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Summary: Electron beam therapy (EBT) is an established treatment for mycosis fungoides (MF), but evidence for the use of EBT in advanced cutaneous conditions is limited, and optimal scheduling of the regimen for such conditions remains unclear. We report the case of a 44‐year‐old woman diagnosed with MF with widespread cutaneous lesions, including multiple huge tumours in the craniofacial area. Low‐dose total skin (TS)EBT and subsequent localized skin (LS)EBT achieved striking improvements in eruptions. Oral etretinate was also administered during therapy. Our experience implies that combined TSEBT and LSEBT may be worth attempting when a patient presents with both widespread lesions and prominent tumours, even when the tumours are extremely large. [ABSTRACT FROM AUTHOR]

Background. Photodynamic therapy (PDT) with 5-aminolaevulinic acid (5-ALA) is a noninvasive and effective treatment for superficial skin cancers. Etretinate, a derivate of vitamin A, with the chemical formula ethyl(2E,4E,6E,8E)-9-(4-methoxy-2,3,6-trimethylphenyl)-3,7-dimethyl-2,4,6,8-nona-tetraenoate, has been reported to have antitumour effects and to regulate the proliferation and differentiation of skin cancers. Objective. In order to develop more efficient PDT, we investigated whether etretinate enhanced the cytotoxic action of ALA-based PDT against human squamous cell carcinoma cell line, HSC-5. Method. The in vitro cytotoxicity was measured using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Apoptotic cells were detected by double-staining with fluorescent annexin V and propidium iodide. Intracellular protoporphyrin IX (PpIX) converted from exogenous ALA was measured by a fluorescence meter. Results. HSC-5 cells pretreated with a nontoxic concentration of etretinate became more susceptible to the cytotoxic action of ALA-based PDT. Etretinate-pretreated cells underwent apoptosis in response to ALA-based PDT. Etretinate pretreatment resulted in enhanced accumulation of ALA-dependent intracellular PpIX. Conclusions. The results suggest that etretinate enhances the susceptibility of HSC-5 cells to ALA-based PDT via the intracellular increase of ALA-dependent PpIX. Etretinate might be useful for improvement of ALA-based PDT. [ABSTRACT FROM AUTHOR]

We report a patient with psoriasis and hepatitis C virus infection who initially presented with psoriatic erythroderma and eventually showed complete clearance of psoriatic lesions following acute hepatitis induced by etretinate treatment. Cytokine synthesis capabilities in peripheral blood T cells obtained at different stages were evaluated in this patient. A dramatic increase in the frequency of interferon- γ-producing CD8+ T cells in peripheral blood was observed during the erythrodermic stage. In contrast, the frequencies of interleukin (IL)-4- and IL-13-producing CD4+ T and CD8+ T cells were remarkably high at the resolution stage. These results clearly indicate that a shift towards type 2 cytokine predominance contributes to the resolution of severe psoriasis. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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®, 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. [ABSTRACT FROM AUTHOR]

Two unrelated boys with tyrosinaemia type II, whose skin lesions have been satisfactorily controlled with etretinate, are described. [ABSTRACT FROM AUTHOR]

Twenty-three adult patients (13 males, 10 females) with psoriasis vulgaris had been on long-term PUVA maintenance therapy (mean 4 years 2 months, 210 PUVA exposures). Their psoriasis had broken through PUVA maintenance or relapsed rapidly on discontinuing PUVA. The aromatic retinoid etretinate (Tigason") was commenced to reduce the dose of PUVA required to control their psoriasis. Four patients subsequently cleared on etretinate alone, 11 cleared on the etrerinate-PUVA combination. Five patients improved short of complete clearing and one remained unchanged although his PUVA doses were reduced. The remaining two patients responded poorly due to non-compliance and side-effects respectively. Overall a 58 % reduction in UVA doses was estimated. [ABSTRACT FROM AUTHOR]

Four patients who were suffering typical lichen amyloidosus were treated with etretinate (Tigason®). Itching was relieved in all cases within 2 weeks. The lesions were completely cleared in three cases within 10-20 weeks and markedly improved in one case. No amyloid material could be detected in skin biopsies taken after the treatment period of several months. No immediate relapses were observed after discontinuation of the etretinate treatment. [ABSTRACT FROM AUTHOR]

Cell birth-rates and the labelling index (LI) were measured in a patient with congenital nonbullous ichthyosiform erythroderma (CIE). Measurements were made before and after a course of oral etretinate. The cell birth-rate, following treatment, was less than half of the pretreatment rate. The 1.1 showed little change. The therapeutic effects of oral etretinate may be, to some extent, due to a suppression of cell renewal. The fact that the LI was unchanged when cell production was reduced indicates that the LI alone is an unreliable indicator of proliferative activity. [ABSTRACT FROM AUTHOR]

With the exception of acropustulosis, nail disease responds poorly to etretinate. When used to treat other dermatological conditions etretinate is frequently toxic to the normal nail and may affect any or all of its epidermal components. The desquamative dermatitis, induced by etretinate, may account for many of the drug's side-effects on the nail. These include chronic paronychia, onycholysis, onychomadesis, nail shedding, onychoschizia, fragility and the formation of excess granulation tissue. Some of these changes resemble those found in psoriatic paronychia and similarities are drawn between psoriasis and the retinoid dermatitis which presents with identical features in the discharge from beneath the proximal nail-fold. The desquamative reaction in patients taking etretinate always affects the lips and, in addition, may be widespread or mainly localized to the nail apparatus. [ABSTRACT FROM AUTHOR]

A patient with psoriasis and alcoholic cirrhosis developed increased skin fragility, blistering and leg ulceration whilst taking etretinate (Tigason-Roche). The aromatic retinoids frequently cause dose-related side-effects such as cheilitis, palmar-plantar desquamation, conjunctivitis and hair loss. Skin fragility has also been previously reported but not accompanied by blistering as in this patient. Long-term therapy in our case resulted in excessive accumulation of the drug and, because of pre-existing liver disease, excretion was further delayed and toxicity enhanced. [ABSTRACT FROM AUTHOR]

We describe three patients in whom dose-dependent, reversible kinking of the hair has occurred while receiving etretinate therapy. The morphological changes of the hair consist of incomplete twists, variation in bore and pigmentation. We propose that the changes may result from the drug's effect on the inner root sheath of the hair. [ABSTRACT FROM AUTHOR]

We report a case of oral papillary plasmacytosis which initially responded well to etretinate and, subsequantly, was successfully treated with radiotherapy, with minimal side-effecis. [ABSTRACT FROM AUTHOR]

The scalp hair of 15 patients, who were treated with etretinate for at least 6 months, was investigated, with the aims of confirming the previously described reduction in the duration of anagen and establishing the mechanism of etretinate alopecia. An increase in hair shedding rate and an increase in plucked telogen count, both of which continued for 6 months of treatment, were found, whereas there was no significant increase in the proportion of new, or regrowing, anagen hairs in a cut sample (NAH). The sustained decrease in the duration of anagen was confirmed, and it was further shown that this decrease was progressive. This would appear to be the main cause of the observed increased shedding associated with etretinate treatment. In relation to the mechanism of the alopecia, it was concluded that an arrest at the onset of anagen and a follicular anchorage defect in telogen were causes. The evidence for an arrest at the onset of anagen was a failure of NAH to rise on treatment, and a large increase in NAH on stopping treatment. The evidence for a follicular anchorage defect was a rise in shed rate very early in treatment, and an observed shed rate greater than expected, on the basis of plucked telogen results. later in treatment. These pathogenic mechanisms have never been described previously in drug-induced alopecia, or in the majority of hair disorders in general. However, it would seem highly unlikely that these mechanisms are exclusive to etretinate therapy. [ABSTRACT FROM AUTHOR]

Etretinate and its metabolite acitretin have been shown to be highly effective in the treatment of various disorders of keratinization. including lamellar ichthyosis. The aim of the present study was to provide further information on acitretin dosage regimens in the management of lamellar ichthyosis. Seven patients with classical manifestations of lamellar ichthyosis participated in the study. Five patients improved markedly, and the remaining patients showed mild to moderate improvement. Two patients improved following gradual incremental increase in dosage (⩾35 mg/day). Four patients, including a patient with the erythrodermic variant, required low-dose acitretin treatment (⩽25 mg/day). as higher doses resulted in a marked deterioration in their skin condition. The dichotomy with respect to the response to acitretin suggests that lamellar ichthyosis is a spectrum of at least two conditions. [ABSTRACT FROM AUTHOR]

Pseudoainhum is an infrequent complication in the autosomaf-recessive keratodermas. We describe two related families in which the diagnosis of mal de Meleda keratoderma has been confirmed by mode of inheritance and ultrastructural findings. One family member, a 9-year-old girl, developed pseudoainhum which threatened the viability of her little fingers. This responded to treatment with etretinate. The treatment dilemma posed by keratoderma-induced pseudoainhum in children, i.e. the concern over the possible skeletal toxic effects of long-term etretinate treatment vs, the risks and outcome of surgery, is discussed. [ABSTRACT FROM AUTHOR]

Clinically we have noted that the skin of patients treated with long-term oral etretinate becomes uniformly soft and smooth to touch, like facial skin that becomes smoother and less wrinkled following treatment with topical tretinoin. This suggests that retinoids, whether used systemically or topically, alter the physical properties of the skin, particularly of the stratum cornceum (SC). To study the influence of retinoids on the SC, we serially assessed the functional properties of the SC non-invasively in retinoid-treated humans and experimental animals. SC hydration and barrier function were assessed by measurement of high-frequency conductance and transepidermal water loss (TEWL), respectively. Daily application of topical retinoic acid creams was found to rapidly induce a time- and dose-dependent, linear increase in SC hydration of the forearm skin of healthy adults over a 2-week period and to compromise its water barrier function in a similar fashion. Systemic administration of high-dosage etretinate, 4 or 8 mg/kg/day, to guinea-pigs also induced dose-dependent increases in both SC hydration and TEWL measured on the plantar skin after 1 month. Moreover, in the animals given etretinate 4 mg/kg/day we confirmed a slight but significant decrease in the number of cell layers of the plantar SC. Likewise, patients with various dermatoses began to show similar functional changes of the SC in the uninvolved skin of the flexor surface of the forearms 3 weeks after the start of oral etretinate treatment, consisting of SO mg daily for 2 weeks, followed by gradual dose tapering. Thus, it is reasonable to speculate that oral etretinate changes the properties of the SC to produce smoother skin over the whole body surface, probably by increasing amounts of water-binding substances in the SC as well as by exerting a keratolytic effect, in a fashion similar to that induced by topical tretinoin application. [ABSTRACT FROM AUTHOR]

Elephantiasis nostras verrucosa is characterized by chronic secondary, non-filarial lymphoedema due to recurrent lymphangitis, dermal fibrosis. and epidermal changes consisting of hyperkeratotic, verrucous and papillomatous lesions. Histologically, there is psendoepitheliomatous hyperplasia. Therapeutic efforts should aim to reduce lymph stasis, which will also lead to improvement of the cutaneous changes. In this study, rapid disappearance of the hyperkeratotic and verrucous lesions, remarkable flattening of the papillomatous nodules and improvement of lymphoedema occurred in three obese patients treated with etretinate in an initial dose of 0.6–6.75 mg/kg/day for 4–6 weeks. Monitoring of plasma concentrations of etretinate, acitretin and 13-cis-acitretin by HPLC revealed sufficient short-time absorption (4 h) and bioavailability of the drug (30 days: two out of three patients). Long-term maintenance therapy in one patient produced a remarkable improvement in the lymphoedema: another patient relapsed after discontinuation of the etretinate and responded again after this was reintroduced. In the third patient treatment was withdrawn because of an increase in triglycerides, but improvement persisted f) months later. The clinical side-effects of oral retinoid therapy were moderate and well tolerated. [ABSTRACT FROM AUTHOR]

Anxiety about the use of etretinate in children has been provoked by several reports describing skeletal abnormalities during long-term therapy. However, we have observed no evidence of skeletal toxicity in 42 children treated over an 11-year period. Radiological screening before and during treatment has failed to reveal abnormalities that would influence our decision to commence or to continue etretinate administration. We recommend that children who are to be treated with etretinate should have a baseline selective skeletal survey, with follow-up radiology restricted to those with pretreatment radiological abnormalities and those who develop musculo-skeletal symptoms. In addition we advise that dosage should not exceed 1 mg/kg/day. If these guidelines are followed, we believe that long-term therapy with etretinate can be given to children, with an acceptable margin of safety. [ABSTRACT FROM AUTHOR]

Forty-five patients with extensive chronic plaque or guttate psoriasis were treated with either narrowband (TL-01) phototherapy, etretinate TL-0l combination therapy (re-TL-0l) or etretinate and PUVA (re-PUVA) (15 patients in each group). Re-PUVA was the most effective therapy with 100% satisfactory clearance rate. TL-01 monotherapy had an 80% success rate; the relapse rate compared favourably with re-PUVA (50% in remission after 6 months). In the etretinate-TL-0l group, there was a 93% success rate and a one-third reduction in the total irradiation dose (8·0 J/cm2 vs. 12·7 J/cm2) but the relapse rate was higher, only 33% remaining in remission after 6 months. [ABSTRACT FROM AUTHOR]

The effect of retinoids on the production of interleukin-1 (IL-1) by murine epidermal keratinocytes was investigated. Freshly isolated keratinocytes were cultured in the presence of etretinate. acitretin. All-trans retinoic acid or 13-cis retinoic acid at concentrations of 8 × 10-9-8 × 10-6 mol/l. Exposure of keratinocytes to retinoids increased IL-1 bioactivity in culture supernatants and cell extracts at concentrations as low as 8 × 10-9 mol/l. as assessed by T-cell proliferation. Prolongation of the culture period enhanced the augmentative effect of retinoids. All-trans retinoic acid and 13-cis retinoic acid had a greater ability to induce IL-1 production than the two aromatic retinoids, etretinate and acitretin. Treatment with 8-methoxypsoralen plus ultraviolet A radiation and treatment with triamcinolone acetonide both reduced the effect of retinoids on the production of bioactive IL-1. [ABSTRACT FROM AUTHOR]

Forty-five patients with cutaneous T-cell lymphomas (CTCL), 32 with mycosis fungoides (MF) and 13 with Sézary syndrome (SS), were treated with interferon-α2a (IFN-α2a) (6–9 × 106 IU daily) for 3 months. Those responding to treatment were then treated with interferon-α alone (6–9 × 106 IU three times weekly), and non-responders received a combination of etretinate (0.5 mg/kg/day t and IFN-α2a in similar concentrations. After 12 months of treatment, 28⁄45 patients (62.2%) were in complete or partial (>50%) remission. Of these, 17 (60.7%) were receiving IFN-α alone and 11 the combined interferon-retinoid therapy. Of the patients with MF stage I and II, 20⁄25 were responders (12 receiving IFN-α alone and eight on combined therapy), whereas only 8⁄20 with stage IV or SS responded to treatment (five receiving IFN-α2a alone and three combined therapy). These results suggest that the association of etretinate with low-dose recombinant IFN-α2a is an effective means of treating epidermotropic CTCL, particularly in the early stages. [ABSTRACT FROM AUTHOR]

Forty patients with relapsing plaque psoriasis involving more than 20% body surface were treated either with cyclosporin A (CyA) plus PUVA or the retinoid etretinate plus PUVA (RePUVA). They initially received either CyA (2 weeks) or etretinate (1 week) alone and then PUVA was given concomitantly until complete remission. The patients were monitored over a period of 6 months and any relapse recorded. With each combined treatment regimen, CyA plus PUVA and RePUVA, the patients cleared within comparable periods of time (mean treatment period of 53 vs. 47 weeks after initiation of therapy and 33 vs. 37 weeks after initiation of PUVA). However, the cumulative UVA dose required for clearance (110.9 J/cm2 vs. 62.1 J/cm2 (P < 0.05)) and the incidence of severe and early relapses were significantly higher in the CyA cohort. Within 6 months severe relapses had occurred in 58% of CyA plus PUVA but only in 15% of RePUVA-treated patients (P< 0.001). This suggests that the CyA plus PUVA regimen as performed in this study is less effective than RePUVA. [ABSTRACT FROM AUTHOR]

Two studies were designed to assess the effect of abrasive preparations on the skin and to test the specificity of the effect of topical tretinoin in the management of chronic photodamage to the skin. In the first study two abrasive preparations (Brasivol® fine and Brasivol® medium) were compared with white soft paraffin and no treatment in eight volunteer subjects for their effects on the epidermis. The study was conducted over 3 days and measurements were taken of the effects on dansyl chloride-induced fluorescence to assess desquamation, epidermal thickness, and the tritiated thymidine autoradiographic labelling index. The abrasives were found to increase the desquamation rate significantly and to increase epidermal thickness and the epidermal labelling index compared to white soft paraffin and no treatment. In the second study the effect of one of the abrasive preparations (Brasivol® medium) was compared with 0.005% tretinoin cream (Retin A®) on the photodamaged skin of the dorsal aspects of the forearms of 12 subjects over an 8-week period. Cutaneous blood flow measured by the laser-Doppler flowmeter was found to be significantly increased in the abrasive-treated sites, but there was only a non-significant trend to increased blood flow in the tretinoin-treated sites. Measurements of skin thickness using pulsed A-scan ultrasound demonstrated that both treatments produced significant increases in thickness over the 8-week period hut the increase was greater for the abrasive treated site. Measurements of the skin extensibility at the treated sites were made using a uniaxial extensometer. Forces needed for 30% skin extension were increased in the abrasive-treated sites only. Measurements of epidermal thickness and of [3H]-thymidine autoradiographic labelling indices showed greater increases in the abrasive-treated sites than in tretinoin-treated sites compared to untreated sites, but these increases were not statistically significant. No significant inflammation and no changes in the degree of elastosis or the presence of a `repair zone' were found in any of the post-treatment biopsies. The results indicate that some of the changes produced in the skin by topical tretinoin that are taken to indicate a specific antiphotoageing effect may not in fact be specific and can be achieved by an abrasive preparation. [ABSTRACT FROM AUTHOR]

This is a review of the efficacy of etretinate/acitretin in the treatment of psoriasis and of the currently reported side-effects. The data indicate that retinoids bring significant improvement (if not total clearing) with frequent low-morbidity but rarely serious side-effects. The most serious side-effect of etretinate/acitretin is teratogenicity. [ABSTRACT FROM AUTHOR]

We report the case of a boy, now aged 4 years, with a progressive, painful and disabling palmoplantar keratoderma, associated with well-defined hyperkeratotic plaques around the mouth and nostrils. His mother has an identical palmoplantar keratoderma. The palmoplantar keratoderma failed to improve with etretinate, but considerable benefit resulted from full-thickness excision of the skin of both palms, followed by skin grafting. We believe that he has a distinctive but extremely rare form of hereditary palmoplantar keratoderma, first described by Olmsted. [ABSTRACT FROM AUTHOR]

A case is reported of a patient who developed blistering of the skin followed by ulceration and scarring while on treatment with etretinate. [ABSTRACT FROM AUTHOR]

Possible early side-effects of retinoid treatment on bones were studied with the aid of bone-scintigraphy. Isotretinoin treatment (1.0 mg/kg daily for 4 months) was given to 18 patients with acne. Fifteen patients with psoriasis received etretinate treatment (0.7–1.0 mg/kg/day) for 4 months. In the group treated with isotretinoin, pathological uptake of radiolabel was found in three cases, while in the group treated with etretinate, no bone changes attributable to treatment were found. During isotretinoin treatment, a decrease in growth-plate activity was observed. Bone-scintigraphy is considered to be a suitable method for early screening for bone changes occurring in retinoid treatment. [ABSTRACT FROM AUTHOR]

Quantitative changes in the levels of keratin polypeptides extracted from keratotome shavitigs from psoriatic epidermis were measured by using one-dimensional SDS-PAGE, followed by scanning densitometry. Values obtained were compared with results for non-lesional epidermis and from epidermis from normal individuals. Patients on four different treatment regimens were investigated by repeated sampling over 3–4 months starting before therapy commenced. The levels of four keratins changed significantly: keratins 1 (70 kd) and 2 (66 kd) tended to rise to normal levels, while keratins 16 (50 kd) and 18 (44 kd) fell to normal levels. There were differential effects as well as differences in the rates of normalization depending upon the treatment regimen. The most rapid normalization of the levels of all four keratins was observed with topical dithranol (anthralin) treatment (five patients) with plaque resolution and keratin level normalization after 7–9 weeks. Oral hydroxyurea (three patients) had similar effects, but over a longer time scale (20 weeks). In contrast, oral etretinate (four patients) caused a normalization of all except keratin 2 (66 kd) over a period of 20–28 weeks, and keratin 1 (70 kd) levels tended to ‘overshoot’ the normal level. PUVA (five patients) caused rapid normalization (in 9–12 weeks) of keratins 2 (66 kd) and 18 (44 kd), but had much weaker effects on keratins 1 (70 kd) and 10 (57 kd). These results suggest that resolution of lesions as judged by clinical criteria can occur without normalization of the keratin electrophoretic profile. Possibly the most reliable marker of clinical resolution was the reduction in keratin 16 (50 kd), since treatment effects on the differentiation of keratins 1 (70 kd) and 2 (66 kd) were different. [ABSTRACT FROM AUTHOR]

Sixty patients with palmoplantar pustulosis were treated in a double-blind trial with either acitretin (etretin, Ro 10-1670) or with etretinate. The study consisted of 4 weeks of therapy with three 10 mg capsules/day followed by 8 weeks of therapy with a varying number of capsules given daily according to therapeutic response. At the end of the 12-week treatment period, the mean number of pustules (±SEM) had decreased from 57.8 (±8.6) to 3.9 (±1.6) in the acitretin group and from 57.1 (±14.1) to 5.7 (±2.7) in the etretinate group. With regard to influence on erythema, infiltration, scaling, and area involved, similar improvements were obtained in both treatment groups. Adverse reactions of the hypervitaminosis A type were observed with almost the same frequency and severity in both treatment groups. The mean number of 10 mg capsules used daily was comparable in the two groups: 2.82 (range 1.23–4.67) for acitretin and 2.77 (range 1.60–4.82) for etretinate. It can be concluded that acitretin and tretinate do not significantly differ with regard to efficacy and overall safety in the treatment of patients with palmoplantar pustulosis. [ABSTRACT FROM AUTHOR]

A family with a clinical variant of Papillon-Lefèvre syndrome (PLS), associated with recurrent pyogenic infections, has been followed up for more than 20 years. Of the five living siblings, four were treated with etretinate for a period of at least 21 consecutive months. Clinical follow-up showed that the course of recurrent infections in susceptible PLS patients, although usually more severe in childhood, can be variable and unpredictable. The etretinate therapy resulted in marked improvement of the keratodermas, and was associated with complete remission of the pyodermas on both keratotic and non-keratotic skin. It is, therefore, suggested that etretinate may have a primary role in the prevention of recurrent pyogenic infections in susceptible PLS patients. [ABSTRACT FROM AUTHOR]

In an ongoing study of patients on long-term etretinate (Tigason) therapy, 13 patients with a congenital or inherited disorder of keratinization and 10 patients with psoriasis were examined to investigate the incidence of, and the factors associated with, skeletal hyperostosis. Skeletal scintigraphy, plain radiographs, haematological and biochemical analyses were performed. Using all criteria, 7 of 13 patients with a congenital or inherited disorder of keratinization showed evidence of hyperostosis. No single investigation was able to detect all these cases; in particular, skeletal scintigraphy was positive in only nine of the 13 patients who showed hyperostosis. Eleven of the 13 patients with hyperostosis gave a history of musculoskeletal symptoms compared with three of the 10 patients without hyperostosis. There was no clear association with total dose or duration of treatment. Serum chemistry and haematological studies were normal. In two patients the 24-h urinary calcium excretion was significantly elevated, an abnormality which has not been described previously. Annual lateral thoracic spine radiographs with additional views of symptomatic areas are recommended for patients on longterm etretinate therapy. [ABSTRACT FROM AUTHOR]

Eleven patients with mycosis fungoides (MF) were treated with recombinant alpha-interferon (rIFN-α2a2) in combination with etretinate (seven patients) or alone. One patient, who also received etretinate, went into complete remission and remained without signs of ME after 18 months. Six patients experienced partial remission; one of these was treated with rIEN-α2a alone and was clinically in complete remission, but had still a pleomorphic skin infiltrate. Two patients were non-evaluable, and two stopped therapy due to progressive disease. Five patients discontinued therapy due to side-effects although three had partial remission of their disease. Only four patients received 12 months therapy. The study shows that rIFN-α2a in combination with etretinate or alone can induce remission of MF. [ABSTRACT FROM AUTHOR]

Eighty patients with severe psoriasis were treated in a double-blind fashion with either an initial dose of 10 mg, 25 mg or 50 mg of etretin daily or with placebo. Follow-up examinations were carried out monthly and the efficacy of treatment was evaluated by using the PASI score. Adverse effects of the treatment were recorded monthly; liver enzymes, cholesterol and triglycerides were measured. After 2 months of treatment the maintenance dose was reduced in some of the patients either because of complete remission or adverse effects. After 2 months treatment, groups receiving 25 mg/day and 50 mg/day showed significantly lower PASI scores than the placebo group. The 10 mg/day group showed a response intermediate between the 25 mg and 50 mg groups and the placebo group. Thus, the optimal initial dose seems to be approximately 25 mg/day and the maintenance dose somewhat lower. Six months after the start of treatment there were no significant differences between the four groups; the last follow-up examination took place during the summer and some of the patients probably experienced spontaneous improvement. Although clinical adverse effects were frequent in all groups, severe side effects, namely hair loss and paronychia, occurred frequently only among patients treated with an initial dose of 50 mg of etretin daily. The effect of treatment on liver enzymes, cholesterol and triglycerides was minimal. [ABSTRACT FROM AUTHOR]

The effect of etretinate on the intra-epidermal accumulation of polymorphonuclear leukocytes following epicutaneous application of leukotriene B4 was studied in five psoriatic patients. Polymorphonuclear leukocytes were quantified using the marker enzyme elastase. An inverse relationship was found between the dosage of etretinate and the number of infiltrating polymorphonuclear leukocytes. [ABSTRACT FROM AUTHOR]

Three patients who received etretinate, two for psoriasis vulgaris and one for exfoliative dermatitis, developed clinical and electromyographic features of muscle damage during treatment. In one patient histological and ultrastructural findings indicated segmental muscle necrosis. Withdrawal of the drug led to clinical recovery and normalization of muscle enzyme levels and electromyogram. To the best of our knowledge, this is the first report to show etretinate-induced reversible skeletal muscle damage. [ABSTRACT FROM AUTHOR]

We have studied the effect of systemic administration of etretin (Ro 10–1670) on the epidermal interleukin 1 (IL1) pool in the rat. Hairless rats were given varying doses of etretin intraperitoneally for 21 days, or a fixed dose for 2, 8 and 16 days. Abdominal skin was taken and processed for light microscopy, autoradiography (using [³H]-thymidine) and IL1 assays. IL1 was assayed in supernatants of epidermal extracts by both the lymphocyte activating factor (LAF) assay and the stimulation of prostaglandin E2 (PGE2) release from dermal fibroblasts. A significant increase in both LAF and PGE2 stimulatory activities was found during etretin administration. After 21 days' treatment with varying doses there was a two- to three-fold increase as compared to the controls, with a peak at 2 and 5 mg/kg. At a fixed dose a two-fold increase was found after 2 days and a three- to four-fold increase after 16 days; normal pretreatment values were restored 16 days after cessation of etretin. This is the first demonstration in vivo that a retinoid can modulate IL1 content in a tissue. As epidermal IL1 has been found to be decreased in psoriasis, its modulation by retinoids might have therapeutic significance. [ABSTRACT FROM AUTHOR]

Following recent reports of the development of skeletal abnormalities in patients treated with etretinate (Tigason®), we have examined 19 children and adolescents on long-term treatment with etretinate, using 99mtechnetium methylene diphosphonate (99mTcMDP) whole body bone scans and musculoskeletal assessment. No significant bony abnormalities were detected. We believe that the available evidence does not warrant alarm, and that long-term etretinate therapy can probably be given with a low risk of musculoskeletal toxicity if certain precautions are taken, in particular the use of low maintenance dose levels, early investigation of symptoms of musculoskeletal pain or stiffness, and regular 99mTcMDP bone scans. [ABSTRACT FROM AUTHOR]

We report two patients treated with etretinate (Tigason®) who developed a nodular prurigo-like eruption. We consider this to be an unusual side-effect of the drug. [ABSTRACT FROM AUTHOR]

Radiographic skeletal examinations were performed in eight adult patients who had received the aromatic retinoid etretinate for various disorders of keratinization over periods ranging from 1 to 7 years. Age- and sex-matched controls were also examined. In all the patients, alterations of ossification were found to a varying degree, including calcification of the anterior spinal ligament, vertebral hyperostoses at the anterosuperior and anteroinferior margins of the vertebral bodies, unilateral bridging of vertebral bodies, hyperostoses of the calcanei at the insertion of the plantar ligament and bone accretion at the anterolateral lips of the acetabula. All the bone changes were asymptomatic. Serum calcium, inorganic phosphate, alkaline phosphatase, calcitonin and parathormone were within normal physiological ranges. In general, the bone changes observed after long-term etretinate treatment closely resembled the effects of isotretinoin on the skeleton. [ABSTRACT FROM AUTHOR]

Twenty patients with palmoplantar pustular psoriasis were treated initially for 4 weeks with 70 mg etretinate daily. This led to clinical improvement and a significant fall in pustule count. The patients were then allocated randomly to 30 mg etretinate daily or placebo for a further 12 weeks. There was a rapid deterioration in the clinical condition and a rise in pustule count in the placebo group. The etretinate-treated group still showed clinical improvement and a significantly lower pustule count after 12 weeks. Clinical side-effects were few and adverse effects on liver function and serum lipids were not found. [ABSTRACT FROM AUTHOR]

Six subjects taking isotretinoin were studied, none of whom had clinical or phototest evidence of photosensitivity. Of nine subjects taking etretinate, one had convincing clinical photosensitivity consisting of a burning erythema on sunlight exposure. His phototesting results showed a marked abnormality from 300 ± 5 nm to 365 ± 30 nm which returned close to normal limits within one month of stopping therapy. Although clinically normal, another subject taking etretinate had similar phototest evidence of abnormal photosensitivity. In vitro photohaemolysis studies demonstrated that tretinoin (all-trans-retinoic acid) and isotretinoin have a phototoxic potential, while etretinate has none. However, the major metabolite of etretinate (Ro 10–1670) had a phototoxic potential greater than that of tretinoin. The apparently low incidence of photosensitivity suggests that an idiosyncracy is responsible, perhaps due to a disorder of pharmacokinetics or metabolism. Clinical cases should use appropriate photoprotection against UVB and UVA wavebands. [ABSTRACT FROM AUTHOR]

Discusses the adverse effects of isotretinoin and etretinate on serum lipids. Levels of serum triglyceride and cholesterol after treatment with isotretinoin; Measurements of serum lipids after treatment with etretinate; Changes in lipid metabolism during retinoid administration.

Normal subjects and ichthyotic patients were biopsied before and after etretinate (Tigason®) therapy. Histometric and cell kinetic measurements showed minimal changes following treatment. The metabolic activity across the epidermis was measured by a novel approach using the Quantimet 720 image analyser, and was significantly increased in the normal subjects as demonstrated by glucose-6-phosphate dehydrogenase (G6PDH), succinic dehydrogenase (SDH) and non-specific esterase (NSE) activities. In the ichthyotics studied the levels of G6PDH and SDH activity were significantly lowered following etretinate therapy, to levels similar to those demonstrated in normal subjects. In contrast, the activity of NSE was increased in the ichthyotics after etretinate therapy. It is suggested that the effect of retinoids is to ‘normalize’ the process of epidermal differentiation when it is abnormal. The retinoids have a striking effect on epidermal differentiation, and it is probable that it is via this mechanism that they exert their therapeutic effects in psoriasis and disorders of keratinization. Their exact site of action is uncertain. Effects on glycoprotein synthesis, mannosyl transfer, lipid synthesis and cell replication have all been recorded, but which of these is fundamental to their action is uncertain (Marks et al., 1984). Clearly these compounds have important biological effects that are only partially characterized in biochemical terms. The present study was carried out on normal and ichthyotic subjects, using cytochemical and cell kinetic techniques, to elucidate further the molecular basis of the clinical effectiveness of the retinoids. [ABSTRACT FROM AUTHOR]

Treatment with etretinate in a patient with multiple keratoacanthoma is described. Clinical improvement correlated with normalization of IL-2-production and mitogen induced lymphocyte proliferation. A causal relationship between reduced IL-2-production and eruption of keratoacanthoma is suggested. [ABSTRACT FROM AUTHOR]

In a double-blind controlled study of patients with pustular psoriasis of palms and soles who were allocated at random to etretinate or placebo, we found that etretinate improved the condition as assessed by pustule count and overall clinical response. Side-effects occurred but were accepted by the patients in the short-term. The clinical usefulness of etretinate in this condition will depend on time to relapse, and whether this can be prevented or postponed by continuous treatment. Toxicity in the long-term will also be important. [ABSTRACT FROM AUTHOR]

Acute hepatitis developed in a patient taking etretinate for severe psoriasis. Discontinuation of therapy was followed by progression of the histological changes to chronic active hepatitis, despite improvement of his clinical and laboratory status. This is the third reported case of chronic aetive hepatitis associated with etretinate therapy, and the second patient in our group of twenty-two etretinate-treated patients with severe psoriasis to develop clinically significant hepatic disease. Immunological evaluation revealed a marked increase in the patient's OKMI-staining population of peripheral mononuclear cells and augmentation of Con A-induced lymphocyte blastogenesis in the presence of etretinate. [ABSTRACT FROM AUTHOR]

A 63-year-old woman with eruptive keratoacanthomas on sun-exposed skin is reported. Attempts were made to produce lesions by the application of a tumour homogcnate to the scratched skin, followed by UV-B irradiation; this was positive in two out of three sites, but these factors were probably non-specific stimuli. Treatment with oral etretinate led to most of the tumours disappearing within a month. Recurrence was seen on stopping the drug. Recommencement of therapy followed by a maintenance dose of 10 mg on alternate days, has been associated with freedom from the skin lesions. [ABSTRACT FROM AUTHOR]

A harlequin fetus seen at birth was treated with etretinate and more general measures, including careful attention to fluid balance, calorie intake and temperature control. She improved, continued to develop, and had survived to 5 months at the time of this report. A harlequin fetus was seen on the first day of life. She was the twelfth child of unrelated Bangladeshi parents and was the fifth harlequin fetus in the family (Fig. 1). The other four, two boys and two girls, died shortly after birth. Our patient was treated with etretinate, emollients and humidified temperature control and is reported because of her survival and encouraging progress. [ABSTRACT FROM AUTHOR]

Eighty-four patients with persistent palmoplantar pustulosis (PPP) of long duration were treated with either etretinate or one of three PUVA regimens. PUVA was given either with oral methoxsalen (thirteen cases), with a 1% methoxsalen cream (thirty-three cases) or with trioxsalen baths (eighteen cases). Twenty patients were treated with etretinate. Patients were assessed every fourth week. A mean score for each group was calculated at each visit based on erythema, desquamation, induration and pustulation. In addition, the number of pustules was calculated at each visit. After 12 weeks four of twenty-eight patients treated with local methoxsalen and fourteen of seventeen patients treated with etretinate had completely cleared. At this stage no patient treated with local trioxsalen or oral methoxsalen showed complete clearance. [ABSTRACT FROM AUTHOR]