Methotrexate For Psoriasis Research Articles

Sister Chromatid Exchange in Patients Treated with Methotrexate for Psoriasis

Sister chromatid exchange (SCE), which is considered a sensitive method in evaluation of mutagenicity and may be an indicator of carcinogenicity, was determined in lymphocytes from 8 patients with severe psoriasis who underwent treatment with oral methotrexate (MTX). During the treatment period (median 118 days, range 50-298 days) a significant increase in SCE compared to the pretreatment value was found in 1 patient only. It is concluded that no long-term damage as measured by SCE occurs in lymphocytes from psoriasis patients treated with MTX.

Two patterns of skin ulceration induced by methotrexate in patients with psoriasis

Two patterns of skin ulceration occurred in patients receiving weekly methotrexate for psoriasis. In type I ulceration, psoriatic plaques became painful and eroded shortly after starting methotrexate (MTX) (median, 10 days). Type II ulcers occurred in clinically uninvolved skin affected by other pathology—stasis dermatitis in two and adjacent to an anal fistula in one and had a variable relationship to the duration of methotrexate treatment. Type I ulcers developed at methotrexate doses between 12.5 and 25 (median, 20) tng/wk and healed rapidly (median, 10 days) after dose reduction or withdrawal. Type II ulcers developed at methotrexate doses of 7.5 to 20 (median, 10) mg/wk and took a median of 9 weeks to heal. Type I ulceration may be confused with an exacerbation of psoriasis, and the MTX dose mistakenly increased rather than reduced. Type II ulcers can mimic stasis ulcers and may be overlooked as evidence of MTX toxicity.

Commentary and update: methotrexate for psoriasis--two decades later.

Commentary and update: methotrexate for psoriasis--two decades later.

Methotrexate in psoriasis with and without leucovorin: effect of different dosage schedules on acute liver toxicity

Studies on thirty-six psoriatics revealed no differences in acute liver toxicity of four different intermittent dosage schedules of methotrexate with or without addition of leucovorin, as judged by daily determinations of SGOT for one week. Three patients with psoriatic erythroderma receiving high-dosage methotrexate (100 mg i.v.) with leucovorin rescue responded extremely well to treatment and did not distinguish themselves from the other patients with regard to acute liver toxicity.

Percutaneous Absorption of Methotrexate: Effect on Epidermal DNA Synthesis in Hairless Mice

One of the presumed reasons for the lack of clinical activity of topical methotrexate in psoriasis is insufficient percutaneous penetration necessary to inhibit epidermal DNA synthesis. The present study was undertaken to select a vehicle to optimize penetration of methotrexate in vitro and to determine the effects of this topical formulation on epidermal DNA synthesis in vivo in hairless mouse skin. Increased penetration of methotrexate was obtained in human skin in vitro with Vehicle N compared to water and n-decylmethylsulfoxide vehicles. Repeated topical application of this methotrexate/Vehicle N preparation produced marked epidermal atrophy in treated sites in both normal and hyperproliferative essential fatty acid deficient hairless mouse skin without similar effects at a distant skin site. Local inhibition of epidermal DNA synthesis was also obtained without systemic effects at a distant site. These studies demonstrate that methotrexate in Vehicle N may produce a direct effect on epidermis which may be useful for the topical therapy of psoriasis.

The effect of methotrexate and hydroxyurea on neutrophil chemotaxis.

Methotrexate depresses motility of neutrophils in chamber membranes, but does not interfere with random motility in tubes. Hydroxyurea has no such effect. The therapeutic response to methotrexate in psoriasis may be due in part to a reduction in migration of neutrophils into the epidermis.

Methotrexate hepatotoxicity in psoriasis. Consideration of liver biopsies at regular intervals.

Fibrosis of the liver developed to a degree that contraindicated further treatment with methotrexate in 11 of 43 patients who had been receiving maintenance therapy with methotrexate for psoriasis. Liver biopsy had been performed prior to initiation of methotrexate therapy and was repeated at 12- to 18-month intervals. In this retrospective study, age of the patient and duration of therapy have been found to be significant factors in those patients receiving only the weekly oral dosage schedule. Yearly biopsies of the liver are recommended for patients who receive methotrexate throughout their courses of therapy.

Methotrexate Hepatotoxicity in Psoriasis

Fibrosis of the liver developed to a degree that contraindicated further treatment with methotrexate in 11 of 43 patients who had been receiving maintenance therapy with methotrexate for psoriasis. Liver biopsy had been performed prior to initiation of methotrexate therapy and was repeated at 12- to 18-month intervals. In this retrospective study, age of the patient and duration of therapy have been found to be significant factors in those patients receiving only the weekly oral dosage schedule. Yearly biopsies of the liver are recommended for patients who receive methotrexate throughout their courses of therapy.

Methotrexate in psoriasis: A brief review of indications, usage, and complications of methotrexate therapy

Methotrexate is widely used by dermatologists in the treatment of recalcitrant psoriasis. Despite potentially serious side effects, including hepatic cirrhosis, the drug is relatively safe and remarkably effective when carefully administered to selected patients.

Biological and Biochemical Actions of Methotrexate in Psoriasis

The purpose of this study was to determine whether the biological effects of methotrexate (MTX) in psoriasis occur by direct drug action on the psoriatic plaque or are mediated by systemic action at a site distant from skin. Injection of intralesional MTX into plaques showed a dose-related decrease in mitotic activity accompanied by a production of MTX damaged cells beginning 2hr after injection. These effects were similar to those found in psoriatic epidermis with systemically administered MTX. The data suggest that MTX acts directly on the psoriatic plaque rather than systemically at a distant site. In the EFA rat with a hyperproliferative epidermis intradermal MTX decreased epidermal mitoses and thymidine reversed this effect. Additionally, psoriatic patients were injected intralesionally with MTX simultaneously with either leucovorin, thymidine, uridine, or saline. Thymidine protected against the biologic effects of MTX described above in all patients. Leucovorin with MTX provided only partial protection while uridine and saline had no influence on the MTX effects. These data suggest that the biologic effects of MTX in psoriasis are mediated by the local depletion of the thymidine pool rather than by other biochemical actions. Continued efforts in the investigation of topical MTX analogs seems warranted for the treatment of psoriasis.

Is Methotrexate Therapy for Psoriasis Carcinogenic?

The use of methotrexate in psoriasis has recently been questioned because of possible carcinogenic potential. Two hundred twenty-four patients began methotrexate therapy during 1960 to 1965 at the Cleveland Clinic and at Duke University Medical Center. The incidence of malignant neoplasms and mortality has been studied in 205 of these 224 patients. Mortality increased with hepatic disease. No increased incidence of total internal malignancy was found, nor did any one type of neoplasm appear predominant.

Is methotrexate therapy for psoriasis carcinogenic? A modified retrospective-prospective analysis

The use of methotrexate in psoriasis has recently been questioned because of possible carcinogenic potential. Two hundred twenty-four patients began methotrexate therapy during 1960 to 1965 at the Cleveland Clinic and at Duke University Medical Center. The incidence of malignant neoplasms and mortality has been studied in 205 of these 224 patients. Mortality increased with hepatic disease. No increased incidence of total internal malignancy was found, nor did any one type of neoplasm appear predominant. (<i>JAMA</i>232:359-362, 1975)

Distribution of methotrexate in rat tissues.

SUMMARY The distribution of methotrexate between tissues is a very complex process, dependent in part upon the species studied, the size of the dose and the channel of administration. The nature of the tissue and its content of dihydrofolate reductase also play a part. Elimination of methotrexate in the urine and bile indicate that renal and hepatic function are also important. The amounts of administered methotrexate taken up by the skin and liver were doubled by experi-mental folate depletion. In contrast, folate deficiency did not significantly increase uptake by the kidneys or intestines. The skin uptake of methotrexate was increased about six-fold by prior strip-ping, without infiuencing the hepatic uptake. Methotrexate taken up could be partially displaced by pteridines which have affinity for dihydrofolate reductase. Methotrexate itself was most efficient, but both dihydrofolate and folic acid were more effective than leucovorin, while 5-methyl folate had virtually no effect. These results indicate that a risk of hepatic injury is probably inseparable from the therapeutic action of methotrexate in psoriasis, even though the amount of drug reaching the liver can be reduced by using a logical parenteral schedule.

Absorption and Local Action of Methotrexate in Human and Mouse Skin

The ability of methotrexate sodium to penetrate skin in vivo has been studied in hairless mice and psoriatic patients. When topically applied, methotrexate was rapidly absorbed through hairless mouse skin, but not through human skin. In mice, topically applied methotrexate was detected in the plasma, skin, and liver in amounts comparable to those obtained after intraperitoneal injection. Following topical application in psoriatic patients, methotrexate could be detected in neither plasma nor skin. Repeated topical application and intralesional injections of methotrexate were clinically ineffective in 17 out of 18 psoriatic patients so treated. Possible reasons for the ineffectiveness of local application of methotrexate in psoriasis are discussed.

Use of Methotrexate in Psoriasis

The stimulus to develop guidelines for the use of methotrexate in psoriasis in the summer of 1971 stemmed from the inability to determine the direction the Federal Drug Administration would take regarding the use of this drug. Methotrexate had been in common use in this disease for several years and was generally felt to be a relatively safe medication, documented by many reports in the literature, until isolated reports of hepatic cirrhosis and liver failure appeared. Medico-legal situations soon developed with the potential that large sums might be awarded. It became clear that the situation was getting out of hand at a rapidly accelerating pace. Thus, it was felt that a set of guidelines, possibly approved by an official body of dermatologists, would provide a formal basis for the use of this drug in dermatologic practice. Thus, in July 1971, the Psoriasis Task Force of the National Program of Dermatology

Parenteral methotrexate in psoriasis. A report on the efficacy and toxicity of long-term intermittent treatment.

Thirty-six patients with severe, debilitating, and refractory psoriasis, arthritis, or both were treated with parenteral methotrexate for periods of time that varied from six months to three years. Five of the 36 patients had previously received oral methotrexate without adequate control of the disease. Of the patients, 80% responded to 25 and 50 mg of the drug biweekly. The remaining 20% could be controlled with 75 mg biweekly, however, the incidence of drug-induced toxicity increased significantly with the higher drug dosages, but was not severe enough to cause permanent cessation of therapy. Data obtained were compared with data presented by other investigators using the oral and parenteral routes. The regimen of 25 to 50 mg of biweekly parenteral methotrexate gave therapeutic results comparable to those reported by others using higher parenteral and daily oral dosages. Knowledge of the pharmacology of methotrexate leads one to believe that the use of this regimen will reduce the potential for long-term toxicity.

Radioactive iron studies in patients treated with methotrexate for psoriasis.

Radioactive iron studies in patients treated with methotrexate for psoriasis.

Topical Methotrexate in Psoriasis

Localized areas of psoriasis in nine patients have been treated with topical methotrexate. Clinically, the lesion improved in all instances and in three there was complete clearing. All the patients except one had a reaction in the skin surrounding the treated lesions. This took the form of erythema, and purpura, and in three instances ulceration. Only two patients showed any similar reactions in the psoriatic lesion. Histologically, there was improvement in the psoriasis in six of the patients within 48 hours. The first sign was the reformation of a granular layer, which in three specimens was normal after one week's treatment. The action of topical methotrexate in psoriasis appears to be directly on the epidermal cells.

Action of methotrexate on skin and intestinal epithelium in psoriasis

Twelve patients with psoriasis have been treated with parenteral methotrexate at weekly intervals. Ten patients showed varying degrees of clinical improvement within six weeks, but two did not respond. In some cases, there was a dramatic fall in the mitotic activity of psoriatic epidermis at three and 24 hours after methotrexate, but the count rose again by the third day although in the patients who improved clinically the mitotic index did not return to the pretreatment level by seven days. In other cases there was a gradual fall in the mitotic count from the first to the seventh day. There was a marked fall in the mitotic index of the small intestinal epithelium after methotrexate, but unlike the psoriatic epidermis the mitotic count returned to the preinjection level by the seventh day. The results support the theory that the "healing" action of methotrexate in psoriasis is primarily a direct one on the premitotic and mitotic cells of the epidermis.

AMINOPTERIN FOR PSORIASIS. A DECADE'S OBSERVATION.

Antifolics are rational for psoriasis. Normal renal clearance is of vital importance; this may be true of normal liver functions as well. No fatal or near fatal reactions occurred in our series. We have reviewed two deaths following aminopterin (Aminopterin Sodium) therapy, apparently from inadequate renal clearance, one severe reaction for the same reason, and one death apparently due to inadequacy of bone marrow function. One death after parenteral methotrexate was from sepsis following leukopenia. Fatal reactions may occur after leukopenia develops; it is therefore vital to select patients carefully and to make certain that there are no contraindications at the onset. Antifolics should not be used when there is any possibility of pregnancy, because of possible fetal malformation. However, normal full-term pregnancies have occurred following administration of these compounds to either the father or the mother before the pregnancy started. Most dermatologic teaching services in this country use antifolics for severe psoriasis and would support a petition to the Food and Drug Administration to include listing of severe psoriasis as an indication for these drugs. Most services also would support the continued manufacture of aminopterin. There are many variables to account for relative unpredictability of toxic and beneficial effects, such as instability of the compounds, presence or absence of relative folic acid deficiency in the patient, variable absorption and excretion, and all the other variables which affect the action of any drug. Elderly patients, possibly due to occult decline in renal and liver function, are poor candidates for antifolic therapy. Rare hypersensitivity reactions may occur. Only about 10% of our original group of patients still take antifolics for psoriasis. Reasons for discontinuation of the drugs include lasting remission in about 10%, response to other treatment in some instances, advanced age, unwillingness to undergo necessary safeguards in some, and unknown reasons in others. Two patients have developed leukemia, one of an aleukemic nonclassified variety, and the other an acute leukemia. Neither case of leukemia occurred in close relationship to antifolic therapy. Some of the reactions encountered in the past apparently may now be explained on the basis of impaired renal clearance. Liver function tests (serum glutamic pyruvic transaminase and cephalin flocculation) performed on 31 patients receiving over 100 tablets of aminopterin or in those who have had reactions in the past have showed normal readings for the most part. Three patients showed abnormality in 48-hour cephalin flocculation test reading. Methotrexate for psoriasis needs further investigation, both for oral and parenteral use, because this compound might possibly be safer and more effective than aminopterin if adequate and safe dosage schedules can be found. For summary of standard approach, see Table.