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 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 im- proved their psoriasis area and severityindex "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 in- crease of serum creatinine level above 130 I1mol/L occurred in five patients who could con- tinue 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 Among those patients taking 1.25, 2.5, or 5 mg/kg/ day of cyclosporine, 16.2%, 17.1%, and 17.8%, respectively, were withdrawn from the study.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 clear- ing of psoriatic plaques in patients who were receiv- ing cyclosporine for the treatment of arthropathies. This led to a series of case reports and clinical trials that confirmed the efficacy of cyclosporine in psori- asis even in patients resistant to other therapeutic regimens. 2 The aim of the present study was to con- duct a randomized, controlled, multicenter study to investigate whether an optimal dosage of cyclospo- rine in the long-term treatment of severe plaque psoriasis could be established with regard to effi- cacy, safety, and tolerability. The effect of cyclospo- From the 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 Dermatol- ogy, 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 con- sentwas 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, pa- tients treated with compounds known to interact with cy- closporine metabolism, pregnant or nursing women, pa- tients with impaired renal and/or liver function, infec- tious and neurologic disorders, a history of malignancy, 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.
Transcript
Therapv
Cyclosporine in psoriasis: A multicenterdose-finding study in severe plaque psoriasisEnno Christophers, MD,a Ulrich Mrowietz, MD,a Hans-Heinrich Henneicke,aLothar Farber, MD,b Dieter Welzel, MD,b and the participants in theGerman multicen~erstudy*
Interim results of a randomized, controlled, dose-finding study conducted in 24 dermatologycenters on 217 patients with severe chronic plaque psoriasis (entry psoriasis area and severityindex of at least 15) are presented. Patients were first treated with cyclosporine either 1.25or 2.5 mg/kg/day (Sandimmune); in case of inadequate response the dosage was increasedto a maximum of 5 mg/kg/day. Cyclosporine was given for 12 to 36 weeks. Treatment wasclassified as "successful" if the psoriasis area and severity index was reduced to 25% or lessof 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 in56% 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/dayproved to be effective in some cases, 2.5 mg/kg/day of cyclosporine is the optimal startingdose. 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 weregastrointestinal 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 totalof 1.6% to 3.2% of the patients discontinued the study because of adverse events. (J AM ACADDERMATOL 1992;26:86-90.)
In 1979, Mueller and Herrmannl 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 trialsthat confirmed the efficacy of cyclosporine in psoriasis even in patients resistant to other therapeuticregimens.2 The aim of the present study was to conduct a randomized, controlled, multicenter study toinvestigate whether an optimal dosage of cyclosporine in the long-term treatment of severe plaquepsoriasis could be established with regard to efficacy, safety, and tolerability. The effect of cyclospo-
From the D~partment of Dermatology, University of Kiel'; and theClinical 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 arthropathywas also assessed.
PATIENTS AND METHODSPatient selection
A total of 285 male and female patients from 18 to 70years of age were admitted to the study after written consent was obtained. Patients had to have severe generalizedchronic plaque psoriasis. The psoriasis area and severityindex (PASI) at entry was at least 15.
Patients who received treatment with methotrexate,retinoids, glucocorticosteroids, or PUVA within the last2 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, aswell as alcohol abuse did not enter the study.
As topical therapy during the study, 1% salicylic acidin white petrolatum or bland ointments were used.
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Experimental design
The study was performed as a randomized controlleddose-finding study in 24 dermatology centers in Germany. Within a period of 12 to 36 weeks the dose requiredto induce a remission in each patient was determined.
Patients were randomly assigned to treatment with1.25 or 2.5 mg/kg/day of cyclosporine. The daily dosewas divided into a morning and evening dose taken witha meal. After 2 weeks of treatment, patients with areduction of more than 10% and after 6 weeks of morethan 30% of the baseline PASI continued with theunchanged dose until further evaluation at week 12. Patients with a PASI reduction of less than 10% after 2weeks or less than 30% after 6 weeks were classified astreatment "failures" and reentered the study with a doubled dose. Patients with a regimen of 5 mg/kg/day whofailed to show a reduction ofthe baseline PASI after 2 and6 weeks as already described were withdrawn from thestudy. Patients whose PASI had declined to below 8 or to25% or less of the baseline value were classified assuccessfully treated. Patients who did not fulfill these criteria and who were taking doses less than 5 mg/kg/dayreentered the study at a doubled dose.
Dose reduction. The dose was halved in case of (1) anincrease 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 thethreefold upper limit of normal, and (4) cyclosporinetrough level (Sandimmun-RIA kit, Sandoz) was above250 ng/ml on two consecutive measurements.
Investigations (efficacy, safety, and tolerability). Patients were classified according to the PASI. The PASIvaries in steps of 0.1 from 0.0 to 72.0. Before starting thestudy all investigators took part in a training meeting forPASI scoring to optimize and standardize evaluation ofdisease activity. The severity of the psoriatic lesions wasfurther evaluated according to erythema, infiltration, anddesquamation on a scale from 0 to 4, in which 0 meanscomplete absence and 4 means the most severe involvement. Involvement of nails, severity of arthropathy, andpruritus were also assessed. Pruritus and nail involvementwere classified on a 4-point scale. Arthropathy wasassessed byevaluating the intensityof inflammation, pain,swelling, and impairment of daily activities on a 4-pointscale for each criterion. The following laboratory valueswere determined at baseline, at week 2, and then at4-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 ofcyc1osporine)
diseaseNoncompliance 4.5% 4.3% 1.6%Lack of 8.1% 7.6% 11.0%
efficacyOthers 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/daygroup. 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 frequencyof discontinuation are given in Table 1. Neither thefrequency nor the symptoms that led to withdrawalfrom the study were dose-related. The 1.25 mg/kg/day group consisted of 109 patients (29 female, 80male) and the 2.5 mg/kg/day group consisted of108 patients (28 female, 80 male). The mean age ofboth groups was 42 years.
Dosage and efficacy
Dosage. Forty-four of 109 patients (40%) whostarted with 1.25 mg/kg/day ofcyc1osporine neededto double the dosage and 31 (28%) had to increasethe dosage to 5 mg/kg/day because of an insufficient therapeutic response. With the initial dosage of2.5 mg/kg/day of cyclosporine, 29 patients (27%)needed to increase it to 5 mg/kg/day because of aninadequate therapeutic response. One patient had tohalve the 1.25 mg/kg/day dosage and two patientseach had to halve the 2.5 mg/kg/day and the 5mg/kg/day dose because of increases in serum creatinine. In one patient the 5.0 mg/kg/day dosehad to be reduced because of cyc1osporine troughlevels above 250 ng/m!. Sixteen patients reducedthe dose from 5 to 2.5 mg/kg/day and one patientto 1.25 mg/kg/day because of therapeutic success.
Efficacy. Table II demonstrates the percentage ofpatients with a PASI reduction of at least 75% with
88 Christophers et aZ.
Table II. Efficacy of cyc1osporine in psoriasis*
Initial dosage1.25 mg/kg/day
1.25 mg/kg/day I 2.5 mg/kg/day I 5 mg/kg/day
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Initial dosage2.5 mg/kg/day
2.5 mg/kg/day I 5 mg/kg/day
Cumulative responder rate(PASI reduction ~75%)
18% 43% 63% 56% 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)
*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.ttThe drug was withdrawn because of the side effect.
different cyc1osporine dosages. Nineteen (18%) ofthe 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 27cases (25%) (in total 43%). A final increase of thedosage to 5 mg/kg/day led to a PASI reduction ofmore 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 PASIreduction of more than 75%. Mter increasing thedosage to 5 mg/kg/day of cyc1osporine in theremaining patients, a total of 78 patients (72%) weretreated successfully. The time course of the PASIreduction on the initial doses of 1.25 and 2.5mg/kg/day is shown in Fig. 1. In 24% ofthe patientstaking 1.25 mg/kg/day and in 62% taking 2.5 mg/kg/day no dose adjustment was necessary during 12weeks of treatment because of the response to thisinitial 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 slightimprovement in nail involvement in all groups.
Joints. Arthropathy was present in 107, 182, and59 patients treated with doses of 1.25, 2.5, and 5mg/kg/day, respectively. At the end of treatment,inflammation, pain, swelling, and impairment ofdaily life activities appeared to have been ameliorated in most cases.
Laboratory investigations
Creatinine levels greater than 130 ,umol/L wereobserved in 1%,5%, and 13% of the patients in the1.25, 2.5, and 5 mg/kg/day groups, respectively.Discontinuation of treatment was not necessary inany case. In five patients (one taking 1.25 mg/kg/day, two taking 2.5 mg/kg/day, and two taking 5mg/kg/day) the dose of cyclosporine had to be reduced because of an increase in serum creatinine.Blood urea nitrogen concentration rose above 8.3mmol/L in 4%, 13%, and 18% of the patients, anduric acid greater than 400 ,umol/L could be observedin 19%, 28%, and 43% of the patients. Cholesterolincreased above 6.7 mmol/L in 12%,21%, and 25%of the patients and triglyceride levels increasedabove 2.0 mmol/L in 20%,40%, and 53% of the patients, respectively. SGOT above 20 U/L wasdetected in 11%, 15%, and 33% of the patients and
1.25 mglkgfd(24% of patients)
2.5 mglkgfd(62% of patients)
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%PASI 100
90
80
70
60
50
40
30
20
10
00 2 3 4 5 6 7 8 9
Cyclosporine in psoriasis 89
10 11 12study weeks
Fig. 1. Efficacy of cyclosporine in psoriasis. Change ofPASIon initial dosages of 1.25 and2.5 mg/kg/day.
increased bilirubin levels (> 17 ~mol/L) were foundin 8%, 20%, and 31% of the patients. An increase inalkaline phosphatase above 180 U/L was seen in11%, 13%, and 20% of the patients treated with thethree different cyclosporine dosages.
Blood pressure. Systolic and diastolic blood pressure was altered only slightly. These alterations didnot seem to be dose-related. Systolic and diastolicblood pressure rose to values above 160 and/or 95mm Hg (on two consecutive visits) in 11%, 21%, and26% of the patients taking 1.25,2.5, and 5 mg/kg/day of cyc1osporine, respectively. However, meanvalues in the different dose groups remained almostunchanged.
Adverse events
Adverse events were reported in 10% (n = 109),20% (n = 183), and 32% (n = 60) of the patientstreated with 1.25, 2.5, and 5 mg/kg/day of cyclosporine, respectively. The adverse events occurringwith no causal relation to cyclosporine therapy arelisted in Table III. The most common were gastrointestinal complaints followed by the commoncold and other viral infections.
DISCUSSION
The results of this multicenter dose-finding studyclearly 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 withside effects indicated that long-term treatment ofpsoriasis patients was dependent on finding aneffective low-dose «5 mg/kg/day) regimen. Sideeffects of cyc1osporine in the long-term treatment oforgan transplant recipients include renal dysfunction, arterial hypertension, and an increase in transaminases.4,5 Less severe side effects include gastrointestinal discomfort, hypertrichosis, tremor, andheadaches.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 tobe 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 therapeuticeffect because 24% ofthe patients responded. In 28%of the patients the dosage had to be increased to 5mg/kg/day because of insufficient therapeutic efficacy (PASI reduction <75% of baseline) after 3months of treatment.
No clear correlation between the dosage of cyclosporine and cyclosporine trough levels or betweenthe cyc1osporine trough levels and the PASI reduction was observed.
The overall results of our study are in accordancewith other investigations of low-dose cyc1osporine inpsoriasis.7•9 Recently Ellis et al. lO suggested 5 mg/kg/day of cyclosporine as an optimal starting dos-
90 Christophers et al.
age. However, in their study 65% of patients takingless than 5 mg/kg/day showed significant improvement. In our investigation the same efficacy was seenwith 2.5 mg/kg/day and was correlated with a lowerincidence of side effects.
Adverse events were seen in all three groups ofpatients and were clearly dose-related. A moderateincrease in triglycerides was observed in up to 53%of the patients who received 5 mg/kg/day; however,patients in this study were not questioned about diet.
Recently De Rie et al. 11 analyzed the side effectsof medium-dose and low-dose cyclosporine maintenance therapy in patients with psoriasis and found adose-related increase of side effects, mainly anincrease in serum creatinine and hypertension. Thisled to cyc1osporine withdrawal in about 15% of patients. In our study no significant increase in bloodpressure was observed. Although this cannot befullyexplained at present, the shorter treatment period inour study (mean 12 weeks) compared with thetreatment duration reported by De Rie et al. 11(mean 19.5 months) may playa role.
We recommend 2.5 mg/kg/day of cyc1osporineas the initial dosage for treatment of severe psoriasis. In case of insufficient response this can beincreased to 5 mg/kg/day. A further increase indosage is not recommended because of a potentialincrease in the incidence and severity of adverse effects.
The following investigators participated in the study:from Aue, Dr. Hums, Dr. Pruert; from Berlin, Dr.Albrecht, Dr. Borchers, Prof. Czarnetzki, Dr. Koll, Prof.Meffert, and Dr. Stojanow; from Bochum, Prof. Altmeyer, Dr. EI-Gammal; from Bonn, Prof. Kreysel, Dr.Lindenblatt; from Dortmund, Prof. Tronnier, Dr. Bender;from Dresden, Prof. Barth, Dr. Hubner; from Freiburg,
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Prof. SchOpf, Dr. Kern; from Gera, Dr. Meyer, Dr. Felgentrager; from Halle, Dr. Taube, Dr. Fiedler; fromHamburg, Prof. Mensing, Dr. Radloff; from lena, Prof.Knopf, Dr. Barta; from Kassel, Prof Petres, Dr. Fuller;from Kie1, Prof. Christophers (principal investigator), Dr.Mrowietz; from Krefeld, Prof. Wassilew, Dr. Horn; fromMagdeburg, Prof. Schlenzka, Dr. Peschlow; from Mannheim, Prof. lung, Dr. Weiss; from Marburg, Prof.Friederich, Dr. Georgi; from Munchen, Prof. Borelli, Dr.Huber, Prof. Braun-Falco, and Dr. Bergner; from Munster, Prof. BrOCker, Dr. Ott; from Plauen, Dr. Koch, Dr.Weiss; from Rostock, Dr. Westphal, Dr. Wurdel.
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6. Kahan BD. Cyclosporine. N Engl J Moo 1989;321:172538.
7. Van JoostTH, Bos JD, ReuleF, etal. Low-dose cyclosporinAin severe psoriasis: a double-blind study. Br J Dennatol1988;118:183-90.
8. Griffiths CEM, Powles AV, McFadden J, et al. Long-tenncyclosporin for psoriasis. Br J Dermatol1989;120:253-60.
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10. Ellis CN, Fradin MS, Messana JM, et al. Cyclosporineforplaque-type psoriasis. Results of a multidose, double-blindtrial. N Engl J Moo 1991;324:277-84.
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