Original Article
Cyclosporine for Plaque-Type Psoriasis — Results of a Multidose, Double-Blind Trial
N Engl J Med 1991; 324:277-284January 31, 1991
- Abstract
- Abstract
Background.
Severe plaque-type psoriasis has been successfully treated with orally administered cyclosporine, but there has been no comparative, controlled evaluation of various dosages and their efficacy and side effects.
Methods.
In a 16-week, double-blind trial, we randomly assigned 85 patients with severe psoriasis to receive 3, 5, or 7.5 mg of cyclosporine per kilogram of body weight per day or a placebo consisting of the vehicle for the drug. After eight weeks the dose could be adjusted to improve safety or efficacy while maintaining blinding.
Results.
The psoriasis improved in a dose-dependent fashion. After eight weeks of fixed-dose therapy, 36, 65, and 80 percent of the patients receiving 3,5, and 7.5 mg of cyclosporine per kilogram per day, respectively, were rated as being clear or almost clear of psoriasis; each group had significant improvement (P<0.0001) as compared with the group receiving vehicle, in which none of the patients were rated as clear or almost clear. The patients who received 5 mg per kilogram were the least likely to require dosage adjustments because of side effects or a lack of efficacy. The glomerular filtration rate, measured in a subgroup of 34 patients receiving cyclosporine, decreased by a median of 16 percent. Higher doses of cyclosporine had greater adverse effects on systolic blood pressure, glomerular filtration rate, and serum levels of creatinine, uric acid, bilirubin, and cholesterol. Delayed-type hypersensitivlty reactions to skin-test antigens were reduced by cyclosporine administration. Cyclosporine appears to become concentrated in skin.
Conclusions.
Cyclosporine therapy leads to a rapid and thorough clearing of psoriasis; an initial dose of 5 mg per kilogram per day seems to be appropriate. However, the safety of cyclosporine for the long-term treatment of psoriasis remains to be determined. (N Engl J Med 1991; 324:277–84.)
Media in This Article
Figure 1
Area of Typical Psoriasis before Therapy (Left) and after Eight Weeks of Therapy with 7.5 mg of Cyclosporine per Kilogram per Day (Right).Figure 2
Mean (±1 SE) Psoriasis Area and Severity Index22 during the Study, According to Initial Treatment Assignment.Article Activity
- Article
The effectiveness of cyclosporine in the treatment of psoriasis was a serendipitous finding by Mueller and Herrmann,1 who included four patients with psoriatic arthritis and psoriasis in a study of therapy for rheumatoid arthritis. We confirmed this finding in a double-blind trial of the efficacy of cyclosporine for psoriasis.2 The effective doses of cyclosporine administered to patients with psoriasis in these and other trials ranged from 1 to 15 mg per kilogram of body weight per day.1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 Because the reports were based mainly on studies of small numbers of patients, it has been difficult to determine the proper dose.
Therefore, we conducted a 16-week, double-blind, dose–response trial in a single study center to determine the efficacy of three doses of cyclosporine in 85 patients with psoriasis. In addition, we assessed the clinical and laboratory side effects of each dose, and in 43 patients we evaluated renal function (as described below).
Methods
Patients
Eighty-five patients (66 men and 19 women; mean age, 44 years; range, 19 to 74), were enrolled in this outpatient study. To be enrolled, they were required to have involvement of more than 25 percent of their body-surface area with chronic psoriasis characterized by large plaques (83 patients; mean degree of involvement, 43 percent; range, 25 to 80 percent) or to have- disabling psoriasis (2 patients with severe psoriasis mainly of the hands; degree of involvement, 7 percent and 15 percent). The patients selected had not responded satisfactorily to at least one of the major agents for psoriasis — i.e., ultraviolet B, ultraviolet A with oral psoralen, etretinate, or methotrexate. They were in good health according to their history and physical examination. Women with childbearing potential were excluded from the study. Before enrollment, all patients stopped receiving systemic therapy or phototherapy for at least 30 days and topical medications other than bland emollients for at least 14 days.
All patients gave informed consent after a full explanation of the details, procedures, and potential risks of the study. The protocol and consent form were approved by the institutional review board of the University of Michigan Medical Center, and an application for the use of an investigational new drug was filed with the Food and Drug Administration.
Protocol
Eligible patients were assigned numbers in consecutive order; each number had been preassigned to one of four treatment groups by means of a computer-generated random code in blocks of 17. Three groups received oral cyclosporine (Sandimmune oral solution) daily in a dose of 7.5 mg (n = 15), 5 mg (n = 20), or 3 mg (n = 25) per kilogram of body weight, while the remaining group (n = 25) received vehicle only (consisting of the Sandimmune olive oil Labrafil [peglicol 5 oleate] base). Before therapy, the four groups were similar in various characteristics (Table 1Table 1
Characteristics of the Study Population According to Assigned Treatment.*).An unbalanced design was chosen in anticipation that higher numbers of patients would be required in the groups given lower doses of cyclosporine in order to distinguish their responses from that of the group given the vehicle. An analysis performed before the study indicated that the sample sizes would provide a statistical power of more than 95 percent to detect a dose–response relation by the eighth week of study (assuming linear response rates of 10 percent among the patients assigned to the vehicle and 36 percent, 53 percent, and 75 percent in those assigned to doses of 3, 5, and 7.5 mg of cyclosporine per kilogram, respectively).19
The protocol was designed so that patients received a fixed dose of cyclosporine or vehicle for eight weeks. This period was followed by an eight-week period during which the dose could be adjusted —i.e., increased to the next higher dose if the psoriasis did not respond satisfactorily. Thus, patients who received vehicle for the first eight weeks could subsequently receive 3 mg of cyclosporine per kilogram per day, those who received 3 or 5 mg could receive 5 or 7.5 mg, and those who received 7.5 mg could receive 10 mg. Such increases were allowed again during the 12th week in the same manner; none of the patients receiving 10 mg of cyclosporine per kilogram per day required further increases.
A reduction to the next lower dose was made at any time if the serum creatinine concentration rose to twice the base-line value or above 160 μmol per liter (1.8 mg per deciliter); if the total bilirubin concentration rose above 38 μmol per liter (2.25 mg per deciliter); if the diastolic blood pressure rose above 90 mm Hg and could not be controlled by antihypertensive therapy; if the trough cyclosporine blood level rose above 800 ng per milliliter according to polyclonal radioimmunoassay (performed with the Sandoz kit by Metpath Laboratories, Teterboro, N.J.) and the result was confirmed by high-performance liquid chromatography (performed at the Department of Pathology, University of Michigan Medical Center, with a modification of the method of Annesley et al.20); if renal function declined markedly (see below); or if serious clinical side effects occurred. Patients with intolerance to the vehicle or the lowest dose of cyclosporine were withdrawn from the study; patients with abnormal findings were not allowed to resume receiving the doses at which the abnormalities occurred.
All patients diluted their medication with milk or juice, taking it in a glass (plastic or paper cups that might adsorb cyclosporine were prohibited) and in a single dose each morning. The preparations of cyclosporine and vehicle were identical in their bottling, labeling, and appearance; thus, patients were blinded to their treatments.
The patients avoided taking medications known to influence cyclosporine metabolism21; however, 3 patients took erythromycin for one week during the study, and 17 patients distributed across all treatment groups received calcium-channel-blocking agents for cyclosporine-induced hypertension.
Blinding
A physician who was not blinded to the patients' group assignment and who did not meet them reviewed their laboratory results, including their cyclosporine blood values; he alone prescribed the dose of medication (in milliliters) to an assistant, who instructed the patients at each visit. This physician could reduce the dose if the laboratory results were abnormal. Other physicians, who were blinded to the group assignment and laboratory findings throughout the study, evaluated the patients and performed the clinical assessments; through an assistant, they could request that the unblinded physician increase a patient's dosage at the 8th or 12th week of therapy because of suboptimal clinical response or that he decrease the dosage at any time because of a clinical side effect.
Efficacy and Safety
In each patient, three indicator lesions were selected that represented plaques with relatively mild, moderate, and severe involvement, and then evaluated biweekly for changes in scaling, erythema, plaque thickness, and overall severity according to a seven-point scale for each feature evaluated. A score of 1 indicated that the feature was absent (clear); 2, that it was present as a trace (almost clear); 3, that it was mild; 4, that it ranged between mild and moderate; 5, that it was moderate; 6, that it ranged between moderate and severe; and 7, that it was severe. The global severity of the features in each patient was evaluated before treatment and after 8, 12, and 16 weeks of therapy according to the same scale. A global rating that reflected the percentage and severity of involvement of body quadrants by psoriasis, ranging from 0 to 72 — the psoriasis area-and-severity index22 — was evaluated biweekly. Each patient was evaluated by the same physician at all visits, with few exceptions.
Monitoring included measurement of 24-hour urinary creatinine clearance every four weeks, determination of blood chemical values, a complete blood count with differential count, microscopical urinalysis, measurement of cyclosporine blood levels by radioimmunoassay and high-performance liquid chromatography, and assessment of vital signs every two weeks. Creatinine clearance was also estimated with the Cockcroft—Gault formula.23 Blood pressure was measured by the physician after the patient had sat for three minutes, and also by the patient twice daily.
Renal-Function Tests
The glomerular filtration rate (GFR) was measured in 43 of the 85 patients by determining the clearance of iothalamate sodium I 125 before treatment and after eight weeks of therapy. Patients within each dosage group were assigned to this test before the study, with the use of a table of random numbers.
After initial hydration, each patient received 1.3 MBq (35 μCi) of iothalamate sodium I 125 (Glofil-125, IsoTex Diagnostics, Friendswood, Tex.) mixed with 0.1 ml of epinephrine with a concentration of 1:1000, by subcutaneous injection in the deltoid area. One hour after the compound was administered and after each of three subsequent 20-minute periods, a urine sample and a blood sample were obtained. The average radioactivity level was determined from the levels in three aliquots of the 20-minute plasma or urine samples with a gamma counter (Corning 4000 MultiWell, Medfield, Mass.). The final clearance rate was the mean of values in at least two 20-minute periods, corrected for the standard of 1.73 m2 of body-surface area.
Delayed-Type Hypersensitivity Testing
To assess the potential effects of cyclosporine on responses to skin-test antigens, the patients were tested with a battery of antigens preloaded on an eight-pronged applicator (Multitest CMI, Mérieux Institute, Miami) before treatment and after 8 and 16 weeks of therapy.24 On each test in each patient, we determined the number of positive antigen test sites and the total sum of induration at all positive sites, after correcting for the measurement of induration at control sites in two patients. Some patients (57 percent) were provided with a special caliper and were carefully instructed in recording results of the skin test 48 hours after application of the antigen. The results of skin tests in 43 percent of the patients were interpreted only by the blinded physicians in the study. Because there was no substantive difference between the results of the interpretations of the physicians and those of the patients, we included all values in our analysis.
Patients were classified as having decreased delayed-type hypersensitivity during cyclosporine therapy if they had both a decrease in the number of positive tests and a decrease of 10 percent or more in the total sum of induration, as compared with pretreatment values. Similarly, they were classified as having increased reactivity if they had both an increase in the number of positive tests and an increase of 10 percent or more in total induration. Patients with all other responses were classified as having no change.
Statistical Analysis
In the primary, intention-to-treat analysis, dose-specific changes in laboratory values and efficacy during the first eight weeks of the study were examined by analysis of variance or, if there were substantive differences between groups before therapy, by analysis of covariance in which each base-line value served as the covariate; multiple pairwise comparisons were made with Scheffé's test. Group differences in the proportion of patients with specific global scores for disease severity were analyzed with a chi-square test. Because of dose changes, secondary analyses for the second eight weeks are reported according to the mean dosage, obtained by averaging the mean daily dose in each patient in each group. Each of the initial four dosage groups was kept intact for the second eight weeks; values obtained during this period were compared with pretreatment values, and the comparisons were analyzed with the paired t-test.
Changes in status for delayed-type hypersensitivity were assessed with the sign test in each dosage group as well as for all cyclosporine-treated groups combined. Under the null hypothesis, the proportion of patients with a decrease in delayed-type hypersensitivity would be expected to approximate the proportion with an increase.
son's product—moment correlation analysis for continuou bivariate son's product—moment correlation analysis for continuous bivariate normal data or Spearman's rank-correlation analysis for discrete data. Group changes in GFR were evaluated by the median test, with specific comparisons by Wilcoxon's rank-sum tests. Multiple linear regression modeling of changes in GFR against an assemblage of potential predictor variables was performed with a forward-stepwise selection technique whereby variables were sequen tially included or excluded from the model according to the strength of their respective partial correlations.
All P values are two-tailed. Data were analyzed with the Michigan Interactive Data Analysis System (MIDAS, a statistical software package developed by the Statistical Research Laboratory at the University of Michigan) and are expressed as means ± 1 SEM.
Results
Efficacy during the Fixed-Dose Phase
Before therapy, the mean global scores for disease severity in the four treatment groups ranged from 6.1 to 6.5 (maximum, 7). By the end of the eighth week the mean score for the vehicle-treated patients was virtually unchan±0d (5.9±0.2), showing a decrease of only 3 percent. In contrast, patients receiving 3 mg of cyclosporine per kilogram per day for eight weeks had a 39 percent decrease in the mean global score (to 3.8± 0.4), those receiving 5 mg per kilogram had a 58 percent decrease (to 2.7±0.3), and those receiving 7.5 mg had a 71 percent decrease (to 1.9±0.2 — i.e., to a mean rating of "almost clear"). The improvement in all groups receiving cyclosporine was significantly greater (P<0.0001 for each) than that in the group receiving vehicle only; the responses in the groups receiving 5 and 7.5 mg of cyclosporine per kilogram were not significantly different from each other (P>0.1), but each of these responses was significantly better than that in the group receiving 3 mg (P<0.005 for each comparison). The responses of the three indicator lesions evaluated for scaling, erythema, and plaque thickness were comparable to the global response (P<0.0001 for each cyclosporine group vs. the vehicle group; data not shown). The severe chronic lesions and the milder lesions of each patient responded equally well.
The patients who were rated as being either clear or almost clear of lesions during the first eight weeks of therapy (Fig. 1Figure 1
Area of Typical Psoriasis before Therapy (Left) and after Eight Weeks of Therapy with 7.5 mg of Cyclosporine per Kilogram per Day (Right).) represented 0 percent of the group receiving the vehicle, 36 percent of the group receiving 3 mg of cyclosporine per kilogram per day, 65 percent of the group receiving 5 mg per kilogram, and 80 percent of the group receiving 7.5 mg (P<0.0001). Like the global score, the area—severity index22 showed significantly greater improvement in all groups receiving cyclosporine (P<0.001 for each) than in the group receiving vehicle; the responses in the groups receiving the two highest doses of cyclosporine were not significantly different from each other (P>0.4), but each was significantly better than the response in the group receiving the lowest dose (P<0.01 for each comparison). As compared with pretreatment values, the area—severity index in each of the four groups decreased significantly within two weeks after active therapy was begun (Fig. 2Figure 2Mean (±1 SE) Psoriasis Area and Severity Index22 during the Study, According to Initial Treatment Assignment.).Efficacy during the Adjusted-Dose Phase
Among the patients who participated after the eighth week, suboptimal responses led to at least one increase in the doses of 65, 26, and 15 percent of the patients initially assigned to doses of 3, 5, and 7.5 mg of cyclosporine per kilogram per day, respectively. All patients in the vehicle-treated group required crossover to cyclosporine treatment, and all groups had improvement during the second eight weeks of treatment (Fig. 2).
After 16 weeks, the global score for disease severity fell to 2.5±0.2 in the patients initially assigned to vehicle (—59 percent, n = 23), to 2.4±0.3 in those assigned to 3 mg of cyclosporine per kilogram per day ( — 61 percent, n = 23), to 1.8±0.2 in those assigned to 5 mg ( — 71 percent, n = 18), and to 1.5±0.2 in those assigned to 7.5 mg ( — 77 percent, n = 13) (P<0.0001 for each comparison). The percentage of body-surface area involved by psoriasis decreased from 38 ±3 percent to 13±3 percent in the patients initially assigned to vehicle (P<0.0001); the percentage decreased from 41±4 to 10±3 percent in the patients assigned to the 3-mg dose of cyclosporine, from 46±4 to 3±1 percent in those assigned to 5 mg, and from 46±4 to 1±1 percent in those assigned to 7.5 mg (P<0.0001 for each comparison). Of all patients initially assigned to cyclosporine treatment (except two with protocol violations; see below), 33 percent of those receiving 3 mg, 65 percent of those receiving 5 mg, and 43 percent of those receiving 7.5 mg (P<0.002 for each group vs. The patients assigned to vehicle are represented by circles; these patients received cyclosporine after week 8. Other symbols indicate the dose of cyclosporine to which patients were initially assigned, which could be increased after week 8 because of a suboptimal response of their psoriasis (triangles, 3 mg per kilogram per day; squares, 5 mg per kilogram; and diamonds, 7.5 mg per kilogram). All values indicated by solid symbols are significantly different from values before treatment (week 0) (P<0.005 by paired t-test for each comparison). When the effect of fixed doses was assessed by analysis of variance at week 8, all groups receiving cyclosporine had significant improvement as compared with the group receiving vehicle (P<0.001 for each comparison); the groups receiving 5 and 7.5 mg per kilogram per day had significant improvement as compared with the group receiving 3 mg per kilogram per day (P<0.01 for each comparison) but not as compared with each other (P>0.4). vehicle group, by chi-square test) required no increase or decrease in their doses for reasons of safety or efficacy throughout the entire 16-week study.
Side Effects and Dosage Reductions
The clinical side effects in all patients are shown in Table 2Table 2
Clinical Side Effects According to Assigned Treatment., and changes in blood pressure and laboratory variables in Tables 3Table 3
Changes in Clinical and Laboratory Variables during Study, According to Assigned Treatment. and 4Table 4
Mean (±SE) Levels of Cyclosporine in Keratomes of Psoriatic Skin Lesions and in Whole Blood.. The side effects observed in this study have been noted previously21; higher doses caused greater changes in the GFR, systolic blood pressure, and concentrations of serum creatinine, urea nitrogen, uric acid, bilirubin, and cholesterol (Fig. 3Figure 3
Percentage Change in the GFR during the First Eight Weeks, According to Initial Treatment Assignment. and Table 3). The substantial percentage increase in the bilirubin level during the decrease in aminotransferase levels (Table 3) is of uncertain clinical importance.Over the 16-week study period, four patients were withdrawn because of clinical side effects. One patient (age 29) noticed "ripples" in his visual fields; he was found to be normotensive at office visits and on the twice-daily self-measurements. His cyclosporine blood level was 84 ng per milliliter at the eighth week, when he reported migraine-like symptoms. Earlier blood levels ranged from 233 to 381 ng per milliliter, and upon further questioning he revealed he had had the symptoms before the eighth week. Two patients (ages 28 and 70) had transient dysarthria, confusion, and limb weakness; they were also found to be normotensive, and their cyclosporine blood levels were always less than 125 ng per milliliter. The fourth patient had nausea and diarrhea. All symptoms resolved in these four patients after cyclosporine administration was stopped (7.5, 5, 3, and 5 mg per kilogram per day, respectively). Three patients were withdrawn because of violations of the protocol (one receiving vehicle, one receiving 3 mg of cyclosporine per kilogram, and one receiving 7.5 mg). Doses were reduced in four patients receiving 7.5 mg of cyclosporine per kilogram during the first eight weeks (in three patients because of high cyclosporine blood levels and in one because of a high serum creatinine level) and in two receiving 5 mg and two receiving 7.5 mg during the second eight weeks (in three patients because of high cyclosporine blood levels and in one because of headache). All abnormal conditions resolved after the doses were reduced.
Renal Function
After eight weeks of treatment, the GFR decreased by a median of 2 percent in the patients receiving vehicle (n = 9), 6 percent in those receiving 3 mg of cyclosporine per kilogram per day (n = 12), 15 percent in those receiving 5 mg (n = 10), and 19 percent in those receiving 7.5 mg (n = 12). The decrease in the GFR in the patients receiving 7.5 mg of cyclosporine was significantly greater than that in those receiving vehicle (P = 0.05); the decreases in the other groups did not differ significantly from each other.
Of the 34 patients receiving cyclosporine for the first eight weeks in whom the GFR was measured, 18 had a decrease of 15 percent or more in the GFR and 3 had an increase of at least 15 percent (Fig. 3). When the 10 patients with the greatest decreases (average decrease, 30 percent; average dose, 5.7 mg per kilogram per day) underwent follow-up evaluation one to three months later, they had an average decrease of only 17 percent from pretreatment values (average dose, 3.4 mg per kilogram per day).
A multiple linear regression analysis demonstrated that change in the serum urea nitrogen concentration was the best single predictor of change in the GFR. The best multiple regression model (R = 0.63, P = 0.0002) was % change in GFR = —0.13 (% change in serum urea nitrogen) — 0.73 (% change in diastolic blood pressure) — 5 (for men) or + 10 (for women). For example, a man with a 30 percent increase in the serum urea nitrogen concentration and a 15 percent increase in the diastolic blood pressure during therapy would be predicted to have a decrease in the GFR of 20 percent (—[0.13 × 30] — [0.73 × 15] — 5). After the urea nitrogen concentration was incorporated into the model, the ability to estimate the GFR was not significantly improved by the addition of the changes in the creatinine clearance (whether measured in a 24-hour urine sample or estimated by formula), age, weight, and dose of cyclosporine and the percentage change in the mean arterial blood pressure and serum levels of uric acid, creatinine, and magnesium.
Blood and Tissue Levels of Cyclosporine
The administration of the three initial doses of cyclosporine resulted in substantial overlap among the patients' average blood levels in the second through the eighth week. Nevertheless, there was a strong linear correlation between the dose and the average blood level (r = 0.78, P<0.0001). Mean trough blood levels (Table 4) remained fairly constant in the groups initially assigned to 5 and 7.5 mg of cyclosporine per kilogram per day, but increased steadily in the groups assigned to 3 mg or vehicle as their mean dosage levels were increased. The correlations between relevant variables and dose and blood levels of cyclosporine are shown in Table 5Table 5
Changes in Clinical and Laboratory Variables in Relation to Dose of Cyclosporine and Mean Blood Level of Cyclosporine during Fixed-Dose Phase (First Eight Weeks).*. The drug appeared to be concentrated in the skin at levels estimated to be near the peak values in blood26 and approximately 10 times those in trough blood samples (Table 4).Delayed-Type Hypersensitivity
After eight weeks of therapy, the patients' responses to skin testing did not differ statistically among the four treatment groups. After 16 weeks, of 42 patients who underwent skin testing while receiving a mean dose of 5.0 mg of cyclosporine per kilogram per day (all doses averaged together), 20 patients (48 percent) had decreased reactivity, 6 (14 percent) had increased reactivity, and 16 (38 percent) had no change (P = 0.009). The results were similar when the patients who had received vehicle for the first eight weeks were excluded. Before therapy, nine patients (22 percent) had no positive responses to any of the test antigens and were classified as anergic; at the 16th week, all were found to have remained anergic. Of the nonanergic patients, therefore, 61 percent had decreased skin reactivity; however, the ratio of patients with decreased reactivity to those with increased reactivity was unchanged (3.3:1). The status for skin-test reactivity did not correlate with clinical outcome or the dose or level of cyclosporine in blood or skin.
Discussion
The results of this multidose study suggest that an appropriate initial dose of cyclosporine for the treatment of psoriasis is 5 mg per kilogram per day. The dose of 3 mg per kilogram per day proved to be less effective (Fig. 2); only 36 percent of patients assigned to the group receiving this dose had clearing or near clearing of their psoriasis in the first two months of therapy. When dosage adjustments to achieve a maximal clinical response with minimal side effects were allowed during the second eight weeks of this study, the doses of the patients initially receiving 3 mg per kilogram per day were increased to an average of 4.5 mg per kilogram per day during this period (an increase of 50 percent). Patients receiving 5 mg per kilogram per day had an increase to only an average of 5.5 mg per kilogram (an increase of 10 percent). Although patients receiving 7.5 mg per kilogram per day had a slightly better clinical response than those receiving 5 mg per kilogram, their average dose was decreased to 7.0 mg per kilogram per day. Over the entire 16-week study period, 65 percent of patients assigned to a dose of 5 mg per kilogram per day required no dosage change for reasons of safety or efficacy, as compared with 33 and 43 percent of patients assigned to doses of 3 and 7.5 mg per kilogram per day, respectively.
Our impression that 5 mg per kilogram per day is an appropriate initial dose may be due in part to a bias introduced by our protocol, which required clearing or near clearing to be achieved within 16 weeks of therapy. In some patients, 3 mg per kilogram per day or less may be a sufficient dose, especially when the time to clearing is relatively unimportant or when ancillary therapies may be used.12
Clinical improvement as reflected by the psoriasis area—severity index22 or the global severity score correlated more strongly with the dose level than with the average blood level of cyclosporine (Table 5), and there was no clear therapeutic range of blood levels. Of 12 patients whose blood levels of cyclosporine averaged more than 200 ng per milliliter on high-performance liquid chromatography, 11 (92 percent) had clearing or near clearing of their lesions by the 16th week; however, 75 percent of patients with average blood levels of less than 200 ng per milliliter also had such improvement. Indeed, of the 63 patients who had clearing or near clearing by the 16th week, 23 (37 percent) had average blood levels below 100 ng per milliliter. Other investigators have had similar results.27 There was also no range of cyclosporine levels in skin that would predict clinical efficacy.
The side effects of most concern in our study were neurologic and nephrologic. Adverse neurologic effects have been observed during cyclosporine therapy; some have been associated with low serum cholesterol levels,28 which was not the case in our patients. Cyclosporine may cause vasoconstriction29 , 30; such an effect on cerebral vasculature could explain the side effects we observed.
With regard to nephrologic effects, the GFR in our 34 cyclosporine-treated patients in whom it was measured decreased by a median of 16 percent after they had received an average dose of 5.2 mg per kilogram per day for eight weeks. Our results were similar to those in 11 patients of Powles et al.,31 who had a median decline of 10 percent in the GFR after they had received an average of 3 mg of cyclosporine per kilogram per day for an average of nine weeks. In contrast, Gilbert et al.32 reported a median decrease of 52 percent in the GFR in five patients who received an average of 4.7 mg per kilogram per day for an average of nine weeks. This discrepancy may be due to the small number of patients and their low pretreatment GFRs in the study of Gilbert et al.
In our study the GFR was reduced by 15 percent or more in 18 of 34 patients receiving cyclosporine (53 percent). Nevertheless, in a subgroup of our patients who had large enough decreases in the GFR to warrant repeated testing, the mean GFR increased toward its pretreatment level in conjunction with a moderate reduction in the average dose over a period of one to three months. Similar improvement in the GFR has occurred in patients with psoriasis in whom cyclosporine was stopped after 1 1/2 to 2 1/2 years of therapy.31 Changes in the GFR during eight weeks of cyclosporine therapy in our healthy population could be estimated by the use of a formula incorporating the serum urea nitrogen concentration and diastolic blood pressure, along with correction for the patient's sex. Further studies will be needed to determine whether the formula is useful in patients with different characteristics or disease states or over longer periods.
Previous studies examining delayed-type hypersensitivity responses have shown that in comparison with control subjects, patients with psoriasis have decreased reactivity to skin-test antigens.33 34 35 The 22 percent incidence of anergy among our patients confirmed these reports. Treatment with cyclosporine reduced the skin-test response in 61 percent of our non-anergic patients; whether this side effect reflects a local inhibitory effect of cyclosporine in the skin36 37 38 39 or general immunosuppression is unknown. However, no signs of immunosuppression, such as an unexpected frequency of infections or tumors, were observed among our patients.
Cyclosporine causes a rapid and thorough clearing of psoriasis, with a high likelihood of success. Further study of its safety and efficacy in long-term use will be required to determine whether it is suitable for long-term therapy for psoriasis.
Supported by a grant from Sandoz Research Institute (East Hanover, N.J.), by the Babcock Dermatologie Endowment (Ann Arbor), and by a Clinical Research Center grant (M01–RR–00042) from the National Institutes of Health.
Presented in part at the annual meetings of the Society for Investigative Dermatology, Washington, D.C., May 2 to 5, 1990, and the American Academy of Dermatology, Atlanta, December 1 to 6, 1990.
Drs. Ellis and Voorhees are consultants to Sandoz Pharmaceuticals Corporation (the manufacturer of cyclosporine [Sandimmune]).
We are indebted to Ronnie Brown, Harrold Carter, Benjie Johnson, Glenn Kolansky, M.D., Kathy Omoto, M.S., Harriet Selin, Gretta Smith, Cyndi Stam, Marcy Waldinger, and Dale Yessian for invaluable assistance.
Source Information
From the Dermatopharmacology Unit, Department of Dermatology (C.N.E., M.S.F., M.D.B., M.T.S., A.H.H., S.W., T.A.H., T.G.P., M.E.-M., E.D., K.D.C., J.J.V.); the Nephrology Division. Department of Internal Medicine (J.M.M., L.L.R.); and the Department of Pathology (T.M.A.), University of Michigan Medical Center, Ann Arbor. Address reprint requests to Dr. Ellis at the Department of Dermatology, University of Michigan Medical Center, 1910 Taubman Center, 1500 E. Medical Center Dr., Ann Arbor, MI 48109–0314.
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