Leslie L. Rocher

Cyclosporine for plaque-type psoriasis: Results of a multidose, double-blind trial

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 less than 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 hypersensitivity 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.

Cyclosporine-Induced Hyperuricemia and Gout

To evaluate the frequency and the pathogenesis of hyperuricemia and gout during cyclosporine therapy, we studied renal-transplant recipients who were treated with either cyclosporine and prednisone (n = 129) or azathioprine and prednisone (n = 168). Among the patients with stable allograft function and serum creatinine concentrations below 265 mumol per liter, hyperuricemia was more common in the cyclosporine group than in the azathioprine group (84 percent vs. 30 percent; P = 0.0001). Gout developed in nine patients (7 percent) in the cyclosporine group, but no episodes occurred in the azathioprine group. Serum urate levels became elevated in 90 percent of the patients in the cyclosporine group who were treated with diuretics, as compared with 60 percent of those not treated with diuretics (P = 0.001); in the azathioprine group, the corresponding values were 47 percent and 15 percent (P = 0.0001). Serum urate levels did not correlate with trough blood cyclosporine levels in a selected subgroup (n = 40) of patients from the cyclosporine group, who were studied from 4 to 96 weeks after transplantation. Detailed studies of urate metabolism in six cyclosporine-treated patients revealed normal turnover rates for urate and decreases in creatinine and urate clearance, as compared with seven control subjects. We conclude that hyperuricemia is a common complication of cyclosporine therapy and is caused by decreased renal urate clearance. Gouty arthritis is the cause of considerable morbidity among renal-transplant recipients who receive cyclosporine.

Cyclosporine in dermatology

Cyclosporine is a potent immunosuppressive agent with no appreciable effect on the bone marrow and a selective inhibitory effect on helper T cells. Oral cyclosporine was first used to prevent organ rejection but also has been reported to be effective in other disorders. In cutaneous diseases that respond to oral cyclosporine helper T cells appear to be involved in their pathogenesis. This article reviews the cutaneous diseases that have been treated with cyclosporine and its pharmacology and side effects. Two significant adverse side effects are renal dysfunction and hypertension, both of which are reversible when short-term low-dose (less than 5 mg/kg per day) oral cyclosporine is discontinued. Lymphoma is unlikely in an otherwise healthy patient who has received low-dose oral cyclosporine for limited periods. The use of oral cyclosporine in any patient should be carefully considered in terms of the risk/benefit ratio and needs to be carried out under close medical supervision. In view of the limited experience with cyclosporine in dermatology, whenever possible its use should be confined to formal clinical studies with established protocols and guidelines. Further controlled studies need to be performed to evaluate the efficacy of low-dose cyclosporine in many dermatoses and its side-effect profile, particularly over the long term.

Episodic hyperhidrosis, hypothermia, and agenesis of corpus callosum

Episodic hyperhidrosis and hypothermia are the primary symptoms of a rare central nervous system disorder of thermoregulation which is often associated with agenesis of the corpus callosum and can present in childhood or adult years. During attacks, patients may exhibit confused, withdrawn, and lethargic behavior and ataxia or other neurologic symptoms. A 21-year-old man with temperature chronically between 30 and 32 °C transiently responded to phenobarbital and to cyproheptadine therapy. A 34-year-old woman with frequent, brief episodes of hypothermia and hyperhidrosis improved with chlorpromazine treatment. Episodic thermoregulatory disturbance has been atttributed to “vagal attacks” or “diencephalic epilepsy,” but the pathophysiology remains undefined.

Progression of Diabetic Retionopathy after Pancreas Transplantation

The progression of diabetic retinopathy after combined pancreatic and kidney transplantation was studied in eight patients for 12 to 49 months. Four patients who had rapid pancreatic graft failure constituted a control group for comparison with four patients who retained functioning grafts. Using Fishers exact probability test, the authors found no posttransplantation difference between the two groups in visual acuity lost, severity of diabetic macular edema, extent of capillary closure, progression of preretinal gliosis, development of disc or preretinal neovascularization, or worsening of the severity of the retinopathy. Achievement of normoglycemia by pancreatic transplantation is not effective in halting the progression of diabetic retinopathy in patients who already have severe diabetic microangiopathy joined the current follow-up.

The impact of nonidentical ABO cadaveric renal transplantation on waiting times and graft survival

Blood type O recipients of cadaveric renal transplants have longer pretransplant waiting periods than blood type A, B, and AB recipients. To evaluate reasons for and consequences of this discrepancy, we studied both the frequency of various donor and recipient blood type combinations and their outcomes. Among 37,659 cadaveric renal transplants performed during 1983 through 1989, there were 2,625 transplants (7%) received by patients of compatible but nonidentical blood types. Of 18,575 type O donor organs, 16,784 were received by type O patients for a recipient to donor ratio of 0.9. The corresponding ratios were greater than 1.0 for all other blood types (1.02 for blood type A, 1.14 for type B, and 2.18 for type AB). This causes blood type O patients to have a lower access to transplantation and to have significantly longer waiting times than patients of all other blood types. This inequality of access diminished significantly (P less than 0.001) over the years, but did not resolve by 1989. Analysis of relative risk for first graft loss by multiple regression (Cox) showed that transplantation across compatible blood types had a 9.1% higher risk (P less than 0.1) than that of transplantation among identical blood types. Cadaveric renal transplantation within identical blood types optimizes access to transplantation and avoids further aggravating past disadvantages for blood type O recipients.

Amelioration of chronic renal allograft dysfunction in cyclosporine-treated patients by addition of azathioprine

Management of chronic renal allograft dysfunction in cyclosporine-prednisone treated renal allograft recipients remains problematic. We therefore initiated a protocol of azathioprine addition (1.0-1.5 mg/kg/day) to ongoing CsA/Pred therapy. Three groups were treated. Group A (n = 21) had chronic progressive renal dysfunction (serum creatinine greater than or equal to 2.5 mg/dl or more than 15% above baseline) four or more months after transplantation. Group B (n = 8) had frequent or severe rejection episodes occurring despite adequate CsA levels. Group C (n = 7) had constitutional side effects of CsA with or without renal dysfunction persisting despite drug taper or financial difficulty in affording CsA. Aza was initiated 17.8 +/- 2.8 months after transplantation in group A, the mean serum creatinine having risen from 2.55 +/- 27 mg/dl to 3.04 +/- .20 mg/dl (P = .07) over the six months preceding Aza initiation, despite stable and low therapeutic range HPLC whole-blood CsA levels (118 +/- 10 ng/ml vs. 133 +/- 11 ng/ml, P = NS). Renal function declined at a rate of -0.20 +/- .06 Cr1/year in the six-month period before addition of Aza, and then improved at a rate of 0.09 +/- .04 Cr-1/year after addition of Aza (P = .002). These changes in renal function occurred without a decrease in CsA levels (118 +/- 10 six months before Aza vs. 126 +/- 26 six months after Aza, P = NS). In group B Aza was initiated at 58 +/- 8 days after transplantation when mean sCr was 3.56 +/- .29 mg/dl and mean CsA level was 222 +/- 17 ng/ml. At least follow-up 12.7 +/- 2.0 months after addition of Aza, all group B grafts were functioning, mean sCr was 2.69 +/- .31 mg/dl (P = .09 compared with baseline), and mean CsA level was 128 +/- 34 ng/ml (P = .07 compared with baseline). Group C patients had addition of Aza at 43 +/- 19 months after transplantation when mean sCr was 2.97 +/- .60 and mean CsA level was 125 +/- 30 ng/ml; addition of Aza had no influence on the rate of decline in renal function in this group. Of these 36 patients, 6 received therapy for acute rejection over the entire follow-up period of 12.3 +/- 1.4 months after addition of Aza; 4 of these retain graft function. Infectious complications consisted of 2 urinary tract infections, 1 bacterial pneumonia, and one case of otitis media.(ABSTRACT TRUNCATED AT 400 WORDS)

Effects of cyclosporine on renal function in psoriasis patients.

Several prospective studies have documented the effectiveness of oral cyclosporine in the treatment of psoriasis. Despite this, the use of cyclosporine has been limited because of concern about the possibility of drug-induced renal dysfunction. We review the effects of cyclosporine on renal function.

Peripheral blood catalase in patients undergoing renal transplantation

Oxygen free radicals are mediators of tissue injury and catalase is an enzyme which is involved in limiting this process. We examined peripheral blood catalase activity (PBCA) to assess its value as a marker in detecting tissue injury related to renal allograft rejection. Thirty-one consecutive recipients of kidney (n = 29) or simultaneous kidney/pancreas (n = 2) transplants and 10 normal volunteers were studied. Catalase activity, measured by the disk-flotation method, was expressed as Sigma units X 10(-3)/ml (SU/ml) of whole blood. Normal PBCA was determined to be greater than 76 SU/ml. Twenty-nine episodes of renal allograft rejection (diagnosed by clinical criteria +/- biopsy [79%]) were observed in 26 patients. PBCA (mean +/- SEM) was found to be low (64 +/- 1 SU/ml) in 28/29 episodes (chi 2 = 46.3, P less than 0.001), and the decrease (at least two consecutive daily catalase values less than 76 SU/ml) occurred 2 days prior to the clinical/biopsy diagnosis of rejection in 26/28 episodes. The sensitivity of PBCA as a discriminant of rejection was 97%, specificity was 96%, and test accuracy was 96%. PBCA less than 50 SU/ml on two or more occasions occurred in five cases and transplant nephrectomy was required in four of these because of uncontrollable rejection. Nine episodes of cyclosporine nephrotoxicity occurred in 7 patients and none of these episodes was associated with a decreased PBCA. Our data suggest that decreased PBCA is a sensitive and specific indicator of renal allograft rejection. PBCA remains normal during episodes of cyclosporine nephrotoxicity and therefore provides a rapid and inexpensive discriminant from allograft rejection.

Hyperuricemia and Gout in Cyclosporin A-Treated Renal Transplant Recipients

Hyperuricemia and gout have been reported in patients receiving cyclosporin therapy for immunosuppression after organ transplantation.1–5 We evaluated the frequency and mechanism of hyperuricemia during cyclosporine A therapy in a group of patients who had received a renal transplant.