The Effect of Triacetyl Azauridine on Psoriasis*

THE EFFECT OF TRIACETYL AZAURIDINE ON PSORIASIS* RAYMOND W. TURNER, M.D.t AND PAUL CALABRESI, M.D.t

Chemotherapeutic agents capable of inhibiting produce normal-appearing keratin. Similar results were associated with clinical improvement useful in the treatment of non-neoplastic diseases regardless of the drug employed. of the skin. The use of podophyllin in the topical Aminopterin or methotrexate are frequently therapy of condylomata acuminata is one of the used when more conservative, topical forms of earliest examples of the value of growth-inhibitors treatment are not effective in severe cases of in dermatology. This resinous substance sup- psoriasis. These agents compete with folic acid presses growth by arresting the mitotic process for folio reduetase, blocking the formation of in a similar manner to colchicine (1). Both derma- tetrahydrofolic acid, a component of numerous tologic and systemic manifestations of certain essential coenzymes (12). Since all cells depend disorders associated with hypersensitivity re- upon the products of tetrahydrofolate formation,

cellular replication are becoming increasingly

spond to the immunosuppressive properties of all are susceptible to the antimetabolic effects alkylating agents and antimetabolites even when of the folic antagonists, but those with high treatment with corticosteroids has been unsuc- mitotic activity are suppressed earlier than cessful (2, 3, 4). Infections caused by some DNA others with a slower turnover.

Unfortunately, the full potential of the folio

viruses, notably herpes simplex and vaceinia, are inhibited by 5-iodo-2'-deoxyuridine (IUdR) (5), an antimetabolite that interferes with the incorporation of thymidine into DNA (6). Considerable effort is being directed towards the

acid antagonists cannot always be utilized in the

nists in the treatment of psoriasis have been

treatment of psoriasis. Untoward reactions of these drugs involving other tissues may accompany the use of the most advantageous doses (10), and prolonged administration results in cumulative effects (12, 13). Because of these drawbacks it was considered worthwhile to investigate the response of patients with severe psoriasis to 6-azauridine (AzUR), a newer anti-

known for the past 13 years (10). Only recently,

metabolite capable of inhibiting growth of certain

development of dermatologic preparations of this

agent for the treatment of these and related viral infections of the skin (7, 8, 9). The beneficial effects of the folic acid antago-

however, was the nature of this effect clearly attributed, by Van Scott and Reinerton, to an inhibition of cellular reproduction which is markedly increased in psoriatic lesions (11). These investigators have compared other antineoplastic agents with diverse cytotoxic prop-

neoplastic cells without comparable toxicity to normal cells in man (14). The following is a report of the observations in 10 individuals with extensive, resistant psoriasis treated with triacetyl AzUR (TA-AzUR); a preliminary report of trials with TA-AzUR in crties to the antifolates, methotrexate and amin- psoriasis and mycosis fungoides has been preopterin, for their effect on psoriatic epidermis. sented (15). Improvement of the skin lesions was always METHODS associated with a decrease in the mitotic activity Ten patients with severe, disabling psoriasis, of the epidermis thereby restoring its ability to 4 with exfoliative erythroderma and 6 with exten* From the Sections of Dermatology and Clini- sive plaque-like disease, were hospitalized at the cal Pharmacology, Departments of Internal Medi- Grace-New Haven Community Hospital for initiacine and Pharmacology, Yale University School tion of treatment with TA-AzUR. These included 4 women and 6 men whose ages ranged from 30 to of Medicine, New Haven, Connecticut. Presented at the Twenty-fifth Annual Meeting SO years. No other specific treatment for psoriasis of The Society for Investigative Dermatology, was used for at least 4 weeks prior to hospitalizaInc., San Francisco, Calif., June 23, 1964. tion or during treatment with TA-AzUR.

Supported in part by P.H.S. Grants Nos. CA-

The drug was administered orally as the tnPublic Health Service Special Fellow (IF acetyl derivative since, in contrast to free AzUR, it is rapidly absorbed from the gastrointestinal 3-AM-24,279-01). Recipient, Burroughs Wellcome Fund Clinical tract and results in more prolonged levels of 05944, CA-5138 and MO-IFR-38.

AzUR in the circulation (16, 17). All patients were

Pharmacology Award. 551

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treated with an initial dose of 270 mg/kg/day. After 10 to 20 days, the dose was reduced to 135 mg/kg/day. Two patients received 70 mg/kg/day for several weeks. The medication was supplied in gelatin capsules containing 500 mg of the drug and the daily dose was administered in 3 equal portions every S hours. The length of each course of treatment was governed by the clinical response of the

skin lesions and varied between 10 days and 7 months. Therapy was continuous except for occasional interruptions of 1 to 2 weeks in some patients. Six individuals are still on therapy after 7,0,5,4, 2 and 14 months, respectively. The following determinations were carried out in all patients before beginning treatment: hcma-

tocrit, total and differential leukocyte counts,

reticulocyte and platelet counts, serum uric acid and serum iron. These examinations were repeated at 3 to 4 day intervals during the first 3 weeks of

RESULTS

Clinical Observations

All patients showed clinical improvement of their skin lesions. The rate of this change appeared to depend more upon the thickness rather than upon the extent of the original lesions. The

first signs of improvement, however, were observed at about the same interval of time following initiation of drug therapy, regardless of the character of the lesions. By the second day of treatment, erythcma and scaling were noticeably

diminished, particularly in the center of the

localized plaques. Thereafter, the rate of resolution varied among the subjects. The most rapid

therapy, and at weekly or biweekly intervals improvement was seen in the 4 patients with thereafter. Serial biopsies of representative pso- exfoliative erythroderma. Excluding a faintly riatic lesions were performed twice weekly in 5 dusky residual erythema, no evidence of skin patients before and during the first 6 weeks of involvement was discernible after the first 7 to 10 treatment. Microscopic examination of scalp hair days of treatment (Figure 1). In the 6 individuals roots was carried out in 4 patients at different intervals from initiation of therapy. Bone marrow with plaque-like disease, the lesions in 3 cleared aspirations were performed in 9 patients, and the completely after 2 to 7 months of therapy, and

rate of disappearance of Fe59 from the plasma

the other 3 experienced clearing of nearly half

was measured in 4 subjects on treatment. Electro- the skin lesions and a decrease in the substance

r

encephalograms, liver function tests and blood and sealing of the remainder during the first urea nitrogen determinations were obtained in several patients before and at varying intervals month of therapy (Figures 2, 3). After the initial after initiation of therapy. month's improvement the latter group has shown

FIG. 1. 65-year-old white man with exfoliative crythrodormic psoriasis of S weeks' duration: (a) before treatment, (b) after 14 days of treatment with TA-AzIJI4.

553

AZAIJRIDINE IN PSORIASIS

Fio. 2. 52-year-old white woman with plaque-like psoriasis of 7 years' duration: (a) before treat-

ment, (b) after 14 days of treatment with TA-AITJR, (e) after 28 days of treatment with TA-AzIJR, (d) after 60 days of treatment with TA-AzUR.

no further decrease in extent of involvement despite maintenance of drug at the above doses for 1 to 3 months. No sign of relapse, however, has occurred during this time. TA-AzUR therapy was empirically discon-

tinued in 6 patients after varying degrees of clinical improvement. There has been no sign of relapse in one patient with exfoliative erythroderma and another with plaque-like disease one month after discontinuing therapy. The remain-

ing 4 patients showed reactivation of disease shortly after cessation of treatment with gradual recurrence of psoriatic lesions. Within two weeks, 2 individuals had lesions that were identical in distribution and in character to the original clinical picture, while the exacerbation in the other 2

patients was of lesser extent than that seen originally. It appears that the response after reinstitution of therapy is identical to that noted during the first course. Resolution of psoriasis was most rapid during the administration of the initial large doses of TA-AzIJR (270 mg/kg/day), and somewhat more gradual on half that dose (135 mg/kg/day); 70

mg/kg/day failed to control the disease in 2 patients with active disease but has not been tried as maintenance therapy in arrested cases. All patients originally presenting with pruritus experienced complete and lasting relief of this

annoying symptom during the first week of therapy without relation to extent of objective

FIG. 3

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improvement. Several patients reported temporary increase of pruritus during the first 3 days of drug administration.

involvement, biopsy studies during the first

month of treatment showed some shortening of

rete pegs with a decrease in the length of the

dermal-epidermal border. The appearance of the

There was neither subjective nor objective stratum corneum reverted to norr.I during this evidence of stomatitis, gastrointestinal, bepatic, time. As in the other cases, capillary dilatation or renal toxicity; skin ulceration or damage to and cellular infiltrates were still noticeable in hair follicles was not encountered nt any time the dermis after one month of therapy. during the course of the treatment.

Laboratory Studies

Toxicity of TA-AzTJR appeared to be limited Histological Studies to the hematopoietic system (Figure 5). Complete Serial biopsy studies confirmed the clinical blood counts in all patients were normal before impression of improvement in the psoriatic lesions the start of therapy. Those receiving 270 mg/kg/ after therapy with TA-AzT.JR (Figure 4). At the day for 14 days or more showed a decline in the time of the first specimens, 4 days after the begin- reticulocyte count followed by a decrease in the ning of treatment, a prominent layer of granular hematocrit to levels of 32 to 36%. At first, the dose cells was evident subjacent to a thin normal- of TA-AzUR was reduced to 135 mg/kg/day only appearing stratum corneum. In the patients with after the onset of anemia. Later, when the dose exfoliative erythroderma, the histological appear- was decreased as early as 10 days after the start ance of the epidermis was completely normal of therapy, anemia was not observed. Although within 10 to 14 days after the start of therapy, patients receiving higher doses for longer periods while a mild mononuclear infiltrate in the dermis of time developed moderate anemia, prompt and dilatation of the upper dermal capillaries per- reappearance of reticulocytes and gradual return sisted. In the patients with a plaque-like psoriatic of the hematocrit to normal levels was observed

upon continuation of therapy at lower doses.

In three patients mild leukopenia was noted with

leukocyte counts in the range of 3500 to 4000 cells/cu mm. No thrombocytopenia was observed.

Ferrokinetic studies revealed elevation of the serum iron during treatment and delayed clearance of Fe59 from the plasma; the bone marrows showed mild to moderate hypocellularity with megaloblastic changes in the late erythroid elements. The serum uric acid levels, initially higher than normal in half the patients, decreased in all during therapy (19). Electroencephalograms, liver function tests and blood urea nitrogen determinations remained normal during the course of treatment. DiscUssiON

The characteristic thickening and scaling of psoriatic lesions may be regarded as a result of hyperplasia of the germinative cells of human epidermis. Abnormally large numbers of mitotie figures may be identified in the basal cell layer

resulting in an increased rate of turnover of epidermal cells with subsequent impairment of normal production of keratin (11, 18, 20). Although the pathological features of psoriasis are most striking in the epidermis, they are not confined solely to that area. The dilatation of the dermal capillaries is an integral part of the charFm. 4. Histologic sections of sequential biopsy acteristic histopathology. The relationship of this specimens from adjacent sites of a psoriatic lesion. x43. Paticnt with plaque-like psoriasis of 7 aspect of the disease to the etiology and course of years' duration: (a) before treatment, (b) after 21 psoriasis is poorly understood (22, 23). days of treatment with TA-AzUR, (c) after 35 Since neither the locus nor the specific defect days of treatment with TA-AzUR, (d) after 70 days of treatment with TA-AzUR.

responsible for the entire disease process is

555

AZATJRIDINE IN PSORIASIS

H. W. PS OR LAS IS

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FIG. 5. Effects of prolonged administration of TA-AzUR on the hematopoietic system

known, therapeutic efforts in psoriasis are di- need for frequent intravenous injections to mainrected at the more troublesome manifestations of tain desired levels of the antimetabolite in the the disease—the epidermal abnormalities. Im- blood. Both agents exert their effect after conprovement of these abnormalities proceeds in the version to azauridylic acid (AzUMP) which same fashion regardless of the therapeutic means competes with orotidylic acid for the enzyme employed (11, 24, 25): first there is a reduction orotidylie acid decarboxylase thereby blocking in the number of mitoses in the basal layer, then the de novo synthesis of uridylie acid (Figure 6). a layer of granular cells appears, and finally pro- Because the synthesis of nucleic acids in cells duction of a normal stratum corneum ensues. The capable of utilizing preformed uridine derivaunifying factor common to the numerous varie- tives should not be impaired by this metabolic ties of treatment known to be effective in psoria- blockade, a possible explanation for the selective

sis seems to be the capability of the agents to retard cellular multiplication. It is not known if this is the result of a direct or an indirect action on the basal cells or whether some contributing

toxicity of AzLTR may be inferred. Although evidence that these biochemical pathways are opera-

tive in the germinal cells of psoriatie epidermis remains to be obtained, studies in human and

effect of these agents on the dermis is involved. Although psoriasis may be extremely disabling

canine leukocytes suggest that a greater capacity

the process. Because earlier clinical and pharma-

ther clinical and biochemical correlations will be necessary to demonstrate whether such quantitative metabolic differences may be exploited to

to metabolize orotic acid may reflect a greater and refractory to treatment, the risks involved dependence of the cell on the de novo pathway in the use of systemic chemotherapy must be of pyrimidine biosynthesis and an enhanced proportionate to the relatively benign nature of susceptibility to the toxic effects of AzUR. Furcological studies with AzTJR and its triacetyl

derivative had demonstrated lack of severe toxicity at doses capable of interfering with predict the selection of possible candidates for proliferation of certain neoplastic cells (16, 17),

therapy. In the present study, as in earlier clinical trials severe and unresponsive psoriasis were initiated. in patients with neoplastic disease (16, 17), adThe development of TA-AzUR, a convenient ministration of TA-AzUR did not result in severe orally effective derivative of AzUR, obviates the toxicity. Even after prolonged administration of

cautious therapeutic trials in patients with

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556

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drug no evidence of stomatitis, gastrointestinal toxicity, damage to the hair follicles or alopecia was observed. The turnover time of oral and gastrointestinal mucosa is of the same order of magnitude as that of the psoriatic epithelium and that of the hair matrix is even more rapid

no further knowledge to the ctiologic basis of the

disease than a similar response in leukemia or mycosis fungoides, the apparent selective toxicity

for psoriatic cells demonstrated by this antimetabolitc offers a therapeutic advantage deserving of further investigation.

(13). In contrast with other cytotoxic agents used in psoriasis, the inhibitory effects of TA-AzUR

5UMMARY

on epithelial tissues were selectively limited to areas of disease and did not indiscriminately involve all rapidly growing epithelial structures. Toxicity with TA-AzUR appeared to be confined to the hematopoietic system and was suspected but not established by earlier short-term

Triacetyl-6-azauridinc (TA-AzUR), an orally administered antimctabolite, produced salutary effects on the lesions of psoriasis in 10 patients with disabling disease. The drug inhibits orotidylic acid decarboxylase in the de novo pathway of pyrimidine metabolism. The major toxic

studies (16). A mild to moderate anemia de- manifestation of TA-AzUR during prolonged adveloped in most of the patients, and was char- ministration was mild to moderate anemia, acterized by rcticulocytopenia, reduced utiliza- rapidly reversible upon discontinuation of the tion of iron and megaloblastic change in the drug or reduction of therapeutic doses. There were marrow. These changes, which will be reported no cases of oral, gastrointestinal or skin ulcerain detail elsewhere, were rapidly reversible upon tion, and hair loss did not occur. This differential discontinuation of drug and improved even with effect on the reproductive capacities of epithelial

continuation of TA-AzUR at reduced doses. cells suggests that TA-AzUR, at these doses, Three patients demonstrated mild lcukopenia exerts a selective inhibitory effect in psoriatic but no thrombocytopenia was observed. The fact that TA-AzTJR is effective in psoriasis

epidermis without significant toxicity to normal tissues.

is of considerable significance since an insight into the preferential mode of pyrimidine biosynthesis in psoriatic cells may be inferred. Al-

AnDENDUM

though the response to TA-AzUR may contribute

An additional four patients who were not included in the group reported above were treated

557

AZATJRIDINE IN PSORIASIS

with TA-AzTJR. One, with exfoliative erythroderma, had evidence suggesting impaired intestinal absorption. Improvement in his skin lesions

11. VAN SCOTT, E. J. AND REINERTON, R. P.:

was slight and no hematopoietie changes occurred despite prolonged oral administration of the drug.

12. BERLIN,

The remaining three had extensive plaque-like involvement with psoriasis and, in addition to TA-AzTJR, were treated with topical steroids,

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