Short-term etretinate therapy for prurigo chronica multiformis

Prurigo chronica multiformis is an intensely pruritic, chronic cutaneous disorder of unknown etiology without any effective treatment. This is a report on the results of using etretinate therapy to treat prurigo chronica multiformis. Thirty-seven patients (average age; 69.1+/-11.5 year-old) were treated with 30 mg/day etretinate along with topical steroids (very strong classes) and oral antihistamines. Etretinate was discontinued as soon as remission was achieved. Thirty-six patients were followed up for at least four weeks. The number of patients who achieved remission increased progressively after the initiation of etretinate therapy; 18 patients were totally and 14 were partially free of active skin lesions within four weeks. Eventually, 27 patients achieved remission with an average duration of 4.4+/-3.1 weeks etretinate treatment (range; 1-14 weeks), and five achieved partial remission. Four patients discontinued etretinate within two weeks because of the absence of clinical response (two cases) or exacerbation of the skin lesion (two cases). Among the 27 patients who had achieved remission, 23 had recurrence after the cessation of etretinate. The remission period ranged from 1 to 32 weeks with an average duration of 5.7+/-6.7 weeks. Combined treatment with topical steroids and oral antihistamines did not achieve remission in the recurrent cases but re-administration of 30 mg/day etretinate did. Our observation suggests that a moderate dose of etretinate is a safe and effective therapy for prurigo chronica multiformis, which is often resistant to conventional treatment using topical steroids and oral antihistamines.     

Acitretin is converted to etretinate only during concomitant alcohol intake

BACKGROUND: Acitretin has replaced etretinate in the treatment of various disorders of keratinization due to a considerably shorter terminal half-life. Possible esterification of acitretin to etretinate in the presence of ethanol has been reported. OBJECTIVES: To determine the plasma concentrations of etretinate as a metabolite in patients with various disorders of keratinization after multiple acitretin dosing, and to assess the influence of alcohol consumption using a questionnaire. In addition, to study the influence of alcohol consumption on the risk of metabolic formation of etretinate. PATIENTS/METHODS: Eighty-six acitretin (Neotigason(R), Roche)-treated outpatients from three centres provided pre-dose (trough) samples for determining plasma concentrations of acitretin and its metabolites 13-cis-acitretin and etretinate. Patients received acitretin doses of between 0.1 and 1.3 mg kg-1 daily. The concentrations of etretinate, acitretin and 13-cis-acitretin were determined by reverse-phase high-performance liquid chromatography. RESULTS: Of the 86 patients, 30 had detectable plasma etretinate levels. No etretinate was found in 20 patients who reported that they never drank alcohol, while etretinate was found in all 16 patients with an average weekly alcohol consumption of > 200 g ethanol, corresponding to about 15 U (1 U equals half a pint of standard beer or a wine glass of non-fortified wine). Etretinate was detected in 14 of 50 patients with a moderate weekly alcohol intake of up to 200 g ethanol. A trend linking higher alcohol intake with both higher risk of etretinate formation and higher etretinate levels was observed. The study also revealed that the ethylesterification only relates to acitretin (13-trans-) and not to the main metabolite 13-cis-acitretin, although the latter compound showed higher plasma trough concentration levels at steady state. CONCLUSIONS: Owing to the teratogenic potential and possible side-effects of oral retinoids, fertile women especially should be informed about the importance of strict alcohol abstinence during treatment and for at least 2 months after stopping therapy. In case of non-compliance with alcohol abstinence a post-therapy contraceptive period of 2-3 years should be recommended.     

Etretinate. Persistent serum levels after long-term therapy

In 47 patients who received long-term etretinate therapy, we measured serum etretinate concentrations from one to 244 weeks after the discontinuation of therapy. The earliest posttreatment, nondetectable serum concentration of etretinate was observed at five weeks after treatment. Detectable serum concentrations (0.05 to 1.2 micrograms/dL) were observed more than two years (108, 111, 131, 136, and 150 weeks) following the discontinuation of therapy. Sequential serum concentrations obtained on eight individual patients were used to determine half-lives for this late-phase elimination. The median half-life for the 12 curves obtained was 12.5 weeks (range, 5.3 to 24.8 weeks). Since etretinate is stored in fat, we compared each patient's deviation from ideal body weight as a measure of excess body fat with various pharmacokinetic factors of etretinate elimination. Overweight patients tended to have slower elimination, maintain higher serum concentrations, and clear etretinate later.     

A randomized trial of etretinate (Tigason) in palmoplantar pustulosis

5 patients with palmoplantar pustulosis (PPP) were randomized to 8 weeks of daily treatment with either oral etretinate, 1 mg/kg b.w. or placebo. Good or moderate effect was obtained in 18 or 20 patients on etretinate compared o 6 of 21 patients on placebo (p less than 0.001). Etretinate proved to be significantly superior to placebo with regard to influence on the individual symptoms and signs of pustulosis. All patients on etretinate experienced some side effects from the mucous membranes, but they were generally mild. Treatment was discontinued after 4 weeks in 3 patients for reasons unrelated to treatment, in 4 for lack of effect (all on placebo) and in 2 for side effects (both or etretinate). Etretinate is a good alternative to other systemic treatments of PPP.     

Palmoplantar eruption associated with etretinate therapy

Five psoriatic patients developed papular lesions of palms and soles, shortly after beginning treatment with etretinate. Histological examination in two cases was insignificant. The lesions disappeared without tapering the dose of etretinate. The fact that lesions appeared and subsided within a short period may explain why this unusual adverse reaction of etretinate therapy has not been reported previously.     

Glucose and insulin responses are improved in patients with psoriasis during therapy with etretinate

Since lipemia is commonly induced by retinoid therapy, we investigated the effects of etretinate administration on glucose metabolism by obtaining five-hour oral glucose tolerance tests in 23 patients before and after 20 weeks of etretinate therapy for psoriasis. Compared with pretreatment values, peak and aggregate levels for serum glucose and aggregate levels for serum insulin were significantly lower during therapy. The changes were not associated with obesity, weight loss during treatment, or pretherapy glucose tolerance or insulin secretion level. Of 11 patients with impaired or diabetic glucose tolerance prior to therapy, eight patients had improved glucose tolerance after 20 weeks of etretinate treatment. Despite inducing hypertriglyceridemia in most patients, etretinate therapy is associated with a reduction in glucose levels in response to a glucose load.     

New observations on the fine structure of lamellar ichthyosis and the effect of treatment with etretinate

Light and electron microscopy were used to study specimens from four patients suffering from lamellar ichthyosis. Three of these patients had been treated with etretinate for 10 months. Biopsy specimens taken from the patients before treatment showed hyperkeratosis with focal parakeratosis, a thickened granular layer in which the cellular content of tonofibrils and keratohyalin was moderately diminished, and acanthosis with increased cellular activity. During treatment with etretinate there was moderate clinical improvement. The most conspicuous microscopic change was thinning of the cornified layer. The intercellular spaces of the epidermis showed increased amounts of fine and coarse granular substance. The number of keratinosomes was increased. Stimulation of Langerhans' cells was observed. Two new ultrastructural findings in lamellar ichthyosis were discovered. First, the marginal band of the cornified layer was absent in conventional glutaraldehyde-osmium tetroxide fixation. Second, the corneocytes contained electron-lucent crystals. The treatment with etretinate did not influence these structures. The mechanism of action of retinoids in lamellar ichthyosis is discussed.     

Retinoids and the prevention of cutaneous epitheliomas: 1977-1987

In 1977 we undertook a prospective study aimed at evaluating the preventive effects of a retinoid (etretinate, Roche) on the occurrence of skin carcinomas in dermatoses carrying a high risk of malignancy. Ten patients were included in the study: 4 had Xeroderma pigmentosum (XP), 4 had basal cell naevus syndrome (BCN), and there was 1 case each of porokeratosis of Mibelli (PM) and familial epitheliomatosis of Ferguson-Smith (EFS). All recorded carcinomas had been cured before treatment was initiated. The number of epitheliomas which developed during treatment with etretinate was compared with the number of epitheliomas recorded during the months or years preceding this treatment or during trial periods without treatment. The results obtained were very encouraging: 1. In patients with XP the actinic keratosis rapidly regressed, and the dryness of the skin was markedly reduced during the 5 years under etretinate. During the period without etretinate skin dryness and multiple actinic keratosis soon reappeared, as did, in one case, numerous basal cell carcinomas (BCC). However, etretinate did not prevent the occurrence of a malignant melanoma and of a few lesions of lentigo and naevus. 2. In the first case of BCN concerning two sisters, one treated the other untreated, less BCC lesions and, mainly, less BCN lesions were recorded in the sister treated than in the untreated sister. In the second case of BCN 28 BCC lesions developed while the patient was under observation without any treatment during 6 months, whereas only 31 BCC lesions had been recorded during 6 years under etretinate.(ABSTRACT TRUNCATED AT 250 WORDS)     

Oral retinoid therapy for disorders of keratinization: single-centre retrospective 25 years' experience on 23 patients

BACKGROUND: Over the last three decades, the oral retinoids etretinate and acitretin have revolutionized the treatment of disorders of keratinization (DOK). Many patients with DOK require life-long treatment with oral retinoids. However, the longest follow-up data of patients with DOK on oral retinoid therapy is 10 years for adults and up to 11 years for children. OBJECTIVES: The aim of our study was to collect long-term retrospective data including disease response, side-effects and pregnancy outcome in a cohort of patients with DOK who were among the first in the world to commence oral retinoids 25 years ago. METHODS: Between 1979 and 1981, 30 patients with DOK were commenced on oral etretinate in our department. Case notes of these patients were reviewed retrospectively, and patients interviewed where possible to obtain the following information: diagnosis, age when treatment commenced, duration of treatment, reason for discontinuation of therapy, side-effects, abnormal investigation results and pregnancy outcomes. RESULTS: Case notes of 23 of the 30 patients were available for review; of these, two patients were deceased and 14 were interviewed. In the 23 patients, the mean age of commencing treatment was 33.5 years (range 4.2-61) and the mean duration of etretinate therapy was 5.2 years (range 1 month to 14 years). Reasons for discontinuing treatment were an overall improvement in the skin disease (six of 23), no benefit +/- side-effects (11 of 23) and noncompliance (one of 23). Two patients died of causes unrelated to their skin disease or treatment, 12 and 4 years after stopping etretinate. Five patients (one female, four males) subsequently changed to acitretin and are currently continuing therapy. The mean total duration of retinoid therapy (etretinate and acitretin) for the four males was 23.7 years (range 20.6-25.1). The female patient continued intermittent courses (due to planned pregnancies) of oral retinoids for a total of 10.1 years over the last 25 years. Abnormal investigation results included elevated serum triglycerides and cholesterol (two of 23), isolated high triglycerides (three of 23), isolated high cholesterol (three of 23), worsening of liver enzymes in a patient with alcohol dependence, and elevated serum alkaline phosphatase (ALP) in healthy adults (three of 23). In two children, the elevated pretreatment ALP levels increased further after commencing etretinate but returned to normal in adulthood while treatment continued. One patient developed diffuse idiopathic skeletal hyperostosis after 21 years of retinoid therapy. One female patient had two early spontaneous abortions 2.75 and 3.2 years after discontinuing etretinate; she subsequently had two normal children. Two other females had normal children 1, 3 and 5 years after stopping etretinate. Two male patients fathered a total of three healthy children while on etretinate. CONCLUSIONS: This study provides the longest available follow-up data of children and adults with DOK on oral retinoid therapy. Such information is essential for clinicians and their patients with DOK embarking on life-long treatment with retinoids.     

Comparison of therapeutic efficacy of topical PUVA, oral etretinate, and combined PUVA and etretinate for the treatment of psoriasis and development of PUVA lentigines and antinuclear antibodies

Sixty-two and 38 psoriatic patients were treated with topical PUVA and combined etretinate and topical PUVA (Re-PUVA), respectively. In both groups, 50% of the patients showed initial recovery after 6 weeks and over 90% after 14 weeks. Re-PUVA was more effective than PUVA alone in obtaining complete clearance (p<0.05). To clear psoriasis in 50% of the patients, PUVA and Re-PUVA required 63 and 26 weeks, respectively. Furthermore, the integrated clearance rates after 70 weeks were 50% in PUVA and 63% in Re-PUVA. Each therapy showed a similar remission period; psoriasis recurred in 50% of the patients after 4 months. In addition, 17 patients were treated with oral etretinate, and Re-PUVA was found to be more effective than etretinate monotherapy. Another aim was to determine whether etretinate would inhibit the development of PUVA side effects. Adding etretinate failed to inhibit the production of PUVA lentigines but clearly suppressed antinuclear antibody (ANA) expression. Six of 56 patients treated with PUVA alone developed ANA during the treatment. In marked contrast (p=0.05), ANA was detected in none of 34 patients treated with Re-PUVA.     

Acitretin (Ro 10-1670, etretin): overall evaluation of clinical studies

Acitretin (Ro 10-1670, etretin) is the free acid derivative of etretinate. This compound possesses a much shorter half-life of elimination than etretinate and was therefore proposed for clinical development. A total of 635 patients with various dermatoses were studied in 12 main clinical trials performed in Europe and in the United States. It was shown that acitretin is effective in the treatment of psoriasis and other diseases of keratinization. Doses between 25 and 35 mg per day are recommended to initiate treatment since marked improvement or clearing was obtained in the majority of patients within this range. Hypervitaminosis A signs and symptoms have been observed in patients treated with acitretin. It is concluded that the efficacy and safety profile of acitretin resembles that of etretinate.     

Clinical trial of the efficacy and safety of oral etretinate with calcipotriol cream compared with etretinate alone in moderate-severe psoriasis

BACKGROUND: The aim of this clinical trial was to assess the efficacy and safety of calcipotriol cream associated with oral etretinate compared with etretinate alone in the treatment of moderate-severe psoriasis. METHODS: This controlled multicenter trial, within patients (hemiparts), enrolled 86 in- or out-patients (62 males, 24 females), mean (+/-SD) age 57.1 +/- 14.2 years, with psoriasis vulgaris on both sides of the body, and mean (+/-SE) baseline PASI score (Psoriasis Area and Severity Index) 30.7 +/- 0.9. All patients took oral etretinate 50 mg/day and applied calcipotriol cream (50 microg/g) on one half of their body twice a day. Treatment was continued for 9 weeks, and patients were seen every 3 weeks. RESULTS: At the end of the first 3 weeks the PASI score indicated a significant clinical difference between the two sides of the body (P < 0.001, ANOVA), with a reduction of 50.7% in the score for the calcipotriol-treated half, compared with a 39% reduction for the untreated half. By the 9th week of treatment the PASI score was 81.4% lower on the treated half, and 70.3% on the untreated side (P < 0.001, ANOVA). CONCLUSIONS: These findings suggest that patients with moderate-severe psoriasis might benefit from treatment with etretinate plus calcipotriol, with the aim of achieving a faster response and an overall smaller total dose of etretinate.     

Vulval lichen sclerosus et atrophicus treated with etretinate (Tigason)

In an open uncontrolled study eight patients with vulval lichen sclerosus et atrophicus were given etretinate (Tigason) 1 mg/kg/day. The dose was then gradually reduced according to effect and side effects. Six patients showed improvement in symptoms and in clinical morphology based on the physician's evaluation and photographic documentation. In four of five patients where biopsies were taken, there was a marked change in the histological picture towards normalization. Two patients did not respond to the treatment. All patients experienced the well-known side effects of etretinate in various degree. We conclude that treatment with etretinate should be tried in vulval lichen sclerosus et atrophicus if the result of other therapeutical efforts are unsatisfactory.     

Etretinate or cyclosporin-A treatment normalizes the enhanced respiratory burst of polymorphonuclear leukocytes in psoriasis

Summary During a therapeutic trial to treat psoriasis with either etretinate or cyclosporin A (CyA) we measured the respiratory burst activity of polymorphonuclear leukocytes (PMN). Six patients received 0.5–0.75 mg/kg etretinate and 14 patients 2.5–5.0 mg/kg CyA over a period of 10 weeks. The extent of psoriasis was graded by the psoriasis area-and-severity index (PASI score). The respiratory burst of PMN isolated from the peripheral blood was measured employing luminol-enhanced chemiluminescence at weeks 0, 3 and 10 and compared with that of 26 healthy control individuals. PMN were stimulated with zymosan particles, aggregated immunoglobulin (aggIg) and concanavalin A (ConA). Both treatment regimens improved psoriasis; at 10 weeks there was an approximate 40% PASI score reduction under etretinate and an 80% improvement under CyA. Before treatment the respiratory burst was abnormally high under stimulation with the three stimuli in patients (p=0.021 to<0.0001). After 3 to 10 weeks PMN activity normalized in all patients and even tended to drop below values correlating with an improvement in skin lesions. We conclude that the elevated respiratory burst of PMN in psoriasis normalizes under treatment with both etretinate and CyA.This paper contains data from the doctoral thesis of J. H.     

Etretinate and visual function: a 1-year follow-up study

Concern has been expressed in the literature that the drug etretinate may be potentially retinotoxic. Four patients are reported who have received long-term treatment with etretinate and who have undergone detailed evaluation for the development of visual dysfunction over a 1-year period. Despite prolonged treatment and high total doses no evidence of ocular toxicity attributable to the drug was found in any of the patients.     

Clinical response and tissue effects of etretinate treatment of patients with solar keratoses and basal cell carcinoma

Patients with basal cell carcinoma and solar keratoses were treated with etretinate. Substantial and prolonged clinical improvement was seen. All patients with solar keratoses showed a decrease in the mean area and number of lesions and eight patients demonstrated complete healing clinically. Two patients experienced recurrence at 9 months after completion of treatment. Histometric and cell kinetic measurements on the epidermis of skin samples from these patients were performed. They revealed epidermal thickening and increased deoxyribonucleic acid (DNA) synthesis both in lesions and in clinically uninvolved skin following treatment. Assessments were also made of enzyme activities in lesions and uninvolved skin with the use of established quantitative cytochemical techniques. Significant reduction in levels of succinic dehydrogenase activity following etretinate treatment was detected in solar keratoses and in basal cell carcinomas. This was also the case for uninvolved skin of patients with solar keratoses. Glucose-6-phosphate dehydrogenase (G6PD) activity was significantly reduced following etretinate treatment in solar keratoses and in basal cell carcinomas, but uninvolved skin did not exhibit significant changes. These changes are in contrast to those previously reported in normal subjects, where the activity increased, but are similar to those observed in patients with ichthyotic disorders. The alterations in the cytochemical profile following administration of etretinate in the lesions of patients reported here are consistent with the view that the drug promotes a more normal pattern of epidermal differentiation. We favor the view that etretinate's antineoplastic action is exerted by preferentially allowing differentiation of normal epidermal cells and inhibiting dysplastic cells.     

Extensive spinal hyperostosis in a patient receiving isotretinoin--progression after 4 years of etretinate therapy

A patient with Darier's disease was discovered to have persistent, asymptomatic cervical and thoracic spinal hyperostoses after receiving isotretinoin for 7 years. The spinal abnormalities have remained asymptomatic but have now progressed following 4 years of etretinate therapy. The development of skeletal abnormalities, in particular spinal hyperostosis, is well-documented in patients receiving the synthetic retinoid, isotretinoin (Accutane, Roaccutane). The occurrence of extraspinal tendon and ligament calcification has been emphasized following long-term therapy with etretinate (Tegison, Tigason), but the relationship between etretinate and spinal hyperostosis is less certain, there being a need for a long-term, prospective, appropriately controlled investigation of patients receiving etretinate. We report a patient with Darier's disease who was discovered to have prominent, asymptomatic cervical and thoracic spinal hyperostoses after receiving isotretinoin for 7 years. Subsequent treatment with etretinate for 4 years did not prevent progression of the spinal abnormalities.     

Treatment of cutaneous lupus erythematosus with etretinate

Nineteen patients with different clinical subsets of cutaneous lupus erythematosus (LE) were treated with the aromatic retinoid etretinate. In 11 of them excellent or good treatment results were obtained within two to six weeks. Best response to etretinate therapy was seen in male patients with discoid lupus erythematosus. Etretinate should prove a valuable drug in LE therapy.     

Epidermodysplasia verruciformis. Clinical and light-and electron-microscopic observations during etretinate therapy

Summary Three patients with epidermodysplasia verruciformis (EV) were treated with etretinate for 9–13 months. The patients had lesions characteristic of EV, including flat warts, common genital warts, pityriasis-versicolor-like lesions and malignant changes such as actinic keratosis and Bowenoid cancer in situ. During etretinate treatment, some flattening of the warts was observed in all three patients, and the lesions on the chest and back became less red and scaling. However, none of the lesions disappeared completely, and when the treatment was discontinued, the lesions relapsed. No malignant changes were detected during the period of therapy. Electron microscopy revealed the presence of typical large, clear cells containing viral particles in the upper epidermis. Etretinate therapy induced the same type of fine-structural changes as those seen in keratinization disorders and genodermatoses. The clear cells and virus particles persisted throughout the treatment period. More long-term, controlled studies are necessary to make possible an estimate of the curative and cancer-inhibitory effect of etretinate treatment in patients with EV.     

A double-blind comparison of acitretin and etretinate in the treatment of severe psoriasis. Results of a Nordic multicentre study

Acitretin, the free acid of etretinate, is less lipophilic and has a much shorter terminal half-life than the parent compound. The present double-blind, randomized study compared the therapeutic effectiveness and the tolerability of acitretin (n = 127) and etretinate (n = 41) in psoriasis. Patients were treated with 40 mg daily for the first 4 weeks and with an individually adjusted dose for the subsequent 8 weeks. The average daily doses of acitretin (0.54 mg/kg/day) and etretinate (0.65 mg/kg/day) were similar. The PASI (Psoriasis Area and Severity Index) scores improved in parallel in the 2 treatment groups. At the completion of the study, the PASI score improvement was 75.8% for acitretin and 70.8% for etretinate. Both acitretin and etretinate resulted in mucocutaneous side effects. Assessments of tolerability by investigators and patients showed a statistically significant difference in favour of etretinate. These results demonstrate that acitretin and etretinate have similar therapeutic effectiveness in psoriasis. Although the tolerance to acitretin was lower than to etretinate, acitretin offers the important advantage of a much shorter period of potential teratogenicity and is, therefore, to be preferred in women of childbearing potential.