Therapv Cyclosporine in psoriasis: A multicenter dose-finding study in severe plaque psoriasis Enno Christophers, MD,a Ulrich Mrowietz, MD,a Hans-Heinrich Henneicke,a Lothar Farber, MD,b Dieter Welzel, MD,b and the participants in the German multicen~er study* Interim results of a randomized, controlled, dose-finding study conducted in 24 dermatology centers on 217 patients with severe chronic plaque psoriasis (entry psoriasis area and severity index of at least 15) are presented. Patients were first treated with cyclosporine either 1.25 or 2.5 mg/kg/day (Sandimmune); in case of inadequate response the dosage was increased to a maximum of 5 mg/kg/day. Cyclosporine was given for 12 to 36 weeks. Treatment was classified as "successful" if the psoriasis area and severity index was reduced to 25% or less of the baseline value or below 8. At the end of the treatment period 18% of patients had improved their psoriasis area and severity index "successfully" with the initial dose of 1.25 mg/ kg/day. "Successful" improvement with the initial dose of 2.5 mg/kg/day was achieved in 56% of the cases. In the 1.25 mg group, 44 patients had to increase their dose to 2.5 mg/kg/ day and 31 patients to 5 mg/kg/day. In 29 patients whose dosages were started at 2.5 mg/ kg/day the dosage was subsequently increased to 5 mg/kg/day. Although 1.25 mg/kg/day proved to be effective in some cases, 2.5 mg/kg/day of cyclosporine is the optimal starting dose. Adverse events were observed in 10% of the patients taking 1.25 mg/kg/day, in 20% taking 2.5 mg/kg/day, and in 32% taking 5 mg/kg/day. The most common were gastrointestinal complaints, followed by the common cold and other viral infections. An increase of serum creatinine level above 130 I1mol/L occurred in five patients who could continue therapy after reducing the dose. Among those patients taking 1.25, 2.5, or 5 mg/kg/ day of cyclosporine, 16.2%, 17.1%, and 17.8%, respectively, were withdrawn from the study. The reasons were lack of efficacy (8.1 % to II %) and noncompliance (1.6% to 4.5%). A total of 1.6% to 3.2% of the patients discontinued the study because of adverse events. (J AM ACAD DERMATOL 1992;26:86-90.)
In 1979, Mueller and Herrmann l reported clearing of psoriatic plaques in patients who were receiving cyclosporine for the treatment of arthropathies. This led to a series of case reports and clinical trials that confirmed the efficacy of cyclosporine in psoriasis even in patients resistant to other therapeutic regimens. 2 The aim of the present study was to conduct a randomized, controlled, multicenter study to investigate whether an optimal dosage of cyclosporine in the long-term treatment of severe plaque psoriasis could be established with regard to efficacy, safety, and tolerability. The effect of cyclospoFrom the D~partment of Dermatology, University of Kiel'; and the Clinical Research Department, Sandoz AG, Niirnberg. b Supported by Sandoz AG, Niirnberg. Reprint requests: Prof. Dr. E. Christophers, Department of Dermatology, University ofKiel, Schittenhelmstr. 7, D-2300 Kiell, Germany. *Participants listed at the end of the article.
16/1/32546
86
rine on nail involvement, pruritus, and arthropathy was also assessed.
PATIENTS AND METHODS
Patient selection A total of 285 male and female patients from 18 to 70 years of age were admitted to the study after written consent was obtained. Patients had to have severe generalized chronic plaque psoriasis. The psoriasis area and severity index (PASI) at entry was at least 15. Patients who received treatment with methotrexate, retinoids, glucocorticosteroids, or PUVA within the last 2 weeks before therapy were excluded. Furthermore, patients treated with compounds known to interact with cyclosporine metabolism, pregnant or nursing women, patients with impaired renal and/or liver function, infectious and neurologic disorders, a history ofmalignancy, as well as alcohol abuse did not enter the study. As topical therapy during the study, 1% salicylic acid in white petrolatum or bland ointments were used.
Volume 26 Number 1 January 1992 Experimental design The study was performed as a randomized controlled dose-finding study in 24 dermatology centers in Germany. Within a period of 12 to 36 weeks the dose required to induce a remission in each patient was determined. Patients were randomly assigned to treatment with 1.25 or 2.5 mg/kg/day of cyclosporine. The daily dose was divided into a morning and evening dose taken with a meal. After 2 weeks of treatment, patients with a reduction of more than 10% and after 6 weeks of more than 30% of the baseline PASI continued with the unchanged dose until further evaluation at week 12. Patients with a PASI reduction of less than 10% after 2 weeks or less than 30% after 6 weeks were classified as treatment "failures" and reentered the study with a doubled dose. Patients with a regimen of 5 mg/kg/day who failed to show a reduction ofthe baseline PASI after 2 and 6 weeks as already described were withdrawn from the study. Patients whose PASI had declined to below 8 or to 25% or less of the baseline value were classified as successfully treated. Patients who did not fulfill these criteria and who were taking doses less than 5 mg/kg/day reentered the study at a doubled dose. Dose reduction. The dose was halved in case of ( 1) an increase of serum creatinine of more than 30%, (2) an increase of serum potassium above the upper limit of normal, (3) an increase in serum total bilirubin or liver enzymes of more than 100% above baseline or above the threefold upper limit of normal, and (4) cyclosporine trough level (Sandimmun-RIA kit, Sandoz) was above 250 ng/ml on two consecutive measurements. Investigations (efficacy, safety, and tolerability). Patients were classified according to the PASI. The PASI varies in steps of 0.1 from 0.0 to 72.0. Before starting the study all investigators took part in a training meeting for PASI scoring to optimize and standardize evaluation of disease activity. The severity of the psoriatic lesions was further evaluated according to erythema, infiltration, and desquamation on a scale from 0 to 4, in which 0 means complete absence and 4 means the most severe involvement. Involvement of nails, severity of arthropathy, and pruritus were also assessed. Pruritus and nail involvement were classified on a 4-point scale. Arthropathy was assessed by evaluating the intensity of inflammation, pain, swelling, and impairment of daily activities on a 4-point scale for each criterion. The following laboratory values were determined at baseline, at week 2, and then at 4-week intervals: serum creatinine, blood urea nitrogen, serum potassium, uric acid, magnesium, cholesterol, triglycerides, bilirubin, SGOT, alkaline phosphatase, albumin, hemoglobin, total white blood cell count, platelets, urine (glucose and protein), and cyclosporine trough levels. All determinations were performed at a central laboratory.
Cyclosporine in psoriasis 87 Table I. Discontinuations throughout the study (percentage of patients on different dosages of cyc1osporine) Reason for discontinuation
Adverse event Concomitant disease Noncompliance Lack of efficacy Others
1.8% 0.9%
3.2% 0.5%
1.6% 1.6%
4.5% 8.1%
4.3% 7.6%
1.6% 11.0%
0.9%
1.6%
1.6%
RESULTS A total of 285 patients were randomized into either the 1.25 mg/kg/day or the 2.5 mg/kg/day group. This analysis is based on data from 217 patients who completed the study. The remaining patients are either still receiving treatment or have discontinued the study. The reasons and the frequency of discontinuation are given in Table 1. Neither the frequency nor the symptoms that led to withdrawal from the study were dose-related. The 1.25 mg/kg/ day group consisted of 109 patients (29 female, 80 male) and the 2.5 mg/kg/day group consisted of 108 patients (28 female, 80 male). The mean age of both groups was 42 years. Dosage and efficacy Dosage. Forty-four of 109 patients (40%) who started with 1.25 mg/kg/day ofcyc1osporine needed to double the dosage and 31 (28%) had to increase the dosage to 5 mg/kg/day because of an insufficient therapeutic response. With the initial dosage of 2.5 mg/kg/day of cyclosporine, 29 patients (27%) needed to increase it to 5 mg/kg/day because of an inadequate therapeutic response. One patient had to halve the 1.25 mg/kg/day dosage and two patients each had to halve the 2.5 mg/kg/day and the 5 mg/kg/day dose because of increases in serum creatinine. In one patient the 5.0 mg/kg/day dose had to be reduced because of cyc1osporine trough levels above 250 ng/m!. Sixteen patients reduced the dose from 5 to 2.5 mg/kg/day and one patient to 1.25 mg/kg/day because of therapeutic success. Efficacy. Table II demonstrates the percentage of patients with a P ASI reduction of at least 75% with
Journal of the American Academy of Dermatology
88 Christophers et aZ. Table II. Efficacy of cyc1osporine in psoriasis*
1.25 mg/kg/day
Cumulative responder rate (PASI reduction ~75%)
I
Initial dosage
Initial dosage
1.25 mg/kg/day
2.5 mg/kg/day
2.5 mg/kg/day
I
43%
18%
5 mg/kg/day
2.5 mg/kg/day
63%
56%
I
5 mg/kg/day
72%
*Percentage of patients with PASI-reduction of at least 75% on three different doses.
Table III. Adverse events* (irrespective of a casual relation to cyclosporine therapy) Gastrointestinal complaints Common cold Viral infections Headache Tremor Fatigue Gingival hyperplasia Edema of the lower limbs Hypertrichosis Paresthesia
Total
1.25 mg/kg/day
15 10
4t
4
2
3 3 3 2
1
4 4 3
1 2
1
2.5 mg/kg/day
5 mg/kg/day
8
3 2
7t
3 1 1 2 1 3 1 2
1 3t 1 1 1
1
*There were single reports of the following: photoallergic eczema, vertigo, hematuria,t swelling of lymph nodes,t alopecia, diabetes mellitus, tarthralgia, t squamous cell carcinoma,t lumbago,t extra systoles.t tThe drug was withdrawn because of the side effect.
different cyc1osporine dosages. Nineteen (18%) of the patients taking 1.25 mg/kg/day were successfully treated. The remaining patients received an increased dose of 2.5 mg/kg/day with which a therapeutic success was achieved in an additional 27 cases (25%) (in total 43%). A final increase of the dosage to 5 mg/kg/day led to a PASI reduction of more than 75% in another 22 patients (20%) (in total 63%). In the group who started with 2.5 mg/kg/ day of cyc1osporine 60 patients (56%) had a PASI reduction of more than 75%. Mter increasing the dosage to 5 mg/kg/day of cyc1osporine in the remaining patients, a total of 78 patients (72%) were treated successfully. The time course of the PASI reduction on the initial doses of 1.25 and 2.5 mg/kg/day is shown in Fig. 1. In 24% ofthe patients taking 1.25 mg/kg/day and in 62% taking 2.5 mg/ kg/day no dose adjustment was necessary during 12 weeks of treatment because of the response to this initial dosage. Pruritus. At the end of treatment, scores decreased by 27.8%,61 %, and 42.8% in the 1.25,2.5, and 5 mg/kg/day groups, respectively. Involvement of nails. Cyc1osporine caused a slight improvement in nail involvement in all groups.
Joints. Arthropathy was present in 107, 182, and 59 patients treated with doses of 1.25, 2.5, and 5 mg/kg/day, respectively. At the end of treatment, inflammation, pain, swelling, and impairment of daily life activities appeared to have been ameliorated in most cases. Laboratory investigations Creatinine levels greater than 130 ,umol/L were observed in 1%,5%, and 13% of the patients in the 1.25, 2.5, and 5 mg/kg/day groups, respectively. Discontinuation of treatment was not necessary in any case. In five patients (one taking 1.25 mg/kg/ day, two taking 2.5 mg/kg/day, and two taking 5 mg/kg/day) the dose of cyclosporine had to be reduced because of an increase in serum creatinine. Blood urea nitrogen concentration rose above 8.3 mmol/L in 4%, 13%, and 18% of the patients, and uric acid greater than 400 ,umol/L could be observed in 19%, 28%, and 43% of the patients. Cholesterol increased above 6.7 mmol/L in 12%,21 %, and 25% of the patients and triglyceride levels increased above 2.0 mmol/L in 20%,40%, and 53% of the patients, respectively. SGOT above 20 U /L was detected in 11 %, 15%, and 33% of the patients and
Volume 26 Number 1 January 1992
Cyclosporine in psoriasis 89 % PASI 100 90 1.25 mglkgfd(24% of patients)
80
2.5 mglkgfd(62% of patients)
70 60 50 40
30 20 10 0
0
2
3
4
5
6
7
8
9
10
11
12
study weeks
Fig. 1. Efficacy of cyclosporine in psoriasis. Change of PASIon initial dosages of 1.25 and 2.5 mg/kg/day.
increased bilirubin levels (> 17 ~mol/L) were found in 8%, 20%, and 31 % of the patients. An increase in alkaline phosphatase above 180 U /L was seen in 11 %, 13%, and 20% of the patients treated with the three different cyclosporine dosages. Blood pressure. Systolic and diastolic blood pressure was altered only slightly. These alterations did not seem to be dose-related. Systolic and diastolic blood pressure rose to values above 160 and/or 95 mm Hg (on two consecutive visits) in 11 %, 21 %, and 26% of the patients taking 1.25,2.5, and 5 mg/kg/ day of cyc1osporine, respectively. However, mean values in the different dose groups remained almost unchanged. Adverse events Adverse events were reported in 10% (n = 109), 20% (n = 183), and 32% (n = 60) of the patients treated with 1.25, 2.5, and 5 mg/kg/day of cyclosporine, respectively. The adverse events occurring with no causal relation to cyclosporine therapy are listed in Table III. The most common were gastrointestinal complaints followed by the common cold and other viral infections.
DISCUSSION The results of this multicenter dose-finding study clearly demonstrate a dose-related therapeutic efficacy of cyclosporine in severe plaque psoriasis. Whereas in the past several regimens have been used
with doses up to 14 mg/kg/day,3 the problems with side effects indicated that long-term treatment of psoriasis patients was dependent on finding an effective low-dose «5 mg/kg/day) regimen. Side effects of cyc1osporine in the long-term treatment of organ transplant recipients include renal dysfunction, arterial hypertension, and an increase in transaminases. 4,5 Less severe side effects include gastrointestinal discomfort, hypertrichosis, tremor, and headaches. 6 These side effects are strongly dosedependent. In this study 62% of patients achieved a PASI reduction of more than 70% in 3 months with an initial dosage of 2.5 mg/kg/day. This dose proved to be optimal as a starting dose with respect to both efficacy and tolerability. Even the lowest dose chosen (i.e., 1.25 mg/kg/day) showed a good therapeutic effect because 24% of the patients responded. In 28% of the patients the dosage had to be increased to 5 mg/kg/day because of insufficient therapeutic efficacy (PASI reduction
In 1979, Mueller and Herrmann l reported clearing of psoriatic plaques in patients who were receiving cyclosporine for the treatment of arthropathies. This led to a series of case reports and clinical trials that confirmed the efficacy of cyclosporine in psoriasis even in patients resistant to other therapeutic regimens. 2 The aim of the present study was to conduct a randomized, controlled, multicenter study to investigate whether an optimal dosage of cyclosporine in the long-term treatment of severe plaque psoriasis could be established with regard to efficacy, safety, and tolerability. The effect of cyclospoFrom the D~partment of Dermatology, University of Kiel'; and the Clinical Research Department, Sandoz AG, Niirnberg. b Supported by Sandoz AG, Niirnberg. Reprint requests: Prof. Dr. E. Christophers, Department of Dermatology, University ofKiel, Schittenhelmstr. 7, D-2300 Kiell, Germany. *Participants listed at the end of the article.
16/1/32546
86
rine on nail involvement, pruritus, and arthropathy was also assessed.
PATIENTS AND METHODS
Patient selection A total of 285 male and female patients from 18 to 70 years of age were admitted to the study after written consent was obtained. Patients had to have severe generalized chronic plaque psoriasis. The psoriasis area and severity index (PASI) at entry was at least 15. Patients who received treatment with methotrexate, retinoids, glucocorticosteroids, or PUVA within the last 2 weeks before therapy were excluded. Furthermore, patients treated with compounds known to interact with cyclosporine metabolism, pregnant or nursing women, patients with impaired renal and/or liver function, infectious and neurologic disorders, a history ofmalignancy, as well as alcohol abuse did not enter the study. As topical therapy during the study, 1% salicylic acid in white petrolatum or bland ointments were used.
Volume 26 Number 1 January 1992 Experimental design The study was performed as a randomized controlled dose-finding study in 24 dermatology centers in Germany. Within a period of 12 to 36 weeks the dose required to induce a remission in each patient was determined. Patients were randomly assigned to treatment with 1.25 or 2.5 mg/kg/day of cyclosporine. The daily dose was divided into a morning and evening dose taken with a meal. After 2 weeks of treatment, patients with a reduction of more than 10% and after 6 weeks of more than 30% of the baseline PASI continued with the unchanged dose until further evaluation at week 12. Patients with a PASI reduction of less than 10% after 2 weeks or less than 30% after 6 weeks were classified as treatment "failures" and reentered the study with a doubled dose. Patients with a regimen of 5 mg/kg/day who failed to show a reduction ofthe baseline PASI after 2 and 6 weeks as already described were withdrawn from the study. Patients whose PASI had declined to below 8 or to 25% or less of the baseline value were classified as successfully treated. Patients who did not fulfill these criteria and who were taking doses less than 5 mg/kg/day reentered the study at a doubled dose. Dose reduction. The dose was halved in case of ( 1) an increase of serum creatinine of more than 30%, (2) an increase of serum potassium above the upper limit of normal, (3) an increase in serum total bilirubin or liver enzymes of more than 100% above baseline or above the threefold upper limit of normal, and (4) cyclosporine trough level (Sandimmun-RIA kit, Sandoz) was above 250 ng/ml on two consecutive measurements. Investigations (efficacy, safety, and tolerability). Patients were classified according to the PASI. The PASI varies in steps of 0.1 from 0.0 to 72.0. Before starting the study all investigators took part in a training meeting for PASI scoring to optimize and standardize evaluation of disease activity. The severity of the psoriatic lesions was further evaluated according to erythema, infiltration, and desquamation on a scale from 0 to 4, in which 0 means complete absence and 4 means the most severe involvement. Involvement of nails, severity of arthropathy, and pruritus were also assessed. Pruritus and nail involvement were classified on a 4-point scale. Arthropathy was assessed by evaluating the intensity of inflammation, pain, swelling, and impairment of daily activities on a 4-point scale for each criterion. The following laboratory values were determined at baseline, at week 2, and then at 4-week intervals: serum creatinine, blood urea nitrogen, serum potassium, uric acid, magnesium, cholesterol, triglycerides, bilirubin, SGOT, alkaline phosphatase, albumin, hemoglobin, total white blood cell count, platelets, urine (glucose and protein), and cyclosporine trough levels. All determinations were performed at a central laboratory.
Cyclosporine in psoriasis 87 Table I. Discontinuations throughout the study (percentage of patients on different dosages of cyc1osporine) Reason for discontinuation
Adverse event Concomitant disease Noncompliance Lack of efficacy Others
1.8% 0.9%
3.2% 0.5%
1.6% 1.6%
4.5% 8.1%
4.3% 7.6%
1.6% 11.0%
0.9%
1.6%
1.6%
RESULTS A total of 285 patients were randomized into either the 1.25 mg/kg/day or the 2.5 mg/kg/day group. This analysis is based on data from 217 patients who completed the study. The remaining patients are either still receiving treatment or have discontinued the study. The reasons and the frequency of discontinuation are given in Table 1. Neither the frequency nor the symptoms that led to withdrawal from the study were dose-related. The 1.25 mg/kg/ day group consisted of 109 patients (29 female, 80 male) and the 2.5 mg/kg/day group consisted of 108 patients (28 female, 80 male). The mean age of both groups was 42 years. Dosage and efficacy Dosage. Forty-four of 109 patients (40%) who started with 1.25 mg/kg/day ofcyc1osporine needed to double the dosage and 31 (28%) had to increase the dosage to 5 mg/kg/day because of an insufficient therapeutic response. With the initial dosage of 2.5 mg/kg/day of cyclosporine, 29 patients (27%) needed to increase it to 5 mg/kg/day because of an inadequate therapeutic response. One patient had to halve the 1.25 mg/kg/day dosage and two patients each had to halve the 2.5 mg/kg/day and the 5 mg/kg/day dose because of increases in serum creatinine. In one patient the 5.0 mg/kg/day dose had to be reduced because of cyc1osporine trough levels above 250 ng/m!. Sixteen patients reduced the dose from 5 to 2.5 mg/kg/day and one patient to 1.25 mg/kg/day because of therapeutic success. Efficacy. Table II demonstrates the percentage of patients with a P ASI reduction of at least 75% with
Journal of the American Academy of Dermatology
88 Christophers et aZ. Table II. Efficacy of cyc1osporine in psoriasis*
1.25 mg/kg/day
Cumulative responder rate (PASI reduction ~75%)
I
Initial dosage
Initial dosage
1.25 mg/kg/day
2.5 mg/kg/day
2.5 mg/kg/day
I
43%
18%
5 mg/kg/day
2.5 mg/kg/day
63%
56%
I
5 mg/kg/day
72%
*Percentage of patients with PASI-reduction of at least 75% on three different doses.
Table III. Adverse events* (irrespective of a casual relation to cyclosporine therapy) Gastrointestinal complaints Common cold Viral infections Headache Tremor Fatigue Gingival hyperplasia Edema of the lower limbs Hypertrichosis Paresthesia
Total
1.25 mg/kg/day
15 10
4t
4
2
3 3 3 2
1
4 4 3
1 2
1
2.5 mg/kg/day
5 mg/kg/day
8
3 2
7t
3 1 1 2 1 3 1 2
1 3t 1 1 1
1
*There were single reports of the following: photoallergic eczema, vertigo, hematuria,t swelling of lymph nodes,t alopecia, diabetes mellitus, tarthralgia, t squamous cell carcinoma,t lumbago,t extra systoles.t tThe drug was withdrawn because of the side effect.
different cyc1osporine dosages. Nineteen (18%) of the patients taking 1.25 mg/kg/day were successfully treated. The remaining patients received an increased dose of 2.5 mg/kg/day with which a therapeutic success was achieved in an additional 27 cases (25%) (in total 43%). A final increase of the dosage to 5 mg/kg/day led to a PASI reduction of more than 75% in another 22 patients (20%) (in total 63%). In the group who started with 2.5 mg/kg/ day of cyc1osporine 60 patients (56%) had a PASI reduction of more than 75%. Mter increasing the dosage to 5 mg/kg/day of cyc1osporine in the remaining patients, a total of 78 patients (72%) were treated successfully. The time course of the PASI reduction on the initial doses of 1.25 and 2.5 mg/kg/day is shown in Fig. 1. In 24% ofthe patients taking 1.25 mg/kg/day and in 62% taking 2.5 mg/ kg/day no dose adjustment was necessary during 12 weeks of treatment because of the response to this initial dosage. Pruritus. At the end of treatment, scores decreased by 27.8%,61 %, and 42.8% in the 1.25,2.5, and 5 mg/kg/day groups, respectively. Involvement of nails. Cyc1osporine caused a slight improvement in nail involvement in all groups.
Joints. Arthropathy was present in 107, 182, and 59 patients treated with doses of 1.25, 2.5, and 5 mg/kg/day, respectively. At the end of treatment, inflammation, pain, swelling, and impairment of daily life activities appeared to have been ameliorated in most cases. Laboratory investigations Creatinine levels greater than 130 ,umol/L were observed in 1%,5%, and 13% of the patients in the 1.25, 2.5, and 5 mg/kg/day groups, respectively. Discontinuation of treatment was not necessary in any case. In five patients (one taking 1.25 mg/kg/ day, two taking 2.5 mg/kg/day, and two taking 5 mg/kg/day) the dose of cyclosporine had to be reduced because of an increase in serum creatinine. Blood urea nitrogen concentration rose above 8.3 mmol/L in 4%, 13%, and 18% of the patients, and uric acid greater than 400 ,umol/L could be observed in 19%, 28%, and 43% of the patients. Cholesterol increased above 6.7 mmol/L in 12%,21 %, and 25% of the patients and triglyceride levels increased above 2.0 mmol/L in 20%,40%, and 53% of the patients, respectively. SGOT above 20 U /L was detected in 11 %, 15%, and 33% of the patients and
Volume 26 Number 1 January 1992
Cyclosporine in psoriasis 89 % PASI 100 90 1.25 mglkgfd(24% of patients)
80
2.5 mglkgfd(62% of patients)
70 60 50 40
30 20 10 0
0
2
3
4
5
6
7
8
9
10
11
12
study weeks
Fig. 1. Efficacy of cyclosporine in psoriasis. Change of PASIon initial dosages of 1.25 and 2.5 mg/kg/day.
increased bilirubin levels (> 17 ~mol/L) were found in 8%, 20%, and 31 % of the patients. An increase in alkaline phosphatase above 180 U /L was seen in 11 %, 13%, and 20% of the patients treated with the three different cyclosporine dosages. Blood pressure. Systolic and diastolic blood pressure was altered only slightly. These alterations did not seem to be dose-related. Systolic and diastolic blood pressure rose to values above 160 and/or 95 mm Hg (on two consecutive visits) in 11 %, 21 %, and 26% of the patients taking 1.25,2.5, and 5 mg/kg/ day of cyc1osporine, respectively. However, mean values in the different dose groups remained almost unchanged. Adverse events Adverse events were reported in 10% (n = 109), 20% (n = 183), and 32% (n = 60) of the patients treated with 1.25, 2.5, and 5 mg/kg/day of cyclosporine, respectively. The adverse events occurring with no causal relation to cyclosporine therapy are listed in Table III. The most common were gastrointestinal complaints followed by the common cold and other viral infections.
DISCUSSION The results of this multicenter dose-finding study clearly demonstrate a dose-related therapeutic efficacy of cyclosporine in severe plaque psoriasis. Whereas in the past several regimens have been used
with doses up to 14 mg/kg/day,3 the problems with side effects indicated that long-term treatment of psoriasis patients was dependent on finding an effective low-dose «5 mg/kg/day) regimen. Side effects of cyc1osporine in the long-term treatment of organ transplant recipients include renal dysfunction, arterial hypertension, and an increase in transaminases. 4,5 Less severe side effects include gastrointestinal discomfort, hypertrichosis, tremor, and headaches. 6 These side effects are strongly dosedependent. In this study 62% of patients achieved a PASI reduction of more than 70% in 3 months with an initial dosage of 2.5 mg/kg/day. This dose proved to be optimal as a starting dose with respect to both efficacy and tolerability. Even the lowest dose chosen (i.e., 1.25 mg/kg/day) showed a good therapeutic effect because 24% of the patients responded. In 28% of the patients the dosage had to be increased to 5 mg/kg/day because of insufficient therapeutic efficacy (PASI reduction
