Abu-Elmagd, K

Ackerman, CD

Fung, JJ

Jegasothy, BV

Starzl, TE

Todo, S

Name not available

FK 506 - A new therapeutic agent for severe recalcitrant psoriasis

D-Scholarship@Pitt

Tacrolimus (FK 506)-A New Therapeutic Agent for Severe Recalcitrant Psoriasis Brian V . Kgegasoth~·K :'I1D: Cheryl D. Ackerman. MD: Satoru Tollo. 1\10; John J. Fung. :'I1D. PhD; Kareem Abu-Elmagd. MD; Thoma:; E. Starzl. MD. PhD • Background.-Psoriasis, a disease of unknown etiology, is in some patients severe, extremely debilitating, and unre-sponsive to conventional therapies, including UV-B, oral psoralen with long-wave UV radiation in the A range (PUVA), oral retinoids, and methotrexate. We report the results from our study of seven patients with refractory psoriasis who were treated with the new immunosuppressive drug, tacroll-mus (FK 506). Observstions.-AII seven patients showed a dramatic resolution of psoriasis that remained in remission as long as they received full-dose therapy. Serial skin biopsy speci-mens demonstrated a rapid disappearance of the inflamma-tory infiltrate and a slower resolution of the epidermal changes. Tacrolimus was well tolerated during the 5.5 to 14 months of observation. Side effects, including nephrotoxic-ity and hypertension, were controlled by appropriate modi-fication of drug dosage. Conclusions.-Tacrolimus, a new immunosuppressive agent, is effective in treating patients with severe recalcitrant psoriasis. The mechanism of Its action in psoriasiS is unknown, but it may be related to Its ability to modulate im-mune function. Further studies will establish criteria for pa-tient selection and drug dosage, to maximize efficacy of this agent in psoriaSiS, while minimizing its toxicity. (Arch Dermatol. 1992;128:781-785) Psoriasis. a common heritable disease that affects the skin, the joints, or both, has many characteristics of an immunologically mediated disease. Included among these characteristics are a variable HLA association, lymphocytic infiltration of skin lesions. and evidence of cytokine actiyity or increased expression of new anti-gens during exacerbations. I.:! Circumstantial eyjdence for an immune etiology is the striking remission of pso-riatic lesions that can be achieved with cyclosporine/" Accepted for publication July 17. 1991. From the Departments of Dermatology (Drs ge~othy and Ack-erman) and Surgery (Drs Todo. Fung, Abu-Elmag-d. and StarzIJ. University of Pittsburgh (Pa) Medical Center and the Veterans Ad-ministration Medical Center. Pittsburgh. Reprint requests to Department of Dermatology. 3601 Fifth Ave. University of Pittsburgh. Pittsburgh, PA 15213 (Dr Jeg-clSothy). Arch Dermatol-Vol 128. June 1992 Table 1.-Clinical Features' No.1 Trans- Disease Age, yl plant Duration. y Previous Sex Type (Psoriasis) Therapy Arthritis Transplant reCipients 1/36/F Heart 12 Topical steroids: -UV-B+tar 2t/40/M liver 22 UV-B+tar: methotrexate + 3!33/F liver 25 PUVA: topical sterOids: -Intraleslonal steroids: methotrexate --4/28/F liver 5 Topical sterOids: -systemic sterOids Psoriasis on Iy 5i49/F - 6 PUVA. UV·B: topical + sterOids: etrellnate 6/30/M - 6 UV-B+tar: topical + sterOids: gold intramuscularly: methotrexate 7/32JF - 9 UV-B+tar: topical + steroids: methotrexate 'PUVA indicates oral psoralen With long-wave UV radiation in the A range (320 to 400 mm): UV-B. ultraviolet B (280 to 320 mm). Minus indicates absent: plus. present. tEnd-stage ilver disease was secondary to methotrexate therapy. an immunosuppressive drug whose use for this purpose has been limited its by nephrotoxicity, hypertension, and other dose-related side effects. We report our expe-rience with tacrolimus (FK 506), another immunosup-pressive drug that is unrelated chemically to cyclospo-rine but also. inhibits helper T -lymphocyte activation and the syntheSIS and expression of cytokinesKfiK~ Encourag-ing results with tacrolimus have been reported in trials of whole organ transplantation."'1II PATIENTS AND METHODS Clinical features are summarized in Table 1. Amelioration of psoriasis in four patients was incidental to the primary ob-jective, preventing organ rejection of heart (one patient) or Ii ver transplantation (three patients). The liwr disease in one T acrohmus-Jegasothy et al 781 Table 2.-Adverse Reaction Surveillance to June 6 Petlent I I 1 2 3 4 5 6 7 Date tacrolimus 7/13190 8/8190 5/24/90 7/16/90 8/27/90 therapy started 2114190 6/30190 FK doses. mglkg per day At start 0.27 0.30 0.35 0.25 0.28 0.29 0.2 3 mo 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. nglmL 1 wk 1.4 2.5 4.3 3.4 1.1 2.0 0.8 3mo 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. mgld At start 20 20 20 20 0 0 0 3 mo 10 0 10 0 0 0 0 Now 0 0 15 0 0 0 0 Creatinine. ILmollL At start 62 53 53 53 88 80 71 3 mo 141 150 150 106 106 133 150 Now 176 159 159 97 159 159 124 Serum urea nitrogen, mmol/L At start 2.5 3.6 3 mo 15.7 7.1 Now 9.3 11.8 Fasting blood glucose. mmol/L At start 4.7 4.7 3 mo 4.9 5.3 Now 5.7 4.0 Uric acid, ILmoi/L At start 636 369 3 mo 565 434 Now 494 571 MagneSium, ILmoi/L At start 0.86 0.58 3 mo 0.49 0.49 Now 0.58 0.62 Potassium, mmol/L At start 4.1 3.2 3 mo 4.1 4.1 Now 4.6 4.8 ._. Cholesterol. ILmoi/L At start 4.3 1.7 . 3 mo 5.3 3.9 Now 4.7 4.7 of the latter patient:; was caused by high-dose methotrexate :;odium treatment fol' psoriasis during a 2-year period. The other three patient:; had ~eyDere recalcitrant p:;orimii:; that had resisted the therapies listed in Table 1. Psoriasis Evaluation The :;everity of psoriasi:; wa:; quantitated using the Psori-asis Area and Severity Index.:··11 The assessment is per-formed by measuring the extent of :;kin involvement and the amount of erythema. infiltration. and desquamation using a scale of 0 to 4 (0 indicates none: 1. slight: 2. moderate: a. se-782 Arch Dermatol-Vol 128. June 1992 4.3 2.5 2.1 3.2 3.6 13.2 9.6 2.5 7.5 10.4 12.8 10.4 10.4 7.1 6.8 5.7 5.1 5.9 5.1 4.4 6.7 5.4 5.7 4.3 5.8 5.0 5.5 5.5 5.5 5.2 214 280 517 321 357 428 464 399 297 410 476 458 476 303 428 0.66 0.62 0.58 0.62 0.58 0.66 0.74 0.58 ... - .. -K------~ 0.49 0.49 ... 0.70 0.45 0.45 0.49 3.5 3.9 4.3 4.8 4.5 3.3 5.2 3.8 4.8 4.5 ----_._--_. -4.3 5.2 4.6 5.0 4.1 _._._-----._-- ---- ---6.3 3.3 4.5 4.7 3.5 5.6 2.9 6.6 3.6 3.6 5.4 ... 6.1 3.7 36 \'ere: and -I. \'erv :;e\·ere). Each of the abo\'e clinical :,iI..'l1:' \\'a,; given an appropriate :'core and a tompo,:ite additive ~umhE>r obtained that repre:Ient~ the m~oria:;iI; Area and peyDerit~· In-dex. In the three patients whose primary dia!£l1o:;i:; wa,; p:,o-riasis. biopsy specimens were obtained before institutin~ treatment. 2 weeks later. and when they were clinically free of lesions. Dose Control Oral tacrolimus therapy was started at 0.15 mgikg. t\\;ce daily. in the patients who did not receive organ tran~plants Tacrolimus-Jegasothy et al t:\,.,;""",;;; ~ ~K '.'.: ":. - -. .: . .. ~ . .:" Fig 1.-Lett. Generalized erythrodermic psoriasis in patient 5 before tacrolimus (FK 506) treatment: right. complete resolution after 3 weeks of tacrolimus treatment. ... _ ........ ,. and the do~age was adjusted. as necessary, according to tac-rolimus plasma levels. Plasma levels were measured at a 12-hour trough using an enzyme-linked immunoassayKl~ Similar dosage adjustments were made when clinical evidence indi-cated incomplete disease control or toxic reactions. No other antipsoriatic therapy was used. The transplant recipients were initially administered intravenous doses of 0.075 or 0.10 mgfkg tacroiimus per day and converted to therapy with oral medications when they could begin oral feeding. Patients who had received transplants also received prednispne initially, doses of which were tapered to levels shown in Table 2 at the time of their last follow-up \'isit. Arch Dermatol-Vol 128. June 1992 " " ~KII-K - . fI.-.\",,-' Fig 2.-Left. Histopathologic findings of patient in Fig 1 show-ing typical changes of pSOriasis before tacrolimus (FK 506) treatment; right. 2 weeks later. Note persistence of epidermal acanthosis. but almost complete resolution of dermal and epidermal inflammation (hematoxylin-eosin. x 1 00). Side Effect Surveillance Extensive medical examinations. including complete neu-rologic assessments. were performed repeatedly. Results of renal function tests and levels of serum cholesterol. uric acid. blood glucose. serum magnesium. and other electrolytes were carefully monitored. Development of high blood pressure (if present) was quantitated by the number of antihypertensive drugs required to maintain a normotensi\'e state. Hyper-kalemia. if it occurred, was treated with the mineralocorti-coid. fludrocortisone acetate. Hypomagnesemia seen in some patients did not require correction. Tacrollmus-Jegasothy et al 783 Table 3.-Psoriasis End Points in Three Nontransplant Patients Week Clinical Base- I I (PAS'- Scores) line 2 4 6 Now Patient 5 67.5 27 2.8 0 0 6 43.4 5.7 0 0 0 7 68.4 34.2 9.8 0 0 Histopathologlct Epidermal acanthosis +++ +++ + + -Munro/Micro-abscesses +++ - - - -Active dermal inflammation ++++ + - - -·PASI indicates Psoriasis Area and Severity Index. tOne plus indicates minimal: three pluses. moderately severe; four pluses. severe: and minus. absent. RESULTS Effect on Psoriasis There was a marked reduction in erythema and scale in all seven patients at the end of 1 week and complete clinical remission within 4 weeks (Fig 1). The remis-sions ha\'e been sustained in all patients. Our follow-up periods range from 5.5 to 14 months. Interpretation of the beneficial effect of tacrolimus was straightforward in the three patients whose primary diagnosis was psoriasis (Table 3) because they were not given sys-temic corticosteroids or other antipsoriatic medica-tions. Improvement of psoriatic arthritis, with reduc-tion in stiffness, pain on movement. and swelling, also occurred simultaneously in all three patients. Serial skin biopsy specimens obtained from the active plaques of psoriasis demonstrated a rapid disappearance of the inflammatory infiltrate in the dermis and the neutro-phib in the stratum corneum (Fig 2). The h~Dperkera­tosis and epidermal acanthosis took longer to re\'ert to normal (Table 3). Efforts to reduce tacrolimus dosage in these three patients resulted in the rapid reappear-ance of early psoriatic skin lesions. which promptly re-solved on returning to the immediately prior dose of tacrolimus. The foul' patients who had organ transplants re-cei\'ed systemic prednisone therapy postoperatively. but their remission persisted after lowering (patient :~F or stopping (patifnt,,; 1. 2. and -!) the corticosteroid therapy (Table 2J. Se\'eral months postoperativel~DI when there was no evidence of graft dysfunction. the liver recipient whose end-stage hepatic disease was caused by methotrexate therapy (patient 2) had small psoriatic plaques develop neal' the exit ,,;ite of his T tube. These psoriatic plaques disappeared \\'ith a minor increase in tacrolimus dose. Toxicity and Metabolic Changes Tacrolimus dosage. plasma levels. and sUl'\'eillance measurements were similar in patients who had and did not have transplants. Transient trembling, paresthe-sias. and insomnia not requiring tacrolimus dose 784 Arch Dermatol-Vol 128. June 1992 changes were noted in three patients. Increases of se-rum creatinine or serum urea nitrogen levels signaled the need for downward dose adjustments. Most pa-tients required a decrease of 10% to 25% of the total dose. Despite careful monitoring of dosage, serum cre-atinine and serum urea nitrogen levels increased at our check points (Table 2). Although generally stable, the final levels of these measures were higher in all patients when compared -with pretreatment values. Three patients had development of arterial hyperten-sion that was controlled -with single antihypertensive drug therapy; one patient who initially required two antihypertensive drugs was later normotensive with no drugs, and one patient with preexisting hyperten-sion requiring one drug for control had no change while receiving tacrolimus therapy. COMMENT Tacrolimus caused a complete remission of psoriasis in all seven treated patients. Improvement was always evident within a few days. In the patients who did not have transplants, tacrolimus dose and plasma levels needed to maintain remission of psoriasis were in the same range as those required to prevent allograft re-jection. Efforts to reduce the dose of tacrolimus in these patients resulted in reactivation of the psoriasis. In one liver recipient (patient 2), dose reduction caused a minor recurrence of psoriasis without evidence of b'Taft rejection. Whether the reward of complete control of psoriasis will be worth the risk of long-term therapy with this powerful drug can be judged only after future studies. The first administration of tacrolimus to a human to prevent organ rejection occurred only 29 months ago.1i Our patients with psoriasis. whose cases are reported herein, have been treated with tacrolimus for 5.5 to 14 months. The results are very encouraging. The only potentially serious side effect was nephrotoxicity. In patients with psoriasis as their primar~D disease. serum creatinine levels increased 27':( to 111 r( (mean, G8,:() above baseline early in their course. but later stabilized at 66% to 74% Eme~nK G8O/C) above pretreatment levels. In the patients with psoriasis who also underwent or-gan transplantation, serum creatinine le\'els increased 100% to 200% (mean. 152q) abO\"e baseline. but later stabilized at :-\:-)('r to 20W, (mean. l!i(jr() abo\'e pre-treatment values. Patients \\'ho are candidates for or-gan transplantation lfsuall~D have some deg1'ee of incip-ient renal compromise. which may ha \'to, predisposed them to greater tacrolimus nephrotoxic reactions, Elevations in serum creatinine and serum urea nitrogen levels responded to close reduction and reached an increased but stable state at the surveil-lance check points. No patient has had an infection. The patients \\ith psoriasis who did not ha\'e transplants who were accepted for our study were those who had severe. widespread treatment-resistant disease that completely ruined their quality of life. Patients v.ith less severe disease are not candidates for treatment with tacrolimus until further experience regarding the severity and long-term effects of nephrotoxic reactions are understood. Tacrolimus-Jegasothy et al The remarkable efficacy of tacrolimus in psoriasis is attributable to its effect on immune modulation. How-e'-er .. this may not be the sole explanation for its effect. I t is knovm that the cytosolic receptors for this drug (called "FK binding protein") as well as the distinct cyclosporine-binding site (cyclophilin) are part of a pre,-ious!y unrecognized class of small molecular '\'eight proteins collectively called "immunophilins." These proteins are found in the cytoplasm of essentially all eukaryotic cells, including those of the skin. from the !()\\'est to highest species. including man.I:l The binding of these immunophilins with cyclosporine, tacrolimus, and presumably other drugs can affect signal trans-duction in nonimmunologic as well as immunoregula-tory cells. Thus, an array of metabolic consequences could result affecting growth control as has been dem-onstrated in the liver.14 Growth control in the skin can-not be excluded as a target of such nonimmunologic ef-fects. This investigation was aided by research grants from the Veter-ans Administration and project grant DK 29961 from the National J nstitutes of Health. Bethesda, Md. References 1. Knlt'l!"l'r .1(;. Krane .JF. (""artpr :\1. Gottlieb A. Role of gro\\·th fad,)r,;, e~·trIkineI;I anri their receptor:: in the pathogene~is of p"ori-;1,1'; . .I 1111'(-,,1 lJel'lllUloi. lr~ll:!lK1Esuppl 1:1355-1405. :2. Ba,d,gaarct n. Gupta A. Taylor S. Ellis C, Voorhees J. Cooper K. ["'Ii'iatie t'pidt'rmal ('ell; demon,trate increa,;(·d numbers and fum'tion on non-Lang-erham: antigen presenting cells, J //I/'esl Drr-,,,,,/oi. f~g~~g:!l:O:tl-l~fKDiK :L :'I1lieller W. Hermann B. Cyclosporine A for psoriasis. X Eng! ./ .lIed. 1 ~li9:;ll 1 :555. -i. Ellis CK, Gorsulowsky DC, Hamilton T. Cyclosporine improves p,oriasis in a double-blind study . .lAMA. 1986:256:3110-3116. '-1. Powles AV, Baker BS. Valdiman;son H, Holme B. Fry L. Four . \var, of expelit'net' with c~Dclosporine A for psoriasis. BI' J Derma-l", 1!1~1EF:l:O:OEI;uppl a6):I;{-1!1. Ii. Kino T, Hataanaka H. Mivata S, et al. FK 506 a novel immuno-suppressant isolated from stre'ptomyces. II: immunosuppressive ef-fect of FK 506 in vitro . .l Antibiot. 1987;40:1256-1265. 7. Tocci MJ, Matkovich DA, CoIlier KA, et al. The immunosup-pressant FK 506 selectively inhibits expression of early T-ceU acti-\'ation genes . .l IlIlmunol. 19o9:14P:T1~-TOSK ~K Starzl TE. Todo S. Fung J, Demetns AJ. Venkataramanan R. .Jain A. FK 506 for liver. kidney and pancreas transplantation. Lan-e et. 1989;2: 1 000-1 004. ~K Todo S. Fung J.J. Starzl TE. et al. Lh·er. kidney. and thoracic organ transplantation under FK 506 . .4.11tl Surg. 1990:212:295-305. 10. Fung JJ, Todo S. Jain A, et al. Conversion of liver allograft re-cipients with cyclosporine related complications from cyclosporine to FK 506. Transplant Proc. 1990:22:6-12 . 11. Fredriksson T. Pettersson U. Severe psoriasis-oral therapy .... ith a new retinoid. Derrn.atologica. 1978;157:238-244. 12. Tamura K, Kobayashi M. Hashimoto K. et al. A highly sensi· tive method to assay FK 506 levels in plasma. Tral1:;p!anf Proc . 19b7;l9(suppl 6):23-29. 13. Schreiber SL. Chemistry and biology of the immunophilins and their immunosuppressive ligands. Science. 1991;251:283-287. 14. Starzl TE, Porter KA, Mazzaferro V, Todo S, Fung J, Francavilla A. Hepatotrophic effects of FK 506 in dogs. Transplan-tation. 1991;51:67-70. In Other AMA Journals ARCHIVES OF INTERNAL MEDICINE Treatment of Painful Diabetic Neuropathy With Topical Capsaicin The Capsaicin Study Group. lArch Intern Med. 1991;151:2225-2229) In this large multicenter study, 277 patients with cutaneous pain secondary to diabetic neuropathy were treated with capsaicin or its vehicle. Those patients who used capsaicin re-ported better pain relief, as evaluated by both the patient and physician. Although the re-sults were significant on a statistical basis, the overall improvement was not terribly impressive. Nevertheless, at the theoretical level, it is important that cutaneous pain of more than the post herpetic type can be modified with topical therapy. Arch Dermatol-Vol 128. June 1992 T acrolimus-Jegasothy at al 785 

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FK 506 - A new therapeutic agent for severe recalcitrant psoriasis

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