Acitretin versus etretinate in psoriasis. Clinical and pharmacokinetic results of a German multicenter study

175 patients with severe psoriasis of different types were treated with 10, 25, or 50 mg acitretin and compared with patients receiving 50 mg etretinate over a period of 8 weeks in a randomized, double-blind multicenter study in the Federal Republic of Germany. Plasma concentrations of etretinate and its metabolite acitretin were measured during therapy and also 3 weeks after cessation of treatment. After 4 weeks of treatment, a trend toward clinical improvement was shown in all groups with increasing dosage. Those groups receiving the lower acitretin doses (i.e., 10 and 25 mg/day) had more dropouts than the groups taking 50 mg acitretin or 50 mg etretinate. Complete remissions before the end of therapy occurred only among those receiving higher doses. Enlargement of psoriatic lesions, however, could be observed during treatment with both retinoids, despite improvement of other parameters, as measured by psoriasis area and severity index (PASI) and psoriasis severity index (PSI). After 8 weeks, a significant improvement was calculated by the PASI score and by a newly defined, corrected PASI score for all four dose regimens compared with baseline levels. A greater than 50% PSI score improvement was seen in 50% of patients treated with 10 mg acitretin, 40.5% with 25 mg acitretin, 53.8% with 50 mg acitretin, and 61.1% with 50 mg etretinate. No statistical differences were found among these groups at any time during the 8-week period. No new or unexpected side effects occurred during acitretin treatment. Moreover, cholesterol levels did not significantly change. Three weeks after cessation of drug administration, the plasma concentrations of acitretin were below the sensitivity level of the assay, whereas etretinate was still quantifiable. It is interesting that acitretin plasma concentrations during therapy with 50 mg acitretin were markedly lower (means = 18 ng/ml) than were acitretin levels during treatment with 50 mg etretinate (means = 36 ng/ml).     

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.     

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.     

Acitretin (Ro 10-1670) in the Treatment of Severe Psoriasis

A randomized double-blind parallel trial comparing acitretin and etretinate was performed in 20 patients with severe psoriasis during a treatment period of 12 weeks. The initial dose was 30 mg/day for 4 weeks, and the mean dose at the end of the study was slightly lower in the acitretin group when compared to the etretinate group (30.7 mg/day and 33.4 mg/day, respectively). Follow-up examinations were carried out every 2 weeks, and the efficacy of treatment was evaluated by using the PASI score. Percentage improvement in the PASI score was 50% at week 10 in both groups, and the difference between them at week 12 was insignificant. Both quantitatively and qualitatively, acitretin and etretinate do not significantly differ.     

Acitretin and etretinate in the treatment of palmoplantar pustulosis: a double-blind comparative trial

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 etretinate do not significantly differ with regard to efficacy and overall safety in the treatment of patients with palmoplantar pustulosis.     

Efficiency of acitretin in the treatment of cutaneous lupus erythematosus

Acitretin (etretin [Ro-10-1670]) is the major metabolite of etretinate with a much shorter elimination half-life. The drug was used in the treatment of 20 patients who had cutaneous lupus erythematosus. All patients responded to treatment, but in five, the result was unsatisfactory. In 15 patients, an excellent (total clearing) or good response (marked reduction of all lesions) was seen. In seven of them, acitretin was superior to previous therapy with antimalarials and/or systemic corticosteroids. In particular, five of six patients with subacute cutaneous lupus erythematosus showed complete clearing of their lesions, usually within two to four weeks. Side effects were the same as with etretinate. It is concluded that acitretin is a highly effective and well-tolerated drug in the treatment of cutaneous lupus erythematosus.     

Lack of significant skeletal changes after long-term, low-dose retinoid therapy: case report and review of the literature

BACKGROUND: Long-term systemic retinoid therapy has been associated with skeletal side effects. There have been reports of diffuse idiopathic skeletal hyperostosis (DISH) syndrome, calcification of ligaments, and osteoporosis, as well as premature fusion of epiphyses and modeling abnormalities of long bones, occurring in patients on chronic high-dose isotretinoin, etretinate, and acitretin therapy. Low-dose acitretin has been used for many years as monotherapy or in combination with other systemic therapies for psoriasis. Evidence to date suggests that the frequency of symptomatic bony effects is quite low in these patients. OBJECTIVE: To present the radiologic findings of a patient on long-term, low-dose acitretin and etretinate and to review the literature on the radiologic evidence of skeletal side effects during retinoid therapy. METHODS: Case report and literature search. RESULTS: A patient on low-dose acitretin had no significant radiologic abnormalities associated with retinoid use after 9 years of treatment. A review of the literature revealed conflicting reports on the incidence of radiologic abnormalities in patients on retinoid treatment. CONCLUSION: The evidence to date does not substantiate a clear link between radiologic skeletal abnormalities and long-term, low-dose acitretin or etretinate therapy.     

An appraisal of acitretin therapy in children with inherited disorders of keratinization

Retinoid therapy represents the treatment of choice for severe inherited disorders of keratinization. This paper reviews our experience of acitretin, compares acitretin with etretinate and defines guidelines for treatment. Forty-six children have received acitretin since 1992 in our hospital: 29 children had either lamellar ichthyosis (nine), non-bullous ichthyosiform erythroderma (five), bullous ichthyosiform erythroderma (four), Sjögren-Larsson syndrome (three) or another rare condition (eight). The other 17 children who had psoriasis (16) and extensive viral warts (one), were excluded. Data on efficacy and tolerability of retinoid therapy were available for all but one patient. The cumulative follow-up was 472 months for acitretin. The mean (± standard deviation) optimal dosage for acitretin was 0-47 ± O17mg/kg per day, and this did not significantly differ between disorders. The overall improvement was considerable, with only three patients responding poorly. Mild to moderate mucocutaneous dryness was frequent. Minor abnormalities of liver function tests (four patients) and triglycerides (one patient) never led to changes of therapy. Irreversible side-effects did not occur. Acitretin therapy for children with inherited keratinization disorders is best started at 0-5 mg/kg per day. It represents a safe and effective treatment, provided that the minimal effective dose is maintained and that side-effects are carefully monitored. When switching from etretinate to acitretin, a 20% reduction is recommended if the etretinate dose is over 0-75 mg/kg per day or if side-effects are dose limiting. Otherwise the same dose can be used.     

Association between long-term acitretin therapy and osteoporosis: no evidence of increased risk

Osteoporosis has been observed with chronic hypervitaminosis A, leading some authors to hypothesize that systemic retinoids may have an effect on bone mineral density. Two previous small studies identified osteoporosis in patients who received long-term therapy with etretinate. Etretinate has now been superceeded by acitretin in clinical use. We hypothesized that bone mineral density is lower in patients taking long-term acitretin than control cases who had never taken acitretin. Thirty Caucasian patients receiving acitretin for a median of 3.6 years for a variety of dermatoses were studied. Bone mineral density measurements were determined using DEXA scanning at two standard sites, the lumbar spine and Ward's triangle. We did not find an association between daily dose of acitretin, total dose administered or overall duration of treatment and risk of osteopenia or osteoporosis. Acitretin appears to be safe for long-term use in patients with chronic dermatoses.     

Etretinate may work where acitretin fails

Acitretin (Ro 10-1670, Neotigason), a second-generation monoaromatic retinoid, is the main acid derivative and active metabolite of etretinate (Ro 10-9359, Tigason). Three patients who were unresponsive to treatment with acitretin but who responded to etretinate are reported. Twenty-nine patients in the U.K. are currently receiving etretinate on a named-patient basis. Possible explanations for the functional discrepancy between the two drugs are discussed.     

A double-blind comparison of acitretin and etretinate in combination with bath PUVA in the treatment of extensive psoriasis

Thirty-four patients with extensive psoriasis were treated in a double-blind parallel fashion with either acitretin plus bath PUVA (trimethylpsoralen bath + UVA) or etretinate plus bath PUVA. Each group consisted of 17 patients. The dose of retinoid was 40 mg/day during the 2-week monotherapy phase and subsequently 20 mg/day during the combination treatment. Bath PUVA was given three times a week starting with a UVA dose of 0.06 J/cm2. Remission (greater than 90% improvement) was achieved in all patients in 6-10 weeks. There were no significant differences in clinical response between the two groups; the mean +/- SD PASI score (psoriasis area and severity index) before treatment was 22.6 +/- 7.1 in the acitretin-PUVA group and 19.4 +/- 7.8 in the etretinate-PUVA group. The corresponding figures after treatment were 0.6 +/- 0.6 and 1.0 +/- 0.5, respectively. Side-effects related to retinoid treatment were frequent in both groups but they were usually mild and well-tolerated. There was only one case of diffuse alopecia after 8 weeks in the etretinate-PUVA group. Scaling of the palms and soles was seen in six patients in the acitretin-group but only in two patients in the etretinate-group. Triglycerides were elevated in about half of the patients in both groups. The present study shows that acitretin is as effective as etretinate in the combination with bath PUVA.     

Side-effect profile of acitretin therapy in psoriasis

Acitretin, the principal and free acid metabolite of etretinate, was used to treat patients with stable, plaque-type psoriasis. For the first 8 weeks, 38 patients received placebo or acitretin, 10, 25, 50, or 75 mg daily, in a double-blind manner. After the double-blind phase, the patients were allowed to continue for a total of 6 months of acitretin therapy at an average dosage of 50 mg/day. When the patients flared after stopping therapy, an additional 6-month course of acitretin therapy was offered. Acitretin, which was as effective as etretinate, had to be given at a dosage of 50 mg/day or more to obtain a significant benefit. Side effects frequently occurred in patients receiving acitretin, 25 mg/day or more, but were generally mild and did not warrant discontinuation of therapy. They were similar to those of etretinate therapy; cheilitis, peeling of palms and soles, and alopecia occurred most frequently. The most common abnormal laboratory test results were elevations in serum triglycerides and, to a lesser extent, serum cholesterol and liver transaminase levels. Acitretin, in view of its much shorter half-life and similar efficacy and side-effect profile compared with etretinate, may be a preferable therapy for psoriasis, especially in women of childbearing age.     

Retinoid therapy for psoriasis

This article focuses on the treatment of psoriasis with acitretin, the only systemic retinoid approved for psoriasis, and also briefly discusses its predecessor, etretinate, which was replaced by acitretin in 1997 and is no longer available. The use of topical tazarotene is also discussed in detail. Combination therapy of retinoids, both topical and systemic,with phototherapy and other therapeutic agents is described. In addition, new retinoid analogues that are undergoing clinical investigation are mentioned. Finally, potential toxicities and adverse effects associated with retinoids are discussed.     

Acrodermatitis continua of Hallopeau in a patient with myelodysplastic syndrome

Summary Acrodermatitis continua of Hallopeau (ACH) is a rare manifestation of pustular psoriasis which may considerably disable affected patients. In this case report we confirm the efficacy of acitretin in the treatment of ACH and. in addition, describe the course of the myelodysplastic syndrome (MDS) from which the patient was suffering. During acitretin treatment, there was a transformation into acute myeloid leukaemia. We discuss the effect of retinoids on the bone marrow of normal subjects, patients with MDS. and patients with acute myeloid leukaemia.
Our experience in the present case, and the information from the available literature, lead us to advise against the use of the aromatic retinoids, acitretin and etretinate, in patients with MDs. If such treatment is indicated, intensive haematological supervision is mandatory.     

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.     

Acitretin in the symptomatic therapy for severe recessive x-linked ichthyosis

Eight men with severe recessive x-linked ichthyosis were treated with acitretin, the main metabolite of etretinate, during four months. All of the patients showed marked clinical improvement of scaling during therapy. Hypervitaminosis A-type adverse reactions were observed in all patients. Although the overall tolerance was good, therapy was interrupted in one atopic patient because of pruritus. There were no undesirable laboratory changes in values. Thirty-five milligrams of acitretin daily provided the best efficacy, with minimal side effects. The beneficial effect of this retinoid lasted between four and six weeks after therapy was stopped. These results suggest that acitretin is a useful agent in the symptomatic therapy of severe recessive x-linked ichthyosis resistant to topical therapeutic modalities. Good results with this agent can be achieved with interval therapy adjusted to seasonal variations of the skin symptoms.     

Clinical Efficacy and Side Effects of Acitretin on the Disorders of Keratinization: A One-year Study

Acitretin, Ro 10-1670, the principal and free acid metabolite of etretinate, was used to treat twenty patients with disorders of keratinization. An open, prospective study of clinical efficacy, tolerability, and the effects of acitretin on lipid metabolism, hepatic function, and the osteoarticular system was performed over a one year period. Each patient was initially treated with 30 mg/day of acitretin or approximately 0.6 mg/kg/day. Doses were adjusted according to the clinical efficacy and maintained for one year. There were no statistically significant changes in liver function tests or lipid profile. Twelve of eighteen evaluated patients developed asymptomatic skeletal changes; the most common change was disc space narrowing, especially at thoracic-spine level (7 of 18 patients). The earliest bone change was detected 9 months after treatment. Acitretin is effective in improving the disorders of keratinization with mild mucocutaneous side effects and asymptomatic osteoarticular changes.     

Clinical and ultrastructural effects of acitretin in Darier's disease

Thirteen patients with Darier's disease with a mean extent of the lesions of 29.4 +/- 10% of the total skin area were treated with acitretin (the main metabolite of etretinate) for 16 weeks. The dose was 30 mg/day during the initial 8 weeks and was later adjusted individually to 10-30 mg/day in order to achieve optimal results. Three patients cleared completely, 7 patients showed marked improvement and 3 patients became slightly better during treatment. The mean extent of the lesions after the treatment was 7.3 +/- 8% of the skin area. Despite good clinical clearing, the improvement at the ultrastructural level was incomplete in the 3 patients studied by electron microscopy. Normal stratification did not develop and the size and number of desmosomes remained reduced. The main side effects during treatment were pruritus in 5 patients, diffuse alopecia in 2 patients and marked elevation in serum triglycerides in 4 patients. On the basis of this study, acitretin would seem to be a useful alternative to etretinate for the treatment of Darier's disease.     

UV-induced isomerization of oral retinoids in vitro and in vivo in hairless mice

Ultraviolet (UV) irradiation causes isomerization and destruction of many vitamin A analogues (retinoids). Using high-performance liquid chromatography (HPLC), we investigated in vitro and in vivo the effects of UV irradiation on 2 all-trans aromatic retinoids (etretinate and acitretin) and on 13-cis retinoic acid (isotretinoin). When etretinate and acitretin dissolved in ethanol were irradiated with UVB (280-320 nm; 10-336 mJ/cm2) or UVA (320-400 nm; 1-5 J/cm2), extensive and reproducible cis-isomerizations occurred at the 13-position (cis/trans ratio approximately 1.6 in all experiments) but there was no progressive photodegradation of the molecules. Irradiation of isotretinoin produced only moderate trans-isomerization but the sum of HPLC peak heights fell with increasing UV doses, being 72% of the original value after 336 mJ/cm2 of UVB. Hairless mice were given etretinate (50 mg/kg bw), acitretin (200 mg/kg) or isotretinoin (50 mg/kg) on days 1, 4 and 7 and were irradiated daily for 8 d with 13 mJ/cm2 UVB plus 1 J/cm2 UVA. Samples of serum, dorsal skin and liver were collected and retinoids analyzed by HPLC. In the etretinate and acitretin-treated, irradiated animals the serum concentrations of the 13-cis isomers were 2-6 times higher than in nonirradiated controls. Irradiated epidermis also contained significantly higher concentrations of 13-cis etretinate and 13-cis acitretin than did control epidermis. The serum and epidermal concentrations of all-trans etretinate and acitretin were unchanged or even increased after irradiation.(ABSTRACT TRUNCATED AT 250 WORDS)     

Efficiency of acitretin in combination with UV-B in the treatment of severe psoriasis

Compared with the antipsoriatic retinoid etretinate, the new aromatic retinoid acitretin represents an important advance due to its rapid elimination kinetics. Since in psoriasis vulgaris retinoids are used predominantly in combination regimens, we investigated the therapeutic efficacy of acitretin and UV-B compared with placebo and UV-B in a double-blind, randomized multicenter trial in 82 patients with severe psoriasis. They were treated with 35 mg of the study medication during the first 4 weeks of therapy and 25 mg thereafter, concomitantly with UV-B irradiation in increasing energy doses. Forty patients who underwent therapy with acitretin and UV-B and 38 patients who underwent therapy with placebo and UV-B were evaluated for efficacy. The target variables--psoriasis severity index and total UV-B dose--were reported at intervals of 2 weeks over a maximum period of 8 weeks. At the end of treatment, the psoriasis severity index decrease was 79% in the acitretin and UV-B group and 35% in the placebo and UV-B group. The response rate, defined as greater than or equal to a 75% decrease of the psoriasis severity index, was 60% for the combination treatment and only 24% for the control treatment. This treatment response was achieved with markedly lower cumulative UV-B energy. The median cumulative UV-B energy applied to reach 75% clinical improvement was 11.8 J/cm2 vs 6.9 J/cm2. Side effects showed a similar pattern in both groups. Our data show that the acitretin dramatically improves the results of UV-B treatment in patients with severe psoriasis. In addition, it markedly decreases the effective cumulative UV-B dose, thereby reducing the potential long-term hazards of UV irradiation. We conclude that the acitretin plus UV-B combination treatment represents a highly effective therapeutic regimen in severe psoriasis.