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.

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.

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.

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.

Beneficial effect of low-dose systemic retinoid in combination with topical tretinoin for the treatment and prophylaxis of premalignant and malignant skin lesions in renal transplant recipients.

Renal transplant recipients experience a greatly increased frequency of neoplastic skin lesions, including aggressive squamous cell carcinomas. Recent reports suggest that high doses of systemic retinoids may exert a chemotherapeutic and chemoprophylactic effect. Similarly, topical retinoid, especially tretinoin, has also been shown to be anti-tumoragenic in various settings. Because of the serious toxicity of high-dose systemic retinoid, a protocol was developed that combined topical tretinoin with low-dose etretinate (10 mg daily) for the treatment of frequently occurring dysplastic skin lesions in renal transplant recipients. Seven patients elected to receive combined tretinoin and etretinate therapy, and 4 were treated with tretinoin alone. Clinical evaluations were performed monthly. By 3 months of therapy, 9 of 11 patients exhibited at least a 25% decrease in the number of neoplastic growths. After 6 months, 6 of 8 evaluable patients, including 2 of 3 individuals receiving tretinoin alone, exhibited at least a 50% decrease. Three of 4 patients on the combined regimen and 2 of 3 receiving tretinoin alone for at least 9 months, exhibited a significant decrease in the rate of development of new squamous cell cancers. At the start of treatment, epidermal specimens were almost completely devoid of Langerhans cells (CD1+ cells). Their density increased greatly and in proportion to the duration of therapy. Long term topical tretinoin with or without low-dose oral etretinate seems to be an effective regimen to suppress the development of new tumors and to reduce the numbers of existing lesions in renal transplant recipients.

Effect of meals on the kinetics of etretinate.

Eight healthy men received 100 mg oral doses of etretinate separated by two-week washout periods in an open, randomized, crossover study. Etretinate was administered during a complete fast, with a standard high fat breakfast, a standard high carbohydrate breakfast, and 16 ounces of whole milk. Plasma samples were obtained at specific times over a 48-hour period. Plasma concentrations of etretinate as well as two of its major metabolites were determined by a specific, reverse-phase, high-performance liquid chromatography method. Plasma concentrations of etretinate were greater when administered with a high fat meal and whole milk compared to ingestion with a high carbohydrate meal or during a complete fast. In contrast, there was no increase in the plasma concentrations of the active metabolites following any of the meals. These data indicate that chronic dosing of etretinate with milk or a high fat meal compared with fasting conditions will result in higher concentrations of etretinate, which may ultimately lead to higher metabolite concentrations.

Methotrexate and etretinate as concurrent therapies in severe psoriasis.

A patient with pustular psoriasis, which was inadequately controlled by high-dose methotrexate and potent topical corticosteroid therapy, was treated with oral methotrexate and the aromatic retinoid etretinate. The patient's psoriasis improved with sustained maximal etretinate therapy and continued high-dose methotrexate therapy. Subsequently, the methotrexate dose was tapered and used of this drug was discontinued. Previously unattainable success in controlling the psoriasis was achieved with continued etretinate treatment. There were no recognizable adverse effects from concurrent therapy. As the methotrexate dose was tapered, the patient noted increased psoriatic arthritic pain, unrelieved at maximal etretinate levels, but improved with indomethacin treatment. Combination therapy with methotrexate and etretinate may be useful in the treatment of severe psoriasis by providing a controlled transition from methotrexate to etretinate therapy alone.

Diazacholesterol-induced ichthyosis in the hairless mouse. Assay for comparative potency of topical retinoids.

Although the new synthetic retinoids are effective when administered systemically, they have not been shown to be effective as topical agents. We compared the topical activity of six synthetic retinoids (two arotinoids, etretinate, all-trans- and 13-cis-tetrazole-retinamide, isotretinoin, and tretinoin) on tail skin in the diazacholesterol-fed mouse model of ichthyosis. Responses were assessed clinically and by measurement of stratum corneum thickness. Although the arotinoids dramatically reduced scaling, they were toxic at concentrations above 0.1%, as was etretinate at 1.0% or greater. Lower concentrations were effective without producing local or systemic toxic reactions. Clinical responses were paralleled by equivalent decrements in stratum corneum thickness, which also permitted quantitative comparisons. The order of potency for the retinoids was as follows: arotinoids, etretinate, tetrazole-retinamides, tretinoin = isotretinoin, vehicle. These results demonstrate that (1) the synthetic retinoids hold promise as topical agents; (2) irritation is not an absolute requirement for topical retinoid activity; and (3) the diazacholesterol-fed mouse offers a new assay of topical retinoid potency in a well-defined animal model of ichthyosis.

Oral treatment of keratinizing disorders of skin and mucous membranes with etretinate. Comparative study of 113 patients.

This study reports comparative results of the effects of an aromatic retinoid, etretinate (RO 10-9359), on various disorders of the skin and mucous membranes. One hundred thirteen patients suffering from psoriasis, lichen planus, keratosis follicularis, and various other disorders were treated and examined. The patients received 25 to 100 mg/day of oral etretinate for up to 30 months. Patients with erythrodermic psoriasis, pustular psoriasis, and keratosis follicularis showed the best response. The conditions of patients with psoriasis vulgaris, palmoplantar psoriasis, and lichen planus also improved, but less impressively. The mucous membrane lesions of lichen planus and leukoplakia showed only moderate improvement. The most striking adverse clinical reactions observed were cheilitis (70%), dryness of the mucous membranes (27%), and hair loss (27%).

Successful treatment of keratoderma hereditaria mutilans with an aromatic retinoid.

Clinical features and treatment of keratoderma hereditaria mutilans (Vohwinkel's syndrome) are described in an 11-year-old boy. The disease, in particular the mutilating complications (pseudo-ainhum), responded satisfactorily to the oral administration of etretinate, an aromatic retinoid.

Nature of skin fragility in patients receiving retinoids for systemic effect.

The origin and frequency of skin fragility, a frequent side effect of oral synthetic retinoids, was studied in ten patients receiving isotretinoin (13-cis-retinoic acid) for disorders of keratinization and in hairless mice treated with isotretinoin and the aromatic retinoid, etretinate (RO 10-9359). Clinical skin fragility occurred in eight of ten patients, and experimental friction blisters could be induced by pencil eraser abrasion in nine of nine patients and in the hairless mice. Light and electron microscopy of friction blisters showed fraying or loss of the stratum corneum and outer layers of the viable epidermis, loss of desmosomes and tonofilaments, and intracellular and intercellular deposits of amorphous material that did not stain with stains for mucin. The skin fragility produced by oral synthetic retinoids is epidermal in origin, since (1) retinoids induce profound disruption of epidermal morphologic appearance, (2) an intraepidermal split is produced by experimental friction blisters, and (3) urinary hydroxyproline excretion in patients receiving retinoids, a measure of collagen catabolism, was not increased.

Dermatologic treatment of cutaneous graft versus host disease.

Cutaneous involvement in graft versus host disease (GVHD) after allogeneic hematopoietic cell transplant can be separated into acute GVHD (aGVHD), lichenoid chronic GVHD (cGVHD) and sclerodermatous cGVHD. It seems clear that these syndromes result from different mechanisms and entail different treatment approaches. Standard treatment of cutaneous aGVHD involves the intensification of immunosuppressive therapy with adequate topical supportive management. In skin-limited disease, phototherapy has shown promising results. In cutaneous cGVHD, the combination of corticosteroids and cyclosporine (ciclosporin) is the recommended therapy, and other immunosuppressants may be added depending on whether lichenoid or sclerodermatous lesions are present. High response rates to phototherapy have been found in lichenoid disease, while sclerodermatous disease responds better to etretinate or extracorporeal photochemotherapy. Localized cutaneous cGVHD may be treated with topical corticosteroids alone. Few reports on the effect of treatments in GVHD clearly describe the cutaneous involvement and the influence of the treatment on the skin. Therefore, dermatologists should be deeply involved in the diagnosis and treatment of GVHD, and good dermatologic grading systems should be developed. Theses changes will increase our knowledge of cutaneous GVHD, and relevant data in the evaluation of the effect of therapy in the disease will be obtained.

Modulation of receptor levels in canine breast tumors by administration of tamoxifen and etretinate either alone or in combination.

Steroid receptors were measured in a series of 30 operable canine mammary gland tumors; both cytoplasmic estrogen (ERc) and progesterone (PgRc) receptor mean concentrations were very low with respect to the mean levels found in humans. Therefore a study was designed to modulate receptor levels by administration of Tamoxifen and Etretinate, either alone or in combination. Forty dogs with resectable, histologically documented mammary gland tumors were subdivided into the following treatment groups: a. Etretinate (1 mg/kg/d) p.o. for 7 days followed by Tamoxifen (0.7 mg/kg/d) p.o. for 7 days; b. Tamoxifen (0.7 mg/kg/d) p.o. for 14 days; c. Etretinate (1 mg/kg/d) p.o. for 14 days; d. 14 days placebo, and cytoplasmic ERc and PgRc and nuclear ER (ERn) were measured before and after the treatment. An increase of ERc and ERn was observed after administration of Tamoxifen, while an increase of ERc only was seen after treatment with Etretinate. We conclude that canine mammary tumors are indeed hormone sensitive despite their very low receptor concentrations and a suitable treatment can in fact modulate receptor levels. However, further studies are needed better to define the optimal treatment regimen in order to achieve maximal steroid receptor induction.

[Influence of oral retinoid on the cell kinetic of normal human epidermis (author's transl)]. / Retinoid-Einfluss auf die Zellkinetik gesunder menschlicher Epidermis.

In 21 healthy volunteers (18-48 years old) autoradiographic studies were performed before, 3 and 7 days after oral administration of aromatic retinoid Ro 10-9359 (75 mg/d) and after oral intake of placebo. After retinoid the 3H-thymidine labelling index was significantly increased, whereas the DNA synthesis time and the cell cycle time were decreased. After placebo no change in epidermal cell kinetic parameters were registered. These findings indicate that therapeutic doses of oral aromatic retinoid clearly stimulate epidermal cell proliferation in normal human epidermis.

DMBA-induced tumors and their prevention by aromatic retinoid (Ro 10-9359).

Both auricles of 21 domestic rabbits were painted with dimethylbenzanthracene (DMBA). Eleven animals of this group were additionally fed aromatic retinoid (AR) by an esophageal tube. Two control animals were not treated at all. Eight or 9 weeks after the beginning of the study six of the seven remaining animals, which had only been painted with DMBA, developed a total of 25 keratoacanthoma-like tumors (KA). On the other hand, none of the seven animals left, which were painted with DMBA and fed AR showed any tumor by this time. The systemic effect of AR was studied in biopsies from the snout and the back. The epidermis of the snout showed 'mucous mataplasia' by histochemical and electron-microscopic criteria, whereas the epidermis of the back was not significantly altered. The production of intra- and extracellular lamellated material indicated an additional effect of AR on epidermal lipid metabolism. The effect of AR in the prevention of DMBA-induced tumors was characterized by 'mucoid cytolysis' and karyolysis.

[Effects of the aromatic retinoid Ro 10-9359 and of 13-cis retinoic acid Ro 4-3780 on the size of sebaceous glands in the Syrian hamster]. / Der Einfluss des aromatischen retinoids Ro 10-9359 und der 13-cis-Retinsäure Ro 4-3780 auf die Talgdrüsen des Syrischen Hamsters.

An aromatic retinoid (Ro 10-9359) in 13-cis retinoic acid (Ro 4-3780) were fed by gastric tube to 170 male adult Syrian hamsters daily for 30 days. A low dose of 1 or 2 mg/kg and a high dose of 20 mg/kg body weight were selected. The effects of both retinoids on the sebaceous glands were assessed planimetrically (15 glands in each animal) using the sebaceous follicle on the ventral side of the earlobes or, in some experiments, the flank organ. Depending on time, the high dose of 20 mg/kg of both retinoids led to a significant diminution of sebaceous follicles from 0.0295 to 0.0125 mm2 (P less than or equal to 0.0005). Clinically, the fur of the animals became very rough and dry. The lower dose of 1 or 2 mg/kg of neither the aromatic retinoid nor the 13-cis retinoic acid led to a significant reduction of sebaceous acini. The fur remained clinically shiny and greasy. The different effects of both compounds in this animal model compared to the human is discussed.

Biological modifiers (etretinate (changed from etetrinate) and alfa 2a) in the treatment of refractory cutaneous T-cell lymphoma.

To assess the efficacy and toxicity of biological modifiers in combination etetrinate, 0.8 mg/kg/day, po and interferon alfa 2a 9.0 MU, three times at week) in the treatment of refractory cutaneous T-cell lymphoma (CTLC) we began a clinical study on 12 heavily treated patients. After 1 year on treatment 10/12 patients (83%) achieved complete response. Two patients were considered failures with disease progression. After a median follow-up of 3 years, seven patients (56%) remained in complete remission. Toxicity was mild. All patients received 93% of the planned dose of etetrinate and interferon. We feel that biological modifiers, as etetrinate and interferons, are agents with limited hematological toxicity even in higher doses. The combination of two agents, with different mechanisms of action, could improve the outcome in patients with refractory CTCL. Controlled trials are necessary to define the roles of this type of therapy as first line of treatment.