMCS contained only one record of a female patient under the age of 50 being prescribed acitretin from 1996-2009, the years during which acitretin had been available in the United States. This corresponds to an estimated 2.3% of all psoriasis patients prescribed acitretin during this time (20,000 out of 890,000). LIMITATIONS: The NAMCS estimates national trends based on a large nationwide database. While the use of acitretin in women under 50 is low, the precision of the estimate is limited by the small sample size provided by this database. CONCLUSIONS: There are now many alternative treatments besides acitretin for women of childbearing potential with moderate to severe psoriasis. Acitretin is used at most infrequently in this population. In females of reproductive potential, acitretin should be reserved for non-pregnant patients who are unresponsive to other therapies or whose clinical condition contraindicates the use of other treatments.

Systemic retinoids in the management of ichthyoses and related skin types.

The term retinoid includes both natural and synthetic derivatives of vitamin A. Retinoid-containing treatments have been used since ~1550BC by the early Egyptians. Treatment of ichthyosiform disorders with retinoids dates back at least to the 1930s. Early use of high-dose vitamin A demonstrated efficacy, but because vitamin A is stored in the liver, toxicity limited usefulness. Interest turned to synthetic retinoids in an effort to enhance efficacy and limit toxicity. Acetretin, isotretinoin and, in the past etretinate, have provided the most effective therapy for ichthyosiform conditions. They have been used for a variety of ages, including in newborns with severe ichthyosis and for decades in some patients. Careful surveillance and management of mucous membrane, laboratory, skeletal, and teratogenic side effects has made systemic retinoids the mainstay of therapy for ichthyosis and related skin types.

Evaluation of the transfusion safety of blood products and determination of plasma concentrations of acitretin and etretinate in patients receiving transfusions.

BACKGROUND: Acitretin and etretinate are potentially teratogenic. Many people taking acitretin for psoriasis have donated blood during the deferral period in Korea. Therefore, many of the blood products from these donors treated with acitretin have been circulated in Korea. STUDY DESIGN AND METHODS: A high-performance liquid chromatography system (HP 1050, Agilent Technologies) was used to measure the drug concentrations in five blood products and in patients. Sixty patients taking acitretin were enrolled to determine their plasma drug levels. Forty-one female patients were recruited to investigate the residual plasma levels of acitretin and etretinate in relation to their teratogenicity. We calculated the elimination rate of acitretin and etretinate during the manufacturing process. RESULTS: Sixty individuals taking acitretin expressed variable acitretin (<2.0-206.8 ng/mL) and etretinate levels (<2.0-9.1 ng/mL). All patients that had a transfusion had concentrations of acitretin and etretinate lower than the lower limit of quantification (LLOQ; 2 ng/mL). The concentrations of acitretin and etretinate in five blood products were less than the LLOQ. Approximately 98.84 percent (log value, 1.94) of the acitretin and 99.93 percent (log value, 3.14) of the etretinate was eliminated during the manufacturing process of albumin. More than 99.99 percent (log values, 5.95-15.76) of acitretin and etretinate was eliminated during the manufacturing processing of immunoglobulin and blood coagulation factors. CONCLUSIONS: We confirmed the effective manufacturing processing of various blood products. We also demonstrated that individuals receiving transfusions with blood products originating from donors treated with acitretin were not at risk for significant exposure to the acitretin and etretinate.

Bacterial infection-induced generalized Hailey-Hailey disease successfully treated by etretinate.

Hailey-Hailey disease (HHD; familial benign chronic pemphigus) is a hereditary blistering disorder characterized by episodic maceration and erosions mainly in intertriginous areas, and generalized eruptions are rarely seen. We report here a 51-year-old woman with generalized HHD who was successfully treated with oral etretinate. The present case suggests that oral etretinate is effective against the generalized eruptions even in cases in which bacterial infection has triggered the generalization of HHD.

The effects of vitamin A derivative etretinate on the skin of MRL mice.

MRL/Mp-lpr/lpr (MRL/lpr) mice are characterized by the disorder of apoptosis due to defects in Fas antigens and autoimmune symptoms including spontaneous lupus erythematosus (LE)-like skin lesions. MRL/Mp- + / + (MRL/n) mice do not carry the defect of lpr mutation nor do they exhibit skin disorders during the first six months of life. Retinoids are known to inhibit the proliferation of skin fibroblasts, collagen synthesis, modulate immune responses, and apoptosis by Fas ligand upregulation in skin fibroblasts. We examined changes in dermal thickness and appearance of skin disorders in five months old MRL/lpr mice by oral treatment with etretinate, a retinoic acid derivative. Etretinate treated MRL/lpr mice did not have skin lesions or dermatopathological characteristics including an increase in cells infiltrating the dermis. The mean dermal thickness of MRL/lpr and MRL/n mice treated with etretinate decreased significantly and apoptotic cells density in the dermis of MRL/lpr mice with etretinate was significantly higher compared with the control group (P < 0.05) although MRL/lpr mice have a defect within the Fas antigen. We assumed that etretinate reduced dermal thickness, and suppressed the appearance of skin lesions by inducting apoptosis and perhaps regulation of cytokine expression.

Punctate palmoplantar keratoderma with pigmentary lesions on the dorsa of feet and ankles: successful treatment with a combination of low-dose oral etretinate and topical calcipotriol.

We describe a patient with typical keratotic lesions of punctate palmoplantar keratoderma on the hands and feet and unique pigmentary lesions on the dorsa of the feet and ankles. A combination of low-dose oral etretinate (10 mg/day) and calcipotriol ointment 0.005% resulted in a complete regression, whereas pigmentary lesions on the dorsa of the feet and ankles did not change during the treatment.