Long -term safety and toxicity of azathioprine in patients with air-borne contact dermatitis

Introduction

Azathioprine, a chemical analogue of purine, is an imidazolyl derivative of mercaptopurine.[1] It is widely used as an immunosuppressive agent. Its immunosuppressive effects are caused by the substitution of naturally occurring purine bases in DNA by its active intracellular metabolite 6thioguanine in actively dividing cells.[2] The drug is metabolized by three competing enzymes hypoxanthine-guanine phosphoribosyl transferase, xanthine oxidase and thiopurine methyl transferase (TPMT).[3] Azathioprine is converted into its inactive metabolites mainly by TPMT. Therefore patients with low TPMT levels are at a major risk of developing myelotoxicity. Since the drug primarily affects the rapidly dividing cells, bone-marrow cells, gastrointestinal tract mucosa and hepatocytes are particularly vulnerable. Also, because of strong immunosuppression, the patients receiving azathioprine become more susceptible to various infections as well as some premalignant and malignant conditions.[4],[5],[6],[7],[8] The majority of the studies related to long term use of azathioprine and its side-effects have been done in renal transplant recipients who have also been receiving some other immunosuppressive drugs like corticosteroids and/ or cyclosporine. Therefore some of the side-effects reported in these studies may have been augmented or actually caused by the other drugs. We studied the safety and toxicity of azathioprine in patients of airborne contact dermatitis who received the drug in varying regimens upto 3 years.

Materials and Methods

Forty-six patients, 35 males and 11 females between 30 and 75 years of age (mean age 45 years) having air-borne contact dermatitis for a period of 6 months to 20 years were included in this study. Diagnosis in each patient was confirmed by patch test. In all the patients, pretreatment hemoglobin, total leukocyte count, platelet count, liver and renal function tests, urinalysis, stools for occult blood, chest X-ray and electrocardiogram were done. Out of these 46 patients, 22 were given azathioprine in a dose of 50 mg twice a day orally for 6 months to 3 years (Group 1), 12 patients were given the drug in a dose of 50 mg once a day and 300 mg once in four weeks orally for a period of 4 months to 2.3 years (Group 3). Eleven patients in group 1,6 in group 2 and 8 patients in group 3 received betamethasone 0.5-2 mg per day orally also for a period of 2 to 44 weeks, 4 to 44 weeks and 3 to 32 weeks respectively. All the patients were evaluated clinically and biochemically every month. The monthly tests included hemoglobin, total leukocyte count, platelet count, blood sugar, liver and renal function tests. The other investigations were repeated every 3 months to look for any side-effects or any change in these parameters.

Results

Out of a total of 46 patients, only 2 (4.3%) patients had severe drug induced side-effects. The first patient had severe nausea, vomiting, pain abdomen, malaise, palpitations and fever after the every first dose. The second patient had fever, malaise, pain abdomen and jaundice after 6 months of therapy, diagnosed as drug induced hepatitis. The hepatitis resolved within 2 months after stopping the drug but reappeared within a week on restarting the drug in a dose of 50 mg daily. The first patient was in group 3 while the other patient belonged to group 1. Seventeen patients developed other milder side-effects which included cutaneous infections and infestations in 12 patients (furunculosis - 7, herpes labialis-1, herpes zoster-1, scabies-1, tinea corporis-2), pulmonary tuberculosis, acneform eruptions, oral ulcers, nausea, and pigmentation of nails in one patient each [Table - 1]. One patient had mild transient reduction in platelet count. Three other patients had raised serum transaminase levels, which were also transient and returned to normal levels after some time even while the drug was continued in the same dosage. Biochemical abnormalities were not detected in the other patients. The side-effects were not related to the age, sex, dose or the duration of azathioprine treatment.

Discussion

Azathioprine is one of the main immunosuppressive drugs used in dermatology.[1],[2],[3],[4],[5],[6],[7],[8],[9] A host of side-effects and complications like nausea, vomiting, abdominal pain, fever, hepatitis, bone marrow suppression, renal toxicity, diffuse alopecia, viral, bacterial, fungal and parasitic infections, various premalignant and malignant neoplasms have been attributed to its long-term use,[1],[4],[5],[6],[7],[8] though the drug on a long term basis has primarily been used in renal transplant recipients. Many dermatologists are conservative and overcautious in using this potentially useful and valuable drug in their day-to-day practice because of the fear of its side-effects. In our study of 46 patients who received the drug for 3 months to 3 years, only 2 patients developed significant side-effects where the drug had to be stopped. In one patient the side-effects affected the gastrointestinal system and in the other it caused hepatitis. The first patient had severe nausea, vomiting, pain abdomen, malaise, palpitations and fever after the first dose itself. In the second patient hepatitis developed after 6 months and resolved in two months after stopping the drug. However when the drug was restarted, though in a lower dose, the hepatitis appeared after one week of therapy and the drug had to be stopped. Three patients had transient rise in their serum transaminase levels which returned to normal levels after some time while they continued the drug in the same dosage. These patients did not have any clinical signs and symptoms. The rest of the patients had milder side-effects primarily of infective origin which were probably not directly attributable to the drug. These side-effects could have been occurred in a normal population also over the study period, or some of these could have been due to the corticosteroids which these patients were taking intermittently. Therefore we feel that azathioprine is a relatively safer drug with less side effects even on long term use. A few patients who develop major side-effects usually do so in the beginning of therapy and are easily detectable.

These patients can be easily treated with alternative drugs. We did not have any patient developing myelotoxicity which is reported to occur in a very small proportion of patients having lower level of enzyme TPMT[9],[10] Therefore it seems logical to use this potentially useful drug in corticosteroidresponsive dermatoses particularly in situations where corticosteroids are to be given for longer durations or if they are contraindicated. However we recommend a regular monitoring of these patients while on treatment. The only disadvantage of this drug is that it is a relatively expensive drug but this seems to be insignificant compared to its benefits.