Abu-Elmagd, K

Ackerman, CD

Fung, JJ

Jegasothy, BV

Starzl, TE

Thomson, AW

Todo, S

Van Thiel, D

D-Scholarship@Pitt

. --/fll.t2 PSORIASIS AND OTHER SKIN DISORDERS FK 506: A New Therapeutic Agent for Severe Recalcitrant Psoriasis K. Abu-Elmagd, D. Van Thiel. B.V. Jegasothy. C.D. Ackerman. S. Todo. J.J. Fung. A.W. Thomson. and T.E. Starzi BETWEEN 12 and 18 months ago we treated three patients with FK S06 who had severe psoriasis that was refractory to conventionai therapy and four patients with w,despread incidental psonasis before undergoing hean or liver transplantation under FK 506. All had dramatic resolution of psonasis. which remaIned in remis-sion as long as full-dose therapy was provided. Serial skin biopsies had a rapid disappearance of the inflammatory infiltrate and slower resolution 01 epidermal changes. FK 506 was well tolerated with onlv minor side effects during the 12 to 18 months of observation. Circumstantiai evidence for an autoimmune etiology of psoriasis is the striking remission of psonatic lesions. which can be achieved with cyclosporine. l - l an immuno-suppressive drug whose use for this pUJ'l)Ose has been limited by nephrotoxicity. hypenension. and other dose-related side effects. We repon here the use of the chemi-cally unrelated drug. FK 506. which also inhibits T helper lymphocyte activation and the synthesis and expression of cytokines. 4K~ METHODS Clinical fealUres are summanzed in Table I. Amelioration ot" psonastS In four patients was Incldentaito the pnmary objective of hean lone I or livertr:m~plantallon Illiree I. The liver disease In one of the tauer patients was caused by methotrexate treatment for psoriasiS over a J)Criod of 2 years. The other three pallents had severe n:caIcitrant psoriasis that had reSisted the therapies listed in Table I. Table 2. Psorililia Endpotnta In Thrw NontnI_ ••• Pltlents BaIlIN Week 2 Week, W". Now Clinical (PASI Scores, Patient 5 67.S 27 2.8 0 0 Patient 6 43.4 5.7 0 0 0 Patient 7 68.4 34.2 9.8 0 0 HlstopatnologlC Epidermal acantnoslS -++ Munro·s mlcroa/lSC8SSeS --+ ActiVe cennal Inflammatlon ++++ The patients were scored for their psonasis seventy using the PSOriasiS Area and Severity Index IPASIl.J The seventy of the p$Oriasis was determined lTable 2) by measuring the amount of erythema. infiltration. and desquamation usmg a scale of 0-4 10 = none. I = slight. 2 = moderate. 3 = severe. 4 '" very severe,. In From the Deparunents of Surgery (K.A-E .. O.V .• S.T •• J.J.F .• A.W.T.. T.E.S.) and Dermatology (S.v.J.. C.D.A.), University Heal1h Center of Pittsburgh, University of Pittsburgh. and the Veterans AdministratIOn Medical Center. Pittsburgh. PA. This wort< was aided by rese8lCt1 grants from the Veterans Administrabon and Project Grant OK 29961 from the NatiOnal Institutes of Health. Bethesda. Maryland. Address repnm requests to Thomas E. Starzi. MD. Deot. of Surgery,3601 Fifth Ave .• Univet'Slly of Pittsburgh, PittsbUrgtl, PA 15213. ~ 1991 by Appleton & Lange 0041-13451911$3.001+0 Table 1. Clinical FeaturM No. qr~ Rec:ipents 1 2-3 4 PSOI'iIIsIa Only 5 6 7 ~ 36IF 40IM 33IF 28IF 49IF 301M P~ heart liver liver liver 12 22 25 5 6 6 9 TClPiC* steroids: UVB + tar UVB + tar: metnotrexate PUVA: toPlC8lllefOlds mtral8SlOl\8l1l8fOldS: m8lholntxate T opicaIllerolds: systemIC steroids PUVA. UVB:!opaI steroids etreanate UVB + tar. topCaI steroids goICIl.M.: metnotrexa18 UVB + Iar. topCaIll8nIIdS mfJlhOtl .... AIlItInIMe ... fJtNA -~ MIl lJIIrII.- A 1:J2O...<IOO Mil: UVB - rf~ B 1280-320 MIl. 'End 1I8IJI-...... - ~faKKKKKKK . . ..,.". + + + + 3322 r,..,.".".tIOn P/'OCIIHJI1IIIt}S. Vol 23. No 6 (Oec:ernber), 1991: pp 3322-3324 2& FK 506 IN TREATING SEVERE PSORIASIS . Tlible 3. AdvwM Ruction Surveillance to End of Januuy 1911-1 2 3 4 5 8 7 Date FK 506 Star1IId 2114.110 6I30.1IO 7/13190 8IMIO 5124Il10 7/18/110 8/27/110 FK doses at start 0.27 0.30 0.35 0.25 0.28 0.29 0.2 (mgtkgld) 3 months 0.33 0.20 0.40 0.18 0.10 0.30 0.32 now 0.21 0.13 0.29 0.18 0.30 0.40 0.32 FK plasma 1 week 1.4 2.5 4.3 3.4 1.1 2.0 0.8 (ngImL) 3 montns 1.5 1.0 0.9 1.2 0.4 0.4 0.9 now 1.1 0.8 0.5 1.4 1.3 0.7 1.2 Steroid dose at start 20 20 20 20 0 0 0 (mgIO) 3 months 10 0 10 0 0 0 0 now 0 0 15 0 0 0 0 Crannma at start 62 53 53 53 88 80 71 (,..mauL) 3 IT1OI"IItIs 141 159 ISO 106 106 133 ISO now 176 159 159 97 159 159 124 BUN at start 2.5 3.6 4.3 2.5 2.1 3.2 3.6 (mmoliLl 3 months 15.7 7.1 13.2 9.6 2.5 7.5 10.4 now 9.3 11.8 12.8 10.4 10.4 7.1 6.8 F8S at stan 4.7 4.7 5.7 5.1 5.9 5.1 4.4 (mmoVLI 3 months ~K9 5.3 6.7 5.4 5.7 ~KP 5.5 now 5.7 .to 5.0 5.5 5.5 5.5 5.2 Uric aad at start 636 389 214 280 517 321 357 (p. moIILI 3 IT1OI"IItIs 565 434 428 464 399 297 410 now 494 571 476 458 478 303 428 Mg at start 0.88 0.58 0.66 0.82 0.58 0.82 0.58 (mmollL) 3 months 0.49 0.49 0.66 0.74 0.58 0.49 0 .• now 0.58 0.82 0.70 0.45 0.45 0 .• K at start 4.1 3.2 3.5 3.9 ~KP 4.& 4.5 (mmotlLI 3 montns 4.1 4.1 3.3 5.2 3.8 4.& 4.4 now 4.6 4.& 4.3' 5.2 4.8 5.0' 4.1 ChoIes1 at start 4.3 1.7 6.3 3.3 4.5 4.7 3.5 (mmotlLI 3 monthS 5.3 3.9 5.6 2.9 6.6 3.6 3.8 now 4.7 4.7 5.4 6.1 3.7 3.8 8P drugs at start 0 0 0 2 0 0 nUmDer 3 months 0 0 0 0 now 0 0 0 ·Par--. ___ unct\IngIICI in AU9I* 1991. tFludiOCOiliaUile ___ I. rm,.,.*DUIIlCUdIIF1urinelI. the three pauents whose primary diagnosis was psonasis. biopSies terol. uric acid. blood glucose. malllesium. and other electrolytes were taken before instituting treatment. 2 weeks later. and when were monitored. A detailed repon of these parameters in a larger they were clinically free of lesions. group of psonasis pauents IS reponed elsewhere in this sympo-Oral FK 506 was stancd at O.IS mg/kg twice daily in the sium.6 nontransplant pauents and adjusted down or up according to the Development of high blood pressure was quanutated (if present! FK 506 plasma levels (measured at 12 hour trough with an by the number of antihypenensive drugs required to maintain a enzyme-linked immunoassay, or when there was clinical evidence normotensIve state. H ypcrtcalemia was treated with the min-of incomplete disease control or toxicity. No other drugs were eraloconicoid f\udroconlsone acetate. Hypomagnesemia was used. The transplant recIpients were staned on 0.075 or 0.10 seen but did not require correction. intravenous FK S06Id and convened to oral dosing when they could eat. Transplant patients aiso had prednisone anitiaily. which RESULTS was tapered to the levels shown In Table) by I February 1991. Effect on PsonaslS These levels have not changed substantially in the ensuing half There was a marked reduction in erythema and scale in all year. Complete medical examinations including neurologic assess- seven patients by I week and complete clinical remission ment were performed repcated1v. oe~ funcuon. serum cholcs- by 3 weeks (Table 2). The remission has been sustained 1 !\ 3324 with follow-ups of 12 to 18 months. The three patients wnose primary diagnosIs was psoriasis (Table 2) were not given steroids or other medications. Improvement of ar-thritis from which they also sutfered occurred simulta-neously. Serial skin biopsies taken from the active plaques of psonasis demonstrated a rapid clearance of the inflamma-tory infiltrate In the dermis and the neutrophils in the stratum corneum. The etfect of FK 506 on the skin infiltrate is described elsewhere in this symposium. 7 The hyperkeratosis and epidermal acanthosis took longer to resolve /Table 2>. In these three patients. efforts to reduce FK 506 dosage resulted in beginning reappearance of the skin lesions. which promptly disappeared after returning to the prior dose. The four patients who had organ transplants received systemic prednisone postoperauvelv. but their remiSSion persisted after lowenng (one easel or stopping the sterOIds {three cases) (Table 3), Several montns postoperative Iv when there was no eVidence 01 gralt dvsfunctlon. the liver recipient whose end-stage nepatlc disease was caused by methotrexate therapy (Patient 2) developed small psonat-ric plaques near the exit site of his T-tube. These disap-peared with a minor increase In FK 506 dose. Toxicity and MetaboliC Changes FK 506 doses. plasma levels. and surveillance parameters were similar in both nontransplant and transplant patients. Temporary trembling. parathesias. and insomnia not re-quiring dose changes were noted in three patients. In-creases of serum creatinine or BUN signaled the need for downward adjustments. and because of careful attention to dose control. there were no alarming patterns of toxicity Jt the check POints (Table 3). While stable. the ultimate level of these measures was higher In aU patients than at the outset. Hirsutism and gingival hvperplasia sometimes associated with cyclosponne were not observed with FK 506. ABU-ELMAGC. VAN THIEL JEGASOTHY ET AL DISCUSSION Complete remission of psoriasis induced by FK 506 was evident more qUickly than has been observed with other immunosuppressive regimens. In the nontransplant pa. tients. the FK 506 doses and plasma levels needed to maintain remission were in the same range as required to prevent allograft rejection. Efforts to give less FK 506 to these patients resulted in reactivation of the psoriasis. In one liver recipient a dose reduction caused a minor recur-rence of psoriasis rather than graft rejecllon. Whether the reward of complete control of psoriasis will be wonh the risk of long-term therapy with this powerful drug wlil be judged with funher observations. In our psoriasis series herein reported. follow-ups have been 12 to 18 months. However. what was seen so far is encour-aging. The only potentially serious side etfect was nephro-toxicity with rises an creatinine and BUN. which reo \ponded so qUickly to dose reduction that they had reached a stable although slightly elevated state at the ,urveiliance check points. No patient has had an infection. Patients with Widespread lesions toften wnh psonauc :tnhritis) that rum the quality of life have been eager to take the risk. Patients with less severe disease should be discouraged from candidacy and treated with less drastic means. REFERENCES I. Mueller W. Hennann B: New Eng! J ~ed 301:555. 1979 (Letter' 2. Ellis CN. Gorsulowsky DC. Hamilton T: J AMA 256:3110. 1986 3. Powles A V. Baker BS. Valdimarsson H. el al: Br J Dennatol 1!2(suppl 36):13.1990 4. Kino T. Hataanaka H. Miyata S. el al: J Antibiol 40: 1256. 1987 5. TOCCI MJ. MatkOVich DA. Collier KA. el al: J Immuno! 143:718. 1989 6. Nikolaldis N. Abu-Elmagd K. Thomson AW. el al: Trans-plant Proc uhls issue. 7. Thomson AW. Nalesmk M. Starzi TE: Transplant Proctthls issue' -

FK 506: A new therapeutic agent for severe recalcitrant psoriasis

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FK 506: A new therapeutic agent for severe recalcitrant psoriasis

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