Short-term cyclosporin monotherapy for chronic severe plaque-type psoriasis

ARTICLE

Cyclosporin at moderate doses is an effective treatment for severe plaque-type psoriasis. Short-term tolerance is good. The long-term tolerance, in particular renal, is under investigation. The efficacy of cyclosporin in psoriasis is only palliative. It may therefore be used for short-term or intermittent treatment of severe episodes, thus preventing the occurrence of long-term side effects. The aim of this study is to evaluate the percentage of patients presenting with severe chronic plaque-type psoriasis successfully treated with a course of Sandimmun^® who do not require systemic treatment following discontinuation of cyclosporin.

Subjects

Patients were included if they were aged over 18 years, out-patients, and had severe and extensive chronic plaque-type psoriasis (at least one plaque outside the usual areas) resistant to psoralen plus ultraviolet A (PUVA) treatment and retinoids. Patients presenting with erythrodermic psoriasis or psoriasis of the palms and soles, kidney failure (serum creatinine higher than the upper limit of the normal range), liver failure, untreated hypertension (diastolic BP higher than 95 mmHg), previously treated with Sandimmun^® or arsenic, or receiving nephrotoxic or anticonvulsant medication were excluded. A history of cancer, monoclonal dysglobulinaemia and severe infection, or pregnancy, lactation and suspected lack of compliance were also exclusion criteria.

Methods

Treatment method

In this multicenter, open, non-controlled study, treatment duration was 28 weeks, followed by a follow-up period of 16 weeks after discontinuation of Sandimmun^®. The study was conducted in 3 phases. The first phase (D0 to W20) was initiated at a dosage of 3 mg/kg/d, with an increase in dosage of 1 mg/kg/d every 4 weeks until remission, but not exceeding 5 mg/kg/d. The dosage was gradually tapered over the second phase from W20 to W28 (2/3 of the maximal dosage from W20 to W24 and 1/3 from W24 to W28), and topical treatments were added in the event of recurrence. After W28 (third phase) the patients were monitored over 16 weeks to detect any relapse. All topical treatments were tolerated thereafter.

Assessment criteria

The main criterion was the absence of relapse, defined as the requirement to resume systemic treatment at W44. Efficacy was assessed by the patient and physician at the end of treatment (W28) using a 4-point scale (1 = recovery, 2 = marked improvement, 3 = slight improvement, 4 = no improvement) and the percentage of relapses on treatment discontinuation was taken into account. The tolerance criteria were the patient's and physician's overall assessment at the end of treatment, the occurrence of side effects, elevated serum creatinine levels and hypertension.

Statistical methods

The results were expressed as the mean or median plus or minus the standard deviation.

Results

Fifty-eight patients were enrolled at 23 centers. The study population comprised 38 men (65.5%) and 20 women (34.5%), mean age 45.8 ± 12.7 years (24-81). The psoriasis was severe (mean percentage of skin area affected on D0 44.7%) and long-standing (mean duration 19 years). The skin lesions were associated with psoriatic arthritis in 25.9% of cases. The previous treatments included PUVA treatment in 53 cases (91.4%), retinoids in 50 cases (86.2%) and methotrexate in 9 cases (15.5%).

The evaluable population consisted of 55 patients (1 not treated, 2 lost to follow-up in W4 and not evaluated). Forty patients (69%) completed the treatment period (D0-W28). The reasons for treatment discontinuation were: side effects (7 cases), treatment failure (1 case), patient's decision (5 cases), other reasons (2 cases).

The overall efficacy (recovery and marked improvement) of Sandimmun^® at W20 was 72% (39 patients improved, i.e. 23 recoveries and 16 marked improvements). The investigator's overall assessments were as follows: no change in 3 cases (5.5%), slight improvement in 7 cases (12.7%), moderate improvement in 6 cases (10.9%), good in 23 cases (41.8%) and excellent in 16 cases (29.1%). The mean effective dose was 3.5 ± 0.9 mg/kg (1.8-6.4 mg/kg) and the mean interval to recovery was 47.7 days (26-133).

At W28 (discontinuation), and at 1 and 4 months post-discontinuation, 28, 64 and 87% of the patients with improvement at W20 had relapsed respectively. Resumption of systemic treatment was necessary in 18 cases out 39 (46%) at 4 months. PUVA treatment was given in 5 cases, Soriatane^® in 3 cases and cyclosporin in 10 cases. No relapse requiring resumption of systemic treatment or premature withdrawal occurred in 18 cases out of 39 (1 patient lost to follow-up and 2 premature discontinuations).

At the end of treatment tolerance was assessed overall by the investigator as excellent in 25 cases (45.5%), good in 15 cases (27.3%), moderate in 8 cases (14.5%) and poor in 7 cases (12.7%). The patient's overall assessment at the end of treatment was excellent in 28 cases (51.9%), good in 16 cases (29.6%), moderate in 5 cases (9.3%) and poor in 5 cases (9.3%). The side effects resulting in premature treatment discontinuation were hypertension (4 cases), elevated serum creatinine levels (2 cases), hypertrichosis (1 case) and one death due to suicide. Forty-two patients (73.7%) presented with at least one side effect over the total duration of the study and the causal relationship with Sandimmun^®‚ and these side effects was certain or probable (French causality assessment score: I₄ + I₃) in 24 cases (42%). The main side effects were: an increase in serum creatinine level greater than 30% (25%), hypertension (40%), paresthesia (5%), hypertrichosis (9%), headache (2%), gingival hypertrophy (3%) and gastrointestinal disorders (9%). Twenty-four side effects persisted following Sandimmun^® discontinuation. Hypertension was reported in 23 cases (40%). In 9 cases (16%) there was exacerbation of known hypertension (5 patients were treated hypertensive subjects and 2 were untreated at inclusion) and de novo hypertension in 14 cases (24%). The median time to onset of hypertension was 56 days (28-167). The median duration of hypertension was 113 days. Treatment was discontinued because of de novo hypertension in 2 cases (4%), hypertension and increased serum creatinine levels in 1 case and known hypertension in 1 case. On discontinuation of treatment, 5 patients had diastolic blood pressure higher than 95 mmHg and 9 patients received antihypertensive treatment. In terms of renal tolerance, an increase in serum creatinine level to 30% above the baseline value occurred in 14 cases (25%) and to 50% above baseline in 6 cases (11%). Serum creatinine level was higher than 124 µM in 2 cases (47%). The median time for serum creatinine values to return to below 30% above initial values was 28 days. The peak serum creatinine level observed during the study period was 139.8 µM. Serum creatinine levels remained high at the last evaluation in 4 cases.

Discussion

This study shows the potential value of a single short-term course of cyclosporin treatment, which in 50% of cases was not followed by resumption of systemic treatment. The efficacy and tolerance of cyclosporin were comparable to those published in the literature. Seventy-two percent of patients showed improvement at W20 (recovery and marked improvement). The patients all had severe psoriasis (mean percentage body area covered 44.7%). The efficacy of cyclosporin has been clearly established in several placebo-controlled series (65% recovery after 8 weeks at 5 mg/kg/d) [1] and in comparison with the reference treatment (etretinate) [2]. The doses required to achieve recovery or improvement range from 2.5 to 5 mg/kg/d in the literature and efficacy is dose-dependent [3].

The treatment regimen enabled resumption of only local treatment in 1 out of 2 cases of severe psoriasis. Resumption of systemic treatment was necessary in only half of the cases at 4 months after discontinuation. Cyclosporin thus induced partial remission, for which local treatment was sufficient in 47% of cases following discontinuation. Given the side effects, particularly the hepatotoxic effects, of other systemic treatments for psoriasis (PUVA treatment, retinoids, methotrexate), cyclosporin and local treatments are the only therapeutic alternatives in certain patients. Short-duration (maximum 12 weeks) and sequential (3 courses of treatment in a year) treatment yielded very satisfactory results in Berth-Jones's series, with good tolerance and no significant change in blood pressure or serum creatinine parameters following treatment discontinuation [4]. A similar study in which short-term cyclosporin treatment was given for atopic dermatitis showed that relapse occurred rapidly after discontinuation of treatment, except in a small number of patients (16%). These patients had the same inclusion criteria as the other patients but they had no recurrence of atopic dermatitis 1 year after the discontinuation of treatment [5]. Cyclosporin might have induced a change in the pattern of the progression of the disease in such patients, unless they were in fact prolonged natural remissions.

The efficacy of treatment in our study was markedly reduced when the dosage was tapered from W20 to W28. Tapering is thus of little value. Maintenance of treatment at a dosage of 1.5 mg/kg/d did not bring about significant improvement compared to a placebo in Ellis's series [6]. The abrupt discontinuation or gradual tapering of treatment has been frequently discussed in the literature. Recurrence is occasionally more serious than the initial form of psoriasis, and the interval to recurrence and frequency suggest the absence of rebound phenomenon [4, 7, 8]. Our study suggests discontinuation of cyclosporin without tapering.

The pattern of side effects emerging during this short-term study was the same as in previous studies [1, 3] except for hypertension. Hypertension occurred in 40% of patients (versus 2-6% and 13-15%), respectively. Seven patients included in our study were hypertensive. However, de novo hypertension emerged in the majority of cases (61%). Five patients remained hypertensive following treatment discontinuation and 9 patients received antihypertensive treatment. The increase in serum creatinine levels did not constitute a major problem but called for dosage reduction in some patients.

CONCLUSION

REFERENCES

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