The treatment of psoriasis with etretinate and acitretin: a follow up of actual use

ARTICLE

The actual usage of a treatment may differ from the established guidelines. For published guidelines on the use of systemic retinoids the reader is referred to some recently published reviews [1-3].

In order to investigate the actual use of systemic retinoids in psoriasis, the case record forms of patients, included for the first time with etretinate or acitretin between 1981 and 1989, were analysed. This time interval was selected in order to assure a follow up period of at least 10 years.

Demographics

The diagnosis-record system indicated 2,000 records of patients with psoriasis. In total, 115 patients had used a retinoid within this episode. The patients'records permitted evaluation in 94 patients, 68 of them were treated with etretinate, 16 with acitretin and 10 with both retinoids. The group comprised 46 men and 48 women. Out of the women 25 were of childbearing potential (12-52 years old).

Most patients were between 40 and 70 years of age.

Subtypes of psoriasis and comorbidity

The vast majority of patients (53) were suffering from an erythematosquamous manifestation. In total 29 patients had a pustular manifestation and 6 of them had erythrodermic psoriasis. 64 extracutaneous manifestations were observed in total. Psoriasis arthropatica was seen in 16 of them.

The frequency of other skin disorders suggested an association between psoriasis and several manifestations of eczema: 9 patients had allergic contact dermatitis, 8 patients suffered from atopic dermatitis and 6 from dyshidrotic eczema of the hand.

Previous treatments

The majority of patients had had psoriasis for more than 5 years. Virtually all patients had used a topical corticosteroid before retinoid treatment was initiated. As calcipotriol was available as a routine treatment after 1992, the use of calcipotriol as indicated in the present study was not representative for the actual use today. Less than 50% of the patients had not used dithranol or tar preparations.

In total 42 had been admitted to the in-patient department for dithranol treatment, before inclusion for retinoid treatment. The admission had been for 2 months or longer in 31 patients.

In 64 patients phototherapy or photo(chemo)therapy had been initiated. In 36 patients another systemic treatment had been given before retinoid treatment.

Indications and pre-retinoid screening

In general, several reasons can be given to select a single treatment. Table I summarises the major argument, which is given in the patient record to initiate retinoid treatment. In 50 patients no major reason has been given. The most frequent reason proved to be insufficient efficacy of previous treatments.

Initiation and duration of treatment

Etretinate was the only systemic retinoid available for routine treatment between 1980 and 1990. Between 1987 and 1990 acitretin was available as experimental treatment. Since 1990 acitretin was the only systemic retinoid available for routine use. Twelve patients were treated with etretinate for more than 1 year, 16 patients for more than 6 months and 42 patients for less than 6 months, whereas the treatment duration was not clear from the patient records in 35 patients. Acitretin was prescribed for more than 1 year in 10 patients, for more than 6 months in 13 patients, 10 patients received acitretin for less than 6 months and in 5 patients the duration was unclear.

Combination treatment

In total 22 patient records revealed no information on any adjunct treatment. In fact in 2 records it was explicitly indicated that the patient had used no adjunct treatments. Table II summarises the combinations. The most frequent combination was retinoid-topical corticosteroids (67%). The combination of retinoid-photochemotherapy was provided in 19% of the patients, while 23% of the patients got retinoid-UVB.

The patient records revealed some co-medications, which might cause drug interactions with acitretin. Tetracylins (2 patients), non-steroid anti-inflammatory drugs (8 patients) and trisporal (2 patients).

Doses

The initial doses of etretinate and acitretin have been recorded in the various manifestations of psoriasis. In pustulosis palmoplantaris the most frequently used initial dose was 50 mg/day. In generalised pustular psoriasis this dose was 50 mg for etretinate and 25-50 mg for acitretin. In acrodermatitis continua Hallopeau, etretinate was started at 30-75 mg and acitretin at 35 mg. The most frequent initial dose in erythrodermic psoriasis was 50 mg for both etretinate and acitretin. In psoriasis arthropathica the most frequently prescribed initial dose was 50 mg for etretinate and 35 mg for acitretin. In erythematosquamous variants of psoriasis the most frequently prescribed initial doses were 50 mg and 75 mg and for acitretin 20 mg and 25 mg.

The maintenance doses were recorded in all patients and varied during treatment. In pustulosis palmoplantaris the most frequently used maintenance doses for etretinate were 25 mg and 50 mg and for acitretin 25 mg and 35 mg. Generalised pustular psoriasis was maintained with doses of 50 mg and 75 mg as most frequent doses for etretinate and 20 mg and 35 mg as most frequent doses for acitretin.

Acrodermatitis continua Hallopeau was maintained with doses between 25 and 50 mg. The most frequent maintenance dose in erythrodermic psoriasis was 50 mg for etretinate and 25 and 35 mg for acitretin. In arthopathic psoriasis the most prescribed maintenance doses were 50 and 75 mg for etretinate and for acitretin 25, 35, and 40 mg.

Dose changes/interruptions

The majority of patients [50] had one or more changes of dosage. In 42 patients the reason for changing the dose was not mentioned. The following reasons for dose changes were recorded. In 31 patients subjective side effects: in 16 patients mucocutaneous side effects, in 16 patients extracutaneous side effects including nausea (4), headache (3), impaired vision (2), joint complaints (2), anorexia (1), dizziness (1), gastric discomfort (1), fatigue (1), restlessness (1). In 8 patients objective side effects necessitated a change of doses: liver function abnormalities (2), hyperlipidaemia (6), abnormal vertebral X-ray (1), kidney function disorders (1). Remaining reasons for changes of the dose were fertile age (1), temporary discontinuation for reason of holidays (1), cholecystectomy (1).

Side effects necessitated discontinuation of treatment in 33 patients. In 4 patients laboratory examinations necessitated discontinuation and in 29 patients various subjective side effects resulted in discontinuation of doses.

Efficacy

The efficacy of etretinate was rather difficult to estimate from the patient records. Often the use of combination therapies was not described (20 patients) and there was no scoring system for efficacy. If no estimation at all was possible such was indicated as unknown, further an attempt was made to judge the efficacy as "good", "variable", "moderate", "poor". Table III summarises the results in various subpopulations. It can be seen that the patients have a rather different response from poor to good. The response in arthropathic psoriasis was poor in the majority of patients. In erythrodermic psoriasis and pustular psoriasis 21 patients showed a good and 7 a poor response out of a total of 43 patients.

Side effects

Mucocutaneous side effects were observed in at least 89% of the patients. In addition, pruritus, dry mouth, vulnerable skin, hair loss and conjunctivitis were each observed in more than 5% of the patients.

Headache, arthralgia/myalgia, dizziness, nausea and fatigue were each observed in more than 5% of the patients. Liver function abnormalities, increased cholesterol and triglycerides were observed in 50% and 42% of the patients or more.

Only in 1 patient treated with etretinate was X-ray examination of the vertebral column performed. Out of the 26 patients treated with acitretin, osteophytes were observed in 2, and ossification of tendons and ligaments in one of them.

Comparing etretinate and acitretin with respect to side effects, it is intriguing that mucocutaneous side effects and subject systemic side effects and occurrence of extraossal hyperostoses were more frequent in the acitretin treated patients. On the other hand the frequency of laboratory side effects were generally comparable.

Discontinuation of retinoid treatment and follow-up

In total 52 out of 94 patients had discontinued etretinate or acitretin treatment during follow-up. At the end of follow-up (May 1999) 5 patients are on continuous acitretin treatment and 36 patients were not under treatment at the Nijmegen Centre anymore and were lost from follow-up.

The majority of patients had discontinued retinoid treatment for reason of subjective side effects. During long-term follow-up, only 2 patients had discontinued treatment for hyperlipidaemia and no single psoriatic patient for hyperostosis. Also in the 12 patients who where treated continuously for more than 3 years no signs of extraossal hyperostoses were observed. Insufficient and sufficient efficacy were the reason for discontinuation in 10 and 8 patients respectively.

After discontinuation of retinoid treatment 16 patients had a severe condition and 13 a moderate condition. Although subsequent treatments with other medications Table IV reviews the treatments by patients during follow-up.

During long-term follow-up, 30 patients came under treatment at our centre. In 19 patients photo(chemo)therapy was given at episodes, methotrexate was prescribed in 12 patients.

Following discontinuation of etretinate or acitretin treatment no relevant adverse events were noticed which could have resulted from retinoid treatment.

Discussion

The present study is a retrospective analysis of "what actually was performed with systemic retinoids in patients with psoriasis". Of course, such implies that we are not dealing with a controlled comparative analysis and that practical issues such as loss from follow-up are a major limitation in the present approach. On the other hand, to be informed about how systemic retinoids actually were prescribed and what the results of such treatment appeared to be, during long-term follow up (at least 10 years) was what we wanted.

Between 1981 and 1990, 94 patients with psoriasis using etretinate and acitretin from a group of 2,000 patients were included in the retrospective analysis, which implies that only 5.7% of the psoriatic patients visiting the Nijmegen centre were regarded as eligible for retinoid treatment. In the same group 4.3% of the patients had been included for methotrexate treatment (K. Blummel, et al. personal communications).

In a search under members of the Dutch patients association for psoriasis, in total 16% had used a systemic treatment during the previous half year [4].

Most patients included for acitretin treatment were beyond 40 years of age. The male/female ratio was approximately 1:1. In view of the teratogenic potential of acitretin such is surprising, however acitretin had been available for some time with the erroneous supposition that one month's contraception was sufficient, which might partly explain this male/female ratio.

In the cohort of patients the frequency of subtypes of psoriasis were: pustular psoriasis (30%), erythrodermic psoriasis (6%) and arthropathic psoriasis (17%). The frequency of these subtypes of psoriasis is much lower in an unselected population [5, 6]. Remarkably, in 9.5% of the patients, allergic contact dermatitis was observed. In the present cohort with a relatively large number of patients with palmoplantar pustulosis, such might well be the result of induced psoriasis by allergic contact dermatitis, a phenomenon which has already been described by Steigleider and Orfanos [7].

The majority of patients in the retinoid cohort have had psoriasis for more than 5 years. In 56% of the patients etretinate or acitretin was the first systemic treatment in these patients. The most important reason for including a patient for retinoid treatment was insufficient therapeutic response to previous treatments. The subtype of psoriasis (pustular- or erythrodermic psoriasis) was the reason for inclusion in 14% of the patients.

In general, less than 10 patients per year were included. In the years 1981-1983 a temporary increase of inclusion was observed, as in those years a strict protocol adherence to liver biopsy in methotrexate treatment was installed.

Continuous treatment for more than one year was recorded only in 20% of the patients. During long-term follow-up, 25% of the patients were included again for retinoid treatment. In 33% of the patients a prolonged treatment for more than one year actually occurred.

Combination treatment has been advocated as a highly effective principle, especially the combination of a retinoid with phototherapy or photochemotherapy [1-3, 8, 9].

The dosage management is recommended to be dependent upon the subtype of psoriasis [1-3].

In patients with pustular psoriasis high doses are recommended, in erythrodermic psoriasis low doses are recommended and intermediate dosages are recommended in chronic plaque psoriasis. In the present study both the initial doses and maintenance doses did not follow this principle. The dosing was set to efficacy and tolerance, but the classical division of doses in the psoriatic subgroups was not evident. In the majority of patients dosage adaptations were needed. Treatment was discontinued in 41% of the patients for reason of side effects, in 13% of them for reason of insufficient efficacy and in 9.5% the treatment could be discontinued as a result of complete clearing. In particular, 56% of patients with pustular and erythrodermic psoriasis responded well to treatment and a poor response in this subgroup was noticed in 16% of them. The present study reconfirmed that systemic retinoids are not effective in arthropathic psoriasis.

The side effects as encountered in the present study largely followed the observed side effects. However, the high percentage of increased serum triglycerides and cholesterol are probably due to the fact that fasting blood was not always investigated, retinoid induced hyperlipidaemia in general affects triglycerides and not cholesterol and triglycerides at the same time. It is of interest that subjective side effects seemed to be more frequent in acitretin treated patients, although increased transaminases or hyperlipidaemia was not different comparing etretinate and acitretin treated patients.

Also in those patients who had continued treatment for more than 3 years, hyperostoses had never been the reason for discontinuation of retinoids. Such is in line with earlier observations in our centre, indicating that the occurrence of diffuse idiopathic hyperostoses is not dependent on the cumulative dose of the retinoid [10].

Follow-up during at least 10 years revealed that no serious side effects occurred in this patient collective (n = 94). In those patients who completed the entire follow-up in our centre (n = 30), photo(chemo)therapy (n = 19) and methotrexate (n = 12) were the most frequently used major treatments.

Article accepted on 20/7/00

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