British Journal of Dermatology (1990) 122, Supplement 36, 27-31.
Oral cyclosporin A in the treatment of psoriasis: an overview of studies performed in The Netherlands M.M.H.M.MEINARDI, M.A.DERIE AND J.D.BOS Department of Dermatology, University of Amsterdam, Academisch Medisch Centrum, Amsterdam, The Netherlands
SUMMARY
This is a review of the clinical studies performed so far in The Netherlands of the treatment of psoriasis with cyclosporin A (CyA), a selective immunosuppressive drug that has caused a major breakthrough in transplant medicine. Data derived from a double-blind placebocontrolled study (5 mg/kg/day of CyA), dose-finding studies (2-5 mg vs 5 mg/kg/day and i mg, 2 mg or 3 mg/kg/day), and long-term treatment of chronic plaque-type psoriasis (11-72 mg/kg/day) suggest an initial starting dose of 3 mg/kg/day irrespective of the severity of the disease. Long-term treatment brought about dose- and time-dependent (reversible) sideeffects, including renal dysfunction and hypertension. Efforts to reduce the dose included concomitant administration of drugs known to have anti-psoriatic efficacy. Only combination with topical steroids appeared to add to the clinical efficacy of CyA, but did not allow a dose reduction sufficient to restore renal function. Dose reduction through intermittent treatment, however, postponed exacerbations sufficiently to permit at least partial normalization of serum creatinine levels. A similar effect was seen in the treatment of pustular palmoplantar psoriasis, which responded to doses of 11-61 mg/kg/day.
On the basis of the results of cyclosporin A (CyA) in clearing the skin lesions of psoriasis,'"* a systematic evaluation of the drug was started in 1985. Because of the dose-dependent side-effects of nephrotoxicity and hypertension, and the possibility of developing tumours, treatment with CyA was initially restricted to the more severe forms of psoriasis. Unfortunately, as topical CyA preparations appeared to be ineffectual in the treatment of psoriatic skin lesions, studies of alternative treatment regimes using reduced doses of CyA were carried out. Furthermore, patients were selected to determine whether the less severe forms of psoriasis required doses sufficiently low to avoid the side-eflfects of severe hypertension and renal Correspondence: Dr M.M.H.M.Meinardi, Department of Dermatology, University of Amsterdam, Academisch Medisch Centrum, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands. 27
28 M.M.H.M.Meinardi et al. dysfuction. These studies showed that the dosage necessary to induce and maintain a remission did not correlate with the extent of the disease. TREATMENT OF CHRONIC PLAQUE PSORIASIS WITH CYCLOSPORIN A
In 1985, the first five patients with severe chronic plaque-type psoriasis were treated in Rotterdam in an open prospective study with 5 mg/kg/day (range 3-6-7-4 mg) of CyA for 8 weeks.' An almost complete remission was obtained in three patients. Three other patients showed a substantial improvement in their nails and one patient had a striking improvement in the symptoms of severe psoriatic arthropathy. A mild and reversible hypertension was observed in two patients and, in one of these, there was evidence of mild renal dysfuction. No other important side-effects were observed. Based on these findings, a double-blind cross-over, placebo-controlled study was carried out in Rotterdam and Amsterdam' which included 20 patients with severe chronic plaque psoriasis. Phase I of this study comprised a double-blind comparison of 4 weeks of CyA treatment vs placebo, followed by a cross-over period during which those previously taking placebo received CyA for a further 4 weeks. As two of the placebo-treated patients dropped out of the study, a total of 18 patients were evaluated. All 18 had received a mean dose of 56 mg/kg/day of CyA for 4 weeks (Phase I). Nearly complete remission was seen in four (22%) of these patients at the end of this period, and a reduction of more than 75% in the Psoriasis Area and Severity Index (PASI)' score was observed in 15 (83%). In the following 8 weeks (Phase 11), the dose required to maintain a remission was 3 mg/kg/day on average. Side-effects included mild hypertension infivepatients, aching muscles in five, fatigue in two, mild hypertrichosis in two males, headache in one, mild gynaecomasty in one male, tremor in one, gastrointestinal complaints in one and verruca vulgaris in one. Subsequent withdrawal of treatment (Phase III) resulted in a relapse in all but one of the patients within 4-12 weeks of stopping the drug. This study, while establishing the efficacy of low-dose CyA in severe forms of psoriasis, also showed that this and the side-effects were dose-dependent (Phase II) and that, in these patients, the skin lesions would recur soon after the drug was stopped (Phase III). A further argument for establishing the lowest effective dose of CyA is to avoid immunosuppression that may facilitate an accelerated expression of tumours induced by other treatments, such as ultraviolet light (UVB), psoralen photochemotherapy with UVA (PUVA), methotrexate or arsenic. Maintenance studies
In a study* to establish the dose required to maintain long-term remission in severe forms of psoriasis, 12 patients were selected who had extensive but stable chronic plaque psoriasis. All the patients in the study were treated with an initial dose of 5 mg/kg/day of CyA, which was gradually reduced according to the clinical efficacy. The doses required to maintain a remission ranged from 1-1-72 mg/kg/day (mean 5 mg/kg/day). Improvement or worsening of the skin lesions was seen as early as the third day. The closer the dose was to the minimum maintenance dose, the slower were the changes achieved. During maintenance treatment, six of the patients developed mild hypertension within an average of 20 weeks (range 4-49 weeks), and seven patients showed an increase in the serum creatinine of greater than 30% over their baseline values within an average of 16 weeks (range
Oral CyA in psoriasis 29 3-22 weeks). To reverse these adverse effects, the dose was reduced but, in three patients, the dose was insufficient to control their psoriasis. In these patients, the effective long-term suppression of skin lesions was not feasible without inducing serious adverse effects. An attempt to reduce the maintenance dose of CyA involved these 12 patients and an additional group of 14 similarly psoriatic patients who had received identical treatment with CyA. Two different treatment strategies were used. The first involved the addition of another anti-psoriatic treatment and the second was intermittent CyA treatment used as monotherapy. In the first treatment strategy, oral CyA was combined with either UVB, anthralin (dithranol), potent topical corticosteroids or etretinate. The corticosteroids proved to be of value, but only to a limited extent, and these combinations were not able to prevent an exacerbation of the psoriasis nor allow a reduction of dosage sufficient to reverse either hypertension or renal dysfunction. No improvement of clinical efficacy was seen with a combination of CyA and bromocriptine nor with domperidone, although this latter agent was able to reduce gastrointestinal discomfort. The lack of additional effectiveness with the combination of CyA and etretinate was confirmed by Heule et al.^ Side-effects arising during a mean maintenance treatment period of 195 months (range 7-37 months) were assessed as a function of dose, and hypertension was observed in 2/5 patients treated with doses below 2 mg/kg/day, in i/io treated with 2-3 mg/kg/day, and in 5/11 treated with doses over 3 mg/kg/day. Renal dysfunction was observed in 2/5 patients receiving doses below 2 mg/kg/day, in 7/10 receiving 2-3 mg/kg/day and in 9/11 receiving doses over 3 mg/kg/day. In addition to being dose-dependent, the side-effects also appeared to be related to time. Other adverse effects included hyperkalaemia (12/26), tremor, myalgia (5/26), hypertrichosis (4/26), gastrointestinal upset, fatigue, headache and severe gingival hyperpiasia (1/26).
Intermittent treatment schedule
When daily maintenance treatment was interspersed with treatment three times a week (using the same dosage as for daily treatment), reversal of CyA-related side-effects was observed and sufficient efficacy maintained for 3-20 weeks (mean 7 weeks). After that time, to avoid a serious recurrence of disease, patients returned to a daily treatment schedule for a few weeks. The thrice-weekly treatment was also used in six patients in an attempt to induce remission (using doses ranging from 5 to 85 mg/kg/day of treatment). Within 6 weeks on average, PASI scores showed 85% reductions. Remission was maintained without adverse effects during the 48 weeks of the study.* Nordic multicentre dose-finding study
The Nordic multicentre, open, imcontrolled study was begun in 1987 to test the efficacy, safety and tolerability of CyA in the induction and maintenance of remission in severe chronic plaque psoriasis. The study was divided into three phases: (I) induction of remission; (II) maintenance of remission; (III) reversibility of CyA-induced side-effects after withdrawal of the drug. The PASI scores had to be at least 18. The starting dose of CyA was 25 mg/kg/day which, for the non-responders (reduction of PASI score < 10%), was raised to 5 mg/kg/day at Week 4 or Week 8 of treatment. At Week 12, patients were classified as responders if reduction in PASI score was > 75%. Patients still not responding were re-entered into the study with a starting dose of CyA 5 mg/kg/day while responders continued taking 25 mg/kg/day until the end of Month 12, unless there was a relapse. Patients receiving 5 mg/kg/day were 'weaned' through a gradual reduction in dosage
30 M.M.H.M.Meinardi et al. to 25 mg/kg/day by the end of Month 6. During Months 13-15, all patients were weaned from CyA. Patients responding to 25 mg/kg/day had a mean PASI score reduction of 60%, while those receiving 5 mg/kg/day had a mean decrease of 80%. The Multicentre 1-2-3 Study The Multicentre Study OL 8021 (the so-called 1-2-3 Study) was designed to investigate CyA requirements in patients with mild-to-moderate psoriasis. All were resistant to topical treatment and would have otherwise been treated with PUVA/UVB or retinoids. The OL 8021 was an open prospective study in which patients were treated for 6 months with oral CyA followed by a treatment-free period of 3 months. The study included 106 patients of both sexes with chronic plaque psoriasis and all were started on oral CyA at a dose of 1 mg/kg body weight/day. If, by the end of the first month of treatment, clinical improvement was insufficient, the dose was increased to 2 mg/kg/day. If improvement was then still considered insufficient, the dose was increased to the maximum of 3 mg/kg/day. If no satisfactory anti-psoriatic efficacy was obtained with 3 mg/kg/day, the patient was withdrawn from the study. After an active-treatment period of 6 months, therapy was stopped and patients observed for a further 3 months or until skin lesions became intolerable. The clinical efficacy of the CyA treatment was measured using the PASI score and an additional 8-point scale of improvement in skin lesions over the baseline condition. Using this scale, a treatment success was defined as a marked improvement (2/8) or total clearing (1/8) of the skin lesions; otherwise, the clinical response was considered insufficient. Five of the 106 patients were withdrawn from the study because of a lack of clinical improvement. Many patients reported that considerable motivation was required to continue taking CyA according to the protocol. Although the results are preliminary, in this group of patients the amount of CyA required was somewhat lower than that required for the more severe forms ofpsoriasis. In spite of this, approximately 70% of these patients required 3 mg/kg/day, and approximately 25% required 2 mg/kg/day to induce and maintain remission. As measured by the PASI, the i mg, 2 mg and 3 mg/kg/day groups did not differ in either initial severity of skin lesions or in the clinical improvement obtained with CyA treatment, a clear indication that the required amount of drug cannot be predicted by the PASI score. As treatment with 3 mg/kg/day was not known to be more likely to induce adverse effects than 2 mg/kg/day, this study suggests that treatment may start with 3 mg/kg/day of CyA, regardless of the severity of the psoriasis. TREATMENT OF PUSTULAR PSORIASIS WITH CYCLOSPORIN A
In the trials mentioned so far, pustular forms of psoriasis have been excluded. Although CyA does not appear to have a direct effect on neutrophils, there is the possibility that, through the complex cytokine-mediated interaction between T cells, keratinocytes and endothelial cells, it may indirectly suppress pustulation. Indeed, in a patient with von Zumbusch generalized pustular psoriasis,'" high doses of the drug (12 mg/kg/day) suppressed pustulation although, in two other similar cases,"'" lower doses (7 mg and 8 mg/kg/day) were ineffective. However, when prednisone 10 mg/day was added to the CyA 8 mg/kg/day treatment, the skin lesions were completely cleared. Such high dosages of CyA inevitably produce side-effects such as hypertension and renal dysfunction, especially when the treatment is long-term. In pustular psoriasis, therefore, CyA should preferably be reserved for only those patients not responding to etretinate alone or with PUVA, or for cases where hepatotoxic drugs are contraindicated.
Ora! CyA in psoriasis 31 In a prospective open study of the clinical efficacy and tolerability of CyA, seven patients with persistent pustulosis palmaris et plantaris (PPP) were treated with oral CyA.'' Clinical efficacy was assessed on a semi-quantitative 0-4-point scale for erythema, desquamation, induration and pustulation. Long-term CyA treatment (mean 19 months, range 5-38 months) was effective at doses ranging from i • i-6-1 mg/kg body weight/day. Side-effects included renal impairment (1/7, controlled by a slight reduction of the dose), nausea (3/7), hypertrichosis (2/7) and tiredness (3/7). Rapid recurrence of the skin lesions was observed on withdrawal of the drug or when the dose was insufficient. RECOMMENDATIONS FOR TREATMENT
These trials have produced impressive results in the treatment of psoriasis with oral CyA. However, the risk of adverse effects, such as hypertension, renal dysfunction and the possibility of producing tumours, should discourage its prolonged use. Cyclosporin A should not be given to patients with a history of frequent treatments with PUVA, UVB, methotrexate or arsenic. As 3 mg/kg/day of CyA does not produce more side-effects than 2 mg/kg/day, as indicated by the results of a study of mild-to-moderate psoriasis, treatment should begin at the higher dose. Treatment commencing with too low a dose would only impede improvement. After 2-4 weeks, the dose can be adjusted according to the efficacy. Severe forms of psoriasis may require substantially higher doses, as much as 7 mg/kg/day, but such high doses should be allowed only in special cases and with frequent monitoring for adverse effects. Complete clearance of the skin lesions should not be the sole objective of treatment. Further clinical improvement may be achieved with CyA in combination with topical corticosteroids. If side-effects arise, the dose should be lowered by 0-5 mg/kg/day at intervals of 2 weeks. After withdrawal of treatment, skin lesions can be expected to recur between the third day and twelfth week. REFERENCES 1 Mueller W, Herrmann B. Cyclosporin for psoriasis. N Engl J Med 1979; 301: 555. 2 Mueller W, Graf U, Die Behandlung der Psoriasis Arthritis mit Cyclosporin A, einen neuen Immunosuppressivum, Schweiz Med Wochenschr 1981; I i i ; 408-13, 3 Harper JI, Keat ACS, Staughton RCD, Cyclosporin for psoriasis. Lancet 1984; ii: 981-2, 4 Van Hooff JP, Leunissen RML, Van der Staak W, Cyclosporine and psoriasis. Lancet 1985; i: 335, 5 Van Joost T, Heule F, Stolz E, Beukers R, Short-term use of cyclosporin A in severe psoriasis, BrJ Dermatol 1986; 114: 615-20, 6 Van Joost T, Bos JD, Heule F, Meinardi MMHM, Low-dose cyclosporin A in severe psoriasis, A double-blind study, Br J Dermatol 1988; 118; 183-90, 7 Fredriksson T, Pettersson U, Severe psoriasis: oral therapy with a new retinoid, Dermatologica 1978; 157: 238-44, 8 Meinardi MMHM, Bos JD, Cyclosporine maintenance therapy in psoriasis. Transplant Proc 1988; 20: Suppl 4: 42-9, 9 Heule F, Bousema MT, Laaijendecker R, van Joost T, Three long-term regimens with cyclosporin for psoriasis vulgaris, Acta Derm Venereol (Stockh) 1989; Suppl 146: 171-5. 10 Meinardi MMHM, Westerhof W, Bos JD, Generalized pustular psoriasis (von Zumbusch) responding to cyclosporin A, Br J Dermatol 1987; 116: 269-70. 11 Coulson IH, Evans CD, Holden CA, Generalized pustular psoriasis after renal transplantation—failure to suppress with cyclosporin A, Clin Exp Dermatol 1988; 13: 416-7, 12 Korstanje MJ, Bessems PJMJ, Hulsmans RFHJ, Van der Staak WJBM. Pustular psoriasis and acrodermatitis continua (Hallopeau) need high doses of systemic ciclosporin A. Dermatologica 1989; 179: 90-1. 13 Meinardi MMHM, de Rie MA, Bos JD, Oral cyclosporin A is effective in clearing persistent pustulosis palmaris et plantaris, Acta Derm Venereol (Stockh) 1990; 70: 77-9,
Oral cyclosporin A in the treatment of psoriasis: an overview of studies performed in The Netherlands M.M.H.M.MEINARDI, M.A.DERIE AND J.D.BOS Department of Dermatology, University of Amsterdam, Academisch Medisch Centrum, Amsterdam, The Netherlands
SUMMARY
This is a review of the clinical studies performed so far in The Netherlands of the treatment of psoriasis with cyclosporin A (CyA), a selective immunosuppressive drug that has caused a major breakthrough in transplant medicine. Data derived from a double-blind placebocontrolled study (5 mg/kg/day of CyA), dose-finding studies (2-5 mg vs 5 mg/kg/day and i mg, 2 mg or 3 mg/kg/day), and long-term treatment of chronic plaque-type psoriasis (11-72 mg/kg/day) suggest an initial starting dose of 3 mg/kg/day irrespective of the severity of the disease. Long-term treatment brought about dose- and time-dependent (reversible) sideeffects, including renal dysfunction and hypertension. Efforts to reduce the dose included concomitant administration of drugs known to have anti-psoriatic efficacy. Only combination with topical steroids appeared to add to the clinical efficacy of CyA, but did not allow a dose reduction sufficient to restore renal function. Dose reduction through intermittent treatment, however, postponed exacerbations sufficiently to permit at least partial normalization of serum creatinine levels. A similar effect was seen in the treatment of pustular palmoplantar psoriasis, which responded to doses of 11-61 mg/kg/day.
On the basis of the results of cyclosporin A (CyA) in clearing the skin lesions of psoriasis,'"* a systematic evaluation of the drug was started in 1985. Because of the dose-dependent side-effects of nephrotoxicity and hypertension, and the possibility of developing tumours, treatment with CyA was initially restricted to the more severe forms of psoriasis. Unfortunately, as topical CyA preparations appeared to be ineffectual in the treatment of psoriatic skin lesions, studies of alternative treatment regimes using reduced doses of CyA were carried out. Furthermore, patients were selected to determine whether the less severe forms of psoriasis required doses sufficiently low to avoid the side-eflfects of severe hypertension and renal Correspondence: Dr M.M.H.M.Meinardi, Department of Dermatology, University of Amsterdam, Academisch Medisch Centrum, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands. 27
28 M.M.H.M.Meinardi et al. dysfuction. These studies showed that the dosage necessary to induce and maintain a remission did not correlate with the extent of the disease. TREATMENT OF CHRONIC PLAQUE PSORIASIS WITH CYCLOSPORIN A
In 1985, the first five patients with severe chronic plaque-type psoriasis were treated in Rotterdam in an open prospective study with 5 mg/kg/day (range 3-6-7-4 mg) of CyA for 8 weeks.' An almost complete remission was obtained in three patients. Three other patients showed a substantial improvement in their nails and one patient had a striking improvement in the symptoms of severe psoriatic arthropathy. A mild and reversible hypertension was observed in two patients and, in one of these, there was evidence of mild renal dysfuction. No other important side-effects were observed. Based on these findings, a double-blind cross-over, placebo-controlled study was carried out in Rotterdam and Amsterdam' which included 20 patients with severe chronic plaque psoriasis. Phase I of this study comprised a double-blind comparison of 4 weeks of CyA treatment vs placebo, followed by a cross-over period during which those previously taking placebo received CyA for a further 4 weeks. As two of the placebo-treated patients dropped out of the study, a total of 18 patients were evaluated. All 18 had received a mean dose of 56 mg/kg/day of CyA for 4 weeks (Phase I). Nearly complete remission was seen in four (22%) of these patients at the end of this period, and a reduction of more than 75% in the Psoriasis Area and Severity Index (PASI)' score was observed in 15 (83%). In the following 8 weeks (Phase 11), the dose required to maintain a remission was 3 mg/kg/day on average. Side-effects included mild hypertension infivepatients, aching muscles in five, fatigue in two, mild hypertrichosis in two males, headache in one, mild gynaecomasty in one male, tremor in one, gastrointestinal complaints in one and verruca vulgaris in one. Subsequent withdrawal of treatment (Phase III) resulted in a relapse in all but one of the patients within 4-12 weeks of stopping the drug. This study, while establishing the efficacy of low-dose CyA in severe forms of psoriasis, also showed that this and the side-effects were dose-dependent (Phase II) and that, in these patients, the skin lesions would recur soon after the drug was stopped (Phase III). A further argument for establishing the lowest effective dose of CyA is to avoid immunosuppression that may facilitate an accelerated expression of tumours induced by other treatments, such as ultraviolet light (UVB), psoralen photochemotherapy with UVA (PUVA), methotrexate or arsenic. Maintenance studies
In a study* to establish the dose required to maintain long-term remission in severe forms of psoriasis, 12 patients were selected who had extensive but stable chronic plaque psoriasis. All the patients in the study were treated with an initial dose of 5 mg/kg/day of CyA, which was gradually reduced according to the clinical efficacy. The doses required to maintain a remission ranged from 1-1-72 mg/kg/day (mean 5 mg/kg/day). Improvement or worsening of the skin lesions was seen as early as the third day. The closer the dose was to the minimum maintenance dose, the slower were the changes achieved. During maintenance treatment, six of the patients developed mild hypertension within an average of 20 weeks (range 4-49 weeks), and seven patients showed an increase in the serum creatinine of greater than 30% over their baseline values within an average of 16 weeks (range
Oral CyA in psoriasis 29 3-22 weeks). To reverse these adverse effects, the dose was reduced but, in three patients, the dose was insufficient to control their psoriasis. In these patients, the effective long-term suppression of skin lesions was not feasible without inducing serious adverse effects. An attempt to reduce the maintenance dose of CyA involved these 12 patients and an additional group of 14 similarly psoriatic patients who had received identical treatment with CyA. Two different treatment strategies were used. The first involved the addition of another anti-psoriatic treatment and the second was intermittent CyA treatment used as monotherapy. In the first treatment strategy, oral CyA was combined with either UVB, anthralin (dithranol), potent topical corticosteroids or etretinate. The corticosteroids proved to be of value, but only to a limited extent, and these combinations were not able to prevent an exacerbation of the psoriasis nor allow a reduction of dosage sufficient to reverse either hypertension or renal dysfunction. No improvement of clinical efficacy was seen with a combination of CyA and bromocriptine nor with domperidone, although this latter agent was able to reduce gastrointestinal discomfort. The lack of additional effectiveness with the combination of CyA and etretinate was confirmed by Heule et al.^ Side-effects arising during a mean maintenance treatment period of 195 months (range 7-37 months) were assessed as a function of dose, and hypertension was observed in 2/5 patients treated with doses below 2 mg/kg/day, in i/io treated with 2-3 mg/kg/day, and in 5/11 treated with doses over 3 mg/kg/day. Renal dysfunction was observed in 2/5 patients receiving doses below 2 mg/kg/day, in 7/10 receiving 2-3 mg/kg/day and in 9/11 receiving doses over 3 mg/kg/day. In addition to being dose-dependent, the side-effects also appeared to be related to time. Other adverse effects included hyperkalaemia (12/26), tremor, myalgia (5/26), hypertrichosis (4/26), gastrointestinal upset, fatigue, headache and severe gingival hyperpiasia (1/26).
Intermittent treatment schedule
When daily maintenance treatment was interspersed with treatment three times a week (using the same dosage as for daily treatment), reversal of CyA-related side-effects was observed and sufficient efficacy maintained for 3-20 weeks (mean 7 weeks). After that time, to avoid a serious recurrence of disease, patients returned to a daily treatment schedule for a few weeks. The thrice-weekly treatment was also used in six patients in an attempt to induce remission (using doses ranging from 5 to 85 mg/kg/day of treatment). Within 6 weeks on average, PASI scores showed 85% reductions. Remission was maintained without adverse effects during the 48 weeks of the study.* Nordic multicentre dose-finding study
The Nordic multicentre, open, imcontrolled study was begun in 1987 to test the efficacy, safety and tolerability of CyA in the induction and maintenance of remission in severe chronic plaque psoriasis. The study was divided into three phases: (I) induction of remission; (II) maintenance of remission; (III) reversibility of CyA-induced side-effects after withdrawal of the drug. The PASI scores had to be at least 18. The starting dose of CyA was 25 mg/kg/day which, for the non-responders (reduction of PASI score < 10%), was raised to 5 mg/kg/day at Week 4 or Week 8 of treatment. At Week 12, patients were classified as responders if reduction in PASI score was > 75%. Patients still not responding were re-entered into the study with a starting dose of CyA 5 mg/kg/day while responders continued taking 25 mg/kg/day until the end of Month 12, unless there was a relapse. Patients receiving 5 mg/kg/day were 'weaned' through a gradual reduction in dosage
30 M.M.H.M.Meinardi et al. to 25 mg/kg/day by the end of Month 6. During Months 13-15, all patients were weaned from CyA. Patients responding to 25 mg/kg/day had a mean PASI score reduction of 60%, while those receiving 5 mg/kg/day had a mean decrease of 80%. The Multicentre 1-2-3 Study The Multicentre Study OL 8021 (the so-called 1-2-3 Study) was designed to investigate CyA requirements in patients with mild-to-moderate psoriasis. All were resistant to topical treatment and would have otherwise been treated with PUVA/UVB or retinoids. The OL 8021 was an open prospective study in which patients were treated for 6 months with oral CyA followed by a treatment-free period of 3 months. The study included 106 patients of both sexes with chronic plaque psoriasis and all were started on oral CyA at a dose of 1 mg/kg body weight/day. If, by the end of the first month of treatment, clinical improvement was insufficient, the dose was increased to 2 mg/kg/day. If improvement was then still considered insufficient, the dose was increased to the maximum of 3 mg/kg/day. If no satisfactory anti-psoriatic efficacy was obtained with 3 mg/kg/day, the patient was withdrawn from the study. After an active-treatment period of 6 months, therapy was stopped and patients observed for a further 3 months or until skin lesions became intolerable. The clinical efficacy of the CyA treatment was measured using the PASI score and an additional 8-point scale of improvement in skin lesions over the baseline condition. Using this scale, a treatment success was defined as a marked improvement (2/8) or total clearing (1/8) of the skin lesions; otherwise, the clinical response was considered insufficient. Five of the 106 patients were withdrawn from the study because of a lack of clinical improvement. Many patients reported that considerable motivation was required to continue taking CyA according to the protocol. Although the results are preliminary, in this group of patients the amount of CyA required was somewhat lower than that required for the more severe forms ofpsoriasis. In spite of this, approximately 70% of these patients required 3 mg/kg/day, and approximately 25% required 2 mg/kg/day to induce and maintain remission. As measured by the PASI, the i mg, 2 mg and 3 mg/kg/day groups did not differ in either initial severity of skin lesions or in the clinical improvement obtained with CyA treatment, a clear indication that the required amount of drug cannot be predicted by the PASI score. As treatment with 3 mg/kg/day was not known to be more likely to induce adverse effects than 2 mg/kg/day, this study suggests that treatment may start with 3 mg/kg/day of CyA, regardless of the severity of the psoriasis. TREATMENT OF PUSTULAR PSORIASIS WITH CYCLOSPORIN A
In the trials mentioned so far, pustular forms of psoriasis have been excluded. Although CyA does not appear to have a direct effect on neutrophils, there is the possibility that, through the complex cytokine-mediated interaction between T cells, keratinocytes and endothelial cells, it may indirectly suppress pustulation. Indeed, in a patient with von Zumbusch generalized pustular psoriasis,'" high doses of the drug (12 mg/kg/day) suppressed pustulation although, in two other similar cases,"'" lower doses (7 mg and 8 mg/kg/day) were ineffective. However, when prednisone 10 mg/day was added to the CyA 8 mg/kg/day treatment, the skin lesions were completely cleared. Such high dosages of CyA inevitably produce side-effects such as hypertension and renal dysfunction, especially when the treatment is long-term. In pustular psoriasis, therefore, CyA should preferably be reserved for only those patients not responding to etretinate alone or with PUVA, or for cases where hepatotoxic drugs are contraindicated.
Ora! CyA in psoriasis 31 In a prospective open study of the clinical efficacy and tolerability of CyA, seven patients with persistent pustulosis palmaris et plantaris (PPP) were treated with oral CyA.'' Clinical efficacy was assessed on a semi-quantitative 0-4-point scale for erythema, desquamation, induration and pustulation. Long-term CyA treatment (mean 19 months, range 5-38 months) was effective at doses ranging from i • i-6-1 mg/kg body weight/day. Side-effects included renal impairment (1/7, controlled by a slight reduction of the dose), nausea (3/7), hypertrichosis (2/7) and tiredness (3/7). Rapid recurrence of the skin lesions was observed on withdrawal of the drug or when the dose was insufficient. RECOMMENDATIONS FOR TREATMENT
These trials have produced impressive results in the treatment of psoriasis with oral CyA. However, the risk of adverse effects, such as hypertension, renal dysfunction and the possibility of producing tumours, should discourage its prolonged use. Cyclosporin A should not be given to patients with a history of frequent treatments with PUVA, UVB, methotrexate or arsenic. As 3 mg/kg/day of CyA does not produce more side-effects than 2 mg/kg/day, as indicated by the results of a study of mild-to-moderate psoriasis, treatment should begin at the higher dose. Treatment commencing with too low a dose would only impede improvement. After 2-4 weeks, the dose can be adjusted according to the efficacy. Severe forms of psoriasis may require substantially higher doses, as much as 7 mg/kg/day, but such high doses should be allowed only in special cases and with frequent monitoring for adverse effects. Complete clearance of the skin lesions should not be the sole objective of treatment. Further clinical improvement may be achieved with CyA in combination with topical corticosteroids. If side-effects arise, the dose should be lowered by 0-5 mg/kg/day at intervals of 2 weeks. After withdrawal of treatment, skin lesions can be expected to recur between the third day and twelfth week. REFERENCES 1 Mueller W, Herrmann B. Cyclosporin for psoriasis. N Engl J Med 1979; 301: 555. 2 Mueller W, Graf U, Die Behandlung der Psoriasis Arthritis mit Cyclosporin A, einen neuen Immunosuppressivum, Schweiz Med Wochenschr 1981; I i i ; 408-13, 3 Harper JI, Keat ACS, Staughton RCD, Cyclosporin for psoriasis. Lancet 1984; ii: 981-2, 4 Van Hooff JP, Leunissen RML, Van der Staak W, Cyclosporine and psoriasis. Lancet 1985; i: 335, 5 Van Joost T, Heule F, Stolz E, Beukers R, Short-term use of cyclosporin A in severe psoriasis, BrJ Dermatol 1986; 114: 615-20, 6 Van Joost T, Bos JD, Heule F, Meinardi MMHM, Low-dose cyclosporin A in severe psoriasis, A double-blind study, Br J Dermatol 1988; 118; 183-90, 7 Fredriksson T, Pettersson U, Severe psoriasis: oral therapy with a new retinoid, Dermatologica 1978; 157: 238-44, 8 Meinardi MMHM, Bos JD, Cyclosporine maintenance therapy in psoriasis. Transplant Proc 1988; 20: Suppl 4: 42-9, 9 Heule F, Bousema MT, Laaijendecker R, van Joost T, Three long-term regimens with cyclosporin for psoriasis vulgaris, Acta Derm Venereol (Stockh) 1989; Suppl 146: 171-5. 10 Meinardi MMHM, Westerhof W, Bos JD, Generalized pustular psoriasis (von Zumbusch) responding to cyclosporin A, Br J Dermatol 1987; 116: 269-70. 11 Coulson IH, Evans CD, Holden CA, Generalized pustular psoriasis after renal transplantation—failure to suppress with cyclosporin A, Clin Exp Dermatol 1988; 13: 416-7, 12 Korstanje MJ, Bessems PJMJ, Hulsmans RFHJ, Van der Staak WJBM. Pustular psoriasis and acrodermatitis continua (Hallopeau) need high doses of systemic ciclosporin A. Dermatologica 1989; 179: 90-1. 13 Meinardi MMHM, de Rie MA, Bos JD, Oral cyclosporin A is effective in clearing persistent pustulosis palmaris et plantaris, Acta Derm Venereol (Stockh) 1990; 70: 77-9,
