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.     

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.     

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.     

Epidermal Langerhans' cells in patients with pustulosis palmoplantaris treated with etretinate or etretinate + methoxsalen photochemotherapy

Epidermal Langerhans' cells (LC) were studied in patients with pustulosis palmoplantaris (PPP) by utilizing the monoclonal antibodies anti-Leu6 and anti-HLA-DR in combination with an immunoperoxidase technique. In non-pustular areas of the skin lesions in PPP, an increased number of epidermal LC was found compared with control subjects. No change in LC counts was observed following etretinate monotherapy for 2 weeks. Etretinate was then combined with PUVA treatment of one palm/sole with the contralateral side as a non-UVA exposed control. After 6-12 weeks of etretinate + PUVA treatment the PPP had resolved and the number of epidermal dendritic HLA-DR+ and Leu6+ cells had normalized. On the contralateral side, etretinate treatment induced a marked clinical improvement and a reduction of HLA-DR+ cells. The observation of an increased LC population in active PPP and a reduction during clinical improvement indicates a close relationship between LC and the activity of PPP.     

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).     

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.     

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.     

A study of etretinate alopecia

Twenty-two patients receiving etretinate were studied in an attempt to clarify the changes in hair cycle dynamics responsible for etretinate alopecia. Shed hair counts and telogen counts on samples of plucked hair were performed prior to therapy and after 6 and 12 weeks' treatment with etretinate. No evidence of anagen effluvium was found. In two individuals there were findings compatible with a classical telogen effluvium, but these had atypical features. The main finding in the study was an increase in the plucked telogen count, maximal at 12 weeks. As an arrest in the onset of anagen could produce only a comparatively small telogen increase, the predominant cause of this increase was a decrease in the duration of anagen. In two subjects there was also evidence of a telogen anchorage defect.     

Combination Therapy with Low-Dose Etretinate and Eicosapentaenoic Acid for Psoriasis Vulgaris

A randomized open study was undertaken to compare the therapeutic effects between low-dose etretinate alone and low-dose etretinate combined with eicosapentaenoic acid in 40 patients with chronic, stable psoriasis vulgaris. Better and more rapid improvement was obtained with the combination therapy for 12 weeks than with low-dose etretinate monotherapy. Eicosapentaenoic acid was safe, and adverse reactions due to low-dose etretinate were mild or tolerable. The combination regimen, therefore, has a satisfactory effect on psoriasis without marked adverse reactions.     

Etretinate therapy reduces polymorphonuclear leukocyte chemotaxis--enhancing properties of psoriatic serum

Using a Boyden chamber technic, we measured the directed chemotaxis of polymorphonuclear leukocytes obtained from control subjects or psoriasis patients when the leukocytes were placed in sera obtained from control subjects or psoriasis patients. The samples from patients were obtained before therapy and after 2 and 4 weeks of etretinate administration. Compared with control sera, the sera from seven untreated psoriasis patients significantly enhanced the chemotaxis of polymorphonuclear leukocytes from control subjects toward a chemotaxin (p less than 0.05). After 4 weeks of etretinate therapy, the chemotaxis-stimulating ability of the sera from psoriasis patients was no longer significantly greater than that of the control sera. This decline in the chemotaxis-stimulating activity of our patients' sera preceded significant clearing of their psoriasis. The levels of circulating etretinate in the blood of our patients could not account for the reduction. Etretinate therapy had no apparent direct effect on the chemotactic activity of polymorphonuclear leukocytes from the psoriasis patients but may act in part by reducing the inflammatory effects of psoriatic sera.     

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.     

Combined treatment of epidermodysplasia verruciformis with etretinate and α-interferon*

Epidermodysplasia verruciformis (EV) is an uncommon cutaneous disease in which a focal and genetically determined immunological impairment is associated with chronic human papilloma virus (HPV) infection. In sun-exposed areas, when an oncogenic HPV type is the agent, skin cancer may occur. The treatment of EV is difficult and often unsatisfactory; etretinate has been reported in some instances as effective in improving lesions. We report a typical case of EV with pityriasis versicolor-like lesions on the trunk and many flat, erythematous wart-like lesions on the face, dorsal areas of the hands and legs. We performed a treatment with etretinate (1 mg/kg/day for 6 weeks) and subsequently with etretinate and α₂r-interferon (3 MU, 3 times per week for 2 weeks, then 6 MU, as above, for 4 weeks). After 4 weeks of therapy with etretinate we observed moderate improvement; we did not observe any further clinical improvement in the final 2 weeks. The subsequent combined treatment with etretinate and a-interferon achieved further improvement. We conclude that the association of etretinate and a-interferon may represent an efficacious treatment of EV.     

Etretinate therapy for papuloerythroderma

Papuloerythroderma, first reported by Ofuji et al. (1984), is a rare cutaneous disorder whose pathogenesis remains unknown. Owing to the small number of cases, there is no recommended choice of treatment. This is the first report on the efficacy of etretinate for papuloerythroderma. Seven male cases ranging in age from 65 to 84 years were treated with moderate doses (0.2-0.6 mg/kg/day) of etretinate. All but one case showed quick and excellent responses and the chronic recalcitrant erythrodermatous lesions disappeared within 2-5 weeks. Eventually all the seven cases could be brought into remission. Once remission was achieved, etretinate was tapered by 0.1-0.2 mg/kg/day over a period of 2-4 weeks. One case remained in complete remission after cessation of etretinate without any treatment for 16 months. Another case could stop etretinate treatment and the subsequent recurrence of papular eruption could be managed by topical steroids. In the other five cases remission could be maintained by daily doses of 0.16-0.36 mg/kg etretinate. None of the patients developed severe side effects. Our observation suggests that etretinate is a safe and effective agent for papuloerythroderma.     

The effect of etretinate compared with different regimens of PUVA in the treatment of persistent palmoplantar pustulosis

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.     

Etretinate in the Treatment of Disseminated Porokeratosis of Mibelli

Abstract: ABSTRACT: A 30-year-old man with disseminated porokeratosis of Mibelli (DPKM) was treated with oral etretinate. The dose ranged between 75 mg/day and 50 mg/day for 21 weeks. An improvement of the lisions was observed especially of very painful verrucous plaques of the left shin. No serious side effects was seen. The patient, who had been incapacitated, is now able to work. The benefit of long-term therapy of etretinate should ne considered against its side effects.     

Two cases of distinctive exudative discoid and lichenoid chronic dermatosis of Sulzberger and Garbe responding to azathioprine

Twenty-eight patients with chronic plaque psoriasis affecting 20-40% of their body surface were treated with either PUVA and placebo (thirteen patients) or PUVA and etretinate (0.75 mg/kg) (fifteen patients). PUVA was given three times a week for a maximum of 10 weeks after a 2-week period on placebo or etretinate alone. Four patients failed to clear with PUVA and placebo compared with one patient with PUVA and etretinate, and the mean total UV-A dose to clear was lower with etretinate (mean = 62.1 J/cm2) than with placebo (mean = 77.3 J/cm2) but none of these differences were significant. Because the additional response to etretinate was only marginal, whilst unwanted effects were common, we found no advantage in adding etretinate to PUVA.     

Etretinate in the Treatment of Disseminated Porokeratosis of Mibelli

A 30-year-old man with disseminated porokeratosis of Mibelli (DPKM) was treated with oral etretinate. The dose ranged between 75 mg/day and 50 mg/day for 21 weeks. An improvement of the lesions was observed, especially of very painful verrucous plaques of the left shin. No serious side effect was seen. The patient, who had been incapacitated, is now able to work. The benefit of long-term therapy of etretinate should be considered against its side effects.     

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.     

Cellular actions of etretinate in psoriasis: enhanced epidermal differentiation and reduced cell-mediated inflammation are unexpected outcomes

Retinoids are potent cell growth and differentiation modulators, but cellular effects of therapeutic retinoids in psoriasis are unknown. We studied the effects of etretinate on pathological activation of keratinocytes and lymphocytes in patients treated systemically with this agent for 8 weeks. Ten patients with extensive psoriasis vulgaris were treated with etretinate at 0.75 mg/kg for 8 weeks. Skin biopsies obtained before and at 8 weeks of treatment were studied using immunohistochemical markers for keratinocyte proliferation or differentiation and for the presence of T-lymphocyte subsets or associated inflammatory proteins. During 8 weeks of treatment, the clinical severity decreased by a mean of 64% (p < 0.001). Compared to a similar group of patients treated with bath PUVA, psoriatic plaque erythema resolved more slowly and less completely (p < 0.05), but improvements in plaque thickness and scale were not significantly different between etretinate and PUVA treatments. Etretinate produced a 44% decrease in epidermal thickness (p < 0.001) and a 62% reduction in keratinocyte proliferation (p < 0.001) after 8 weeks of treatment. Unexpectedly, keratinocyte differentiation was enhanced following etretinate treatment as indicated by increased filaggrin production, increased number and size of keratohyaline granules, greater abundance of keratin filaments, and increased secretion of intercellular lipids from Odland bodies. The stratum corneum in resolving psoriatic lesions was unusually thin, probably caused by retinoid-induced shedding of corneocytes. “Regenerative” epidermal growth was maintained during etretinate treatment, as marked by continued expression of keratin 16 and a3-integrin by suprabasal keratinocytes. Surprisingly, the inflammation-associated proteins HLA-DR and ICAM-1 were no longer produced by epidermal keratinocytes following etretinate treatment, and CD3+, CD8+, and CD25+ T-lymphocyte subsets were reduced by 50-65% in lesional tissue (p < 0.01). Etretinate shows unexpected anti-inflammatory and pro-differentiation actions in psoriasis. Etretinate appears to function as a disease suppressive agent which improves hyperplasia, keratinocyte differentiation and tissue inflammation mediated by cellular immune elements.     

A sequential comparison of etretinate (Tigason®) and isotretinoin (Roaccutane®) with special regard to their effects on serum lipoproteins

Etretinate and isotretinoin were compared with respect to their clinical effects and changes in serum lipoprotein concentrations. Sixteen patients with hyperkeratotic and pustular disorders of hands and feet (mainly palmoplantar pustulosis) underwent a double-blind cross-over study. The daily doses of etretinate and isotretinoin were 50 and 40 mg, respectively. Each drug was given for 2 months with a 2-month intermission. The clinical score was reduced both by isotretinoin (P less than 0.05) and etretinate (P less than 0.001). Both drugs affected the lipoprotein concentrations. Isotretinoin increased the cholesterol concentration in low-density lipoprotein (LDL) by 20% and the triglyceride concentration in very low-density lipoprotein (VLDL) by 35%, but decreased the high-density lipoprotein cholesterol by 12%. Etretinate elevated LDL-cholesterol by 10%. These changes had reverted to normal 8 weeks after the end of treatment. The data suggest that in the diseases studied, etretinate is preferable to isotretinoin with regard to both clinical effect and serum lipid side-effects.