Abu-Elmagd, K

Fung, JJ

Irish, WD

Nikolaidis, NL

Rilo, HR

Starzl, TE

Thomson, AW

Van Thiel, DH

English

PubMed

Name not available

Metabolic effects of FK 506 in patients with severe psoriasis: short-term follow-up of seven cases

D-Scholarship@Pitt

Metabolic Effects of FK 506 in Patients With Severe Psoriasis: Short-Term Follow-Up of Seven Cases N.L. Nikolaidis, K. Abu-Elmagd, A.W. Thomson, H.R. Rilo, W.O. Irish, D.H. Van Thiel, J.J. Fung, and T.E. Starzl CYCLOSPORINE (CyA) has been shown to be effec-tive in a variety of human autoimmune diseases. including psoriasis, nephrotic syndrome, type I diabetes, and sight-threatening uveitis. 1 Its potential side effects include nephrotoxicity, diabetogenicity, and neurotoxic-ity. Several studies (see elsewhere in this symposium) have shown that FK 506 prevents or suppresses autoim-mune disorders in experimental animals and that it induces rapid remission in severe, recalcitrant, chronic plaque-forming psoriasis.2.3 In this paper, the metabolic effects of FK 506 are reported in seven patients with severe recalci-trant chronic plaque-forming psoriasis treated at the U ni-versity of Pittsburgh Medical Center with a median study follow-up time of 6 months. PATIENTS AND MATERIALS Seven patients (2M:5F; mean age 37 years; range 30 to 49 years) with severe. chronic plaque-forming psoriasis unresponsive to conventional therapy were studied. Four patients had psoriatic arthritis and two of these, plus one other. had methotrexate-induced cirrhosis. The median follow-up period for analysis was 6 months (range 4 months-I year). Patients received a starting dose of 0.3 mglkgld FK 506 in oral capsule form. The dose was adjusted according to the FK 506 plasma levels during the study period. No other treatment for psoriasis was administered. One patient with methotrexate-induced cirrhosis required furosemide diuretic ther-apy (40 mgld) from week 5 to week 9. Physical findings, including blood pressure and biochemical indices of renal and hepatic function and other variables, including glucose and cholesterol, were monitored at each clinic visit. Trough plasma FK 506 levels were estimated by ELISA.4 Friedman's test was used to determine whether biochemical parameters changed significantly over time. The Spearman corre-lation coefficient was calculated to investigate the association between FK 506 plasma levels and biochemical parameters. FK 506 plasma levels and biochemical parameters were correlated with time of treatment using Spearman's correlation coefficient. A 95% confidence interval was generated for the correlation be-tween FK 506 plasma levels and time of treatment to compare biochemical parameters and FK 506 plasma levels over time. RESULTS Psoriasis There was complete remission of the psoriasis in all seven cases, as reported elsewhere.2•3 Renal Function All patients showed a rise in serum creatinine compared to pretreatment values during the course of the study. The median values are shown in Fig- h: The maximal median 3.00 r--------------, 2.00 2.50 , , 2.00 I " , , , , I-1.50 1 .50 gKfI--~Ki---DK:IKI --:",'-""':':"",---1 1.00 , I ,I , , I , , I ,,' 1.00 '. I ,,' '/ " 0.50 0.50 1-------------1 0.00 L..---'-_"----'-_"'----'-_-'----'---.l 0.00 2 3 4 8 12 16 20 24 TIME (WEEKS POST TREATMENT) ----- FK -- C .... tlnln. Fig 1. Median serum creatinine and FK 506 plasma levels in seven psoriasis patients treated with systemic FK 506. Horizontal bars denote normal range for serum creatinine. levels of plasma creatinine and B UN (Fig 2) were recorded at 8 weeks, after which BUN levels returned to normal. Elevations in creatinine levels above the normal range were reversible and responded to dose reduction. Uric acid levels showed an early, transient, and minor increase above normal levels. There were no alterations in the serum K + or Mg+ + levels throughout the study period (data not shown). Glucose Homeostasis An elevation in plasma glucose level was evident after 4 weeks of treatment. The median level remained near the upper limit of normal from week 4 to 6 months of treatment (Fig 3). No patients required insulin therapy. From the Division of Transplantation, Dept. of Surgery, Univer-sity of Pittsburgh Medical Center, Pittsburgh, Pennsylvania. Address reprint requests to N.L. Nikolaidis, MD, University of Pittsburgh,3 Lhormer Building, 3515 Fifth Avenue, Pittsburgh, PA 15213. © 1991 by Appleton & Lange 0041-1345/91/$3.00/+0 Transplantation Proceedings, Vol 23, No 6 (December), 1991: pp 3325-3327 3325 3326 40 35 30 ...... 25 "0 Ci .s 20 Z ~ CD 15 10 5 0 ,-------------, 2.00 \ \ , \ \ \I 2 3 4 8 g ~ ~ ~ TIME (WEEKS POST TREATMENT) ----- FK - BUN ...... E Ii .=. ~ I&. Fig 2. Median serum BUN and FK 506 plasma levels in seven psoriasis patients treated with systemic FK 506. Horizontal bars denote normal range for serum BUN. Uver Function The median total bilirubin and liver enzyme (SOOT and som levels remained within the normal range. In two patients with abnormal liver-function tests at the start of treatment, total bilirubin and SOOT remained elevated during the course of the stlldy. 200 ....-------------, 2.00 150 1.50 ...... =a '0 ...... §. :§. co • 100 1.00 .=. I/) \ 0 , \ , ~ 0 , \ , , I&. .a \ \ , \ Cl ' I \ , \I , , , , 50 " ' 0.50 2 3 4 8 12 16 20 24 TIME (WEEKS POST TREATMENT) ----- FK -- Glucose Fig 3. Median plasma glucose and FK 506 plasma levels in seven psoriasis patients treated with systemic FK 506. Horizontal bars denote normal range for plasma gl~coseK NIKOLAIDIS, ABU-ELMAGD, THOMSON ET AL 300 2.00 250 1.50 ...... " 'i5 200 ' " I , Ii , , .s , ...... E e -. 150 1.00 CI r:: !! .... .. ~ • I&. "0 , ~ 100 , , , 0 , , , , " 0.50 50 0 0.00 2 3 4 8 12 16 20 24 TIME (WEEKS POST TREATMENT) ----- FK Fig 4. Median serum cholesterol and FK 506 plasma levels in seven psoriasis patients treated with systemic FK 506. Horizontal bars denote normal range for serum cholesterol. Cholesterol Cholesterol levels tended to be low throughout the study (Fig 4) although one patient persistently showed a minor elevation above the normal range. Blood Pressure Blood pressure determinations remained within the normal range except for one patient, whose blood pressure was at the upper limit of normal before treatment and who exhib-ited minor hypertension between weeks 8 and 24 of treatment. FK 506 Plasma Levels The median FK 506 plasma level (shown in Figs 1 through 4) ranged from 0.5-1.4 ng/mL during the study period. This range of FK 506 plasma levels was effective in inducing and maintaining complete remission in patients unrespon-sive to conventional therapy. Statistical Analyses No significant change with time in any of the biochemical parameters was found using Friedman's test. There was a positive but not significant correlation between FK 506 plasma level and serum creatinine (r = 0.071), BUN (r = 0.084), uric acid (r = 0.193), glucose (r = 0.033) blood pressure (systolic r = 0.778, diastolic r = 0.569), while a negative correlation (r = -0.6333; NS) was found with cholesterol levels. DISCUSSION FK 506 shares with Cy A the potential for impairment of renal function and carbohydrate metabolism. 5 In this study I i I I I I l' I I I f j t. .. .. '" 1" J i l -t;-!;,. t " ~K i. f! ~ !It-t f i t' I f t ff:~ f 'f j: ... ". i -.------------------ _ .. _---------METABOLIC EFFECTS OF FK 506 of a small number of nontransplant patients. plasma levels of FK 506, about I ng/mL and similar to those compatible with organ allograft survival. were highly effective in clearing psoriatic skin lesions within I month of the start of therapy. Associated with this rapid clinical response. however. was evidence of mild renal dysfunction and minor. tran-sient disturbance of carbohydrate metabolism expressed as a mild elevation in the blood glucose level. Although hyperlipidemia is seen in both transplant and non trans-plant patients treated with low-dose Cy A. this investiga-tion has shown low cholesterol levels in FK 506-treated patients compared with values for normal subjects. Similar observations concerning lipid metabolism have been made in FK 506-treated transplant patients. There was no evidence of drug-induced hypertension in the present study. Hypertension may occur in as many as 50% of patients given Cy A for autoimmune disease.6 Liver function was normal in this study; even with low-dose CyA (3 mg/kg/d). disturbances in liver function. particu-larly in bilirubin levels. have been reported in psoriasis patients within 4 months of the start of treatment. 7 3327 These preliminary observations on a small number of nontransplant patients with psoriasis show that effective doses of FK 506 are associated with only minor metabolic side effects. Further studies must now include plasma drug level range and long-term evaluation of FK 506 therapy in psoriasis. REFERENCES I. Thomson A W (ed): Cyclosporine A: Mode of Action and Clinical Application. London. Klumer Academic Press, 1989 2. Jegasothy BV. Ackerman C. Fung JJ. et al: Arch Dermatol (in press) 3. Starzl TE. Abu-Elmagd K. Fung JJ, et al: Presse Med (in press) 4. Tamura K. Kobayashi M, Hashimoto K, et al: Transplant Proc 19(suppI6):23, 1987 5. Starzl TE. Fung JJ, Todo S: JAMA 263:2686, 1990 6. Fradin MS, Ellis CN, Voorhees II. et al: J Am Acad Dermatol 23: 1265, 1990 7. Ellis CN. Fradin MS. Messana JM. et al: N Engl I Med 324:277. 1991 

Metabolic effects of FK 506 in patients with severe psoriasis: Short-term follow-up of seven cases

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Metabolic effects of FK 506 in patients with severe psoriasis: Short-term follow-up of seven cases

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