The evidence for the efficacy of the AZA is growing in the treatment of ocular symptoms in BD; therefore, AZA is one of the most common immune modulator drugs in the treatment of Ocular Behçet’s today. The potential risk of severe adverse effects has limited the use of AZA on a large scale . In previous trials on inflammatory bowel disease (IBD) patients, AZA discontinuing is more common in comparison with placebo because of adverse effects . However, there are limited studies on adverse events of AZA in patients with Ocular Behçet’s.
Here, we examined a well-defined population of ocular Behçet’s patients, treated in the outpatient clinic of BD of a referral center for autoimmune diseases.
Azathioprine is widely used as the systemic drug of the first choice in most of the literature in ocular Behçet’s with the advised dosage of 2.5 mg/kg body weight . In our center, the typical initial dose for AZA in practice would be 2–3 mg/kg/d, which is a relatively comparable dose with the current advised dose for AZA of 2.5 mg/kg body weight . Despite the adequate initial dose, 11 out of 165 patients (6.67%) were shown adverse effects due to AZA. The AZA was discontinued in 5 patients and re-administrated in 2 ones. All side effects were resolved after decreasing the dose of the drug or its discontinuation. However, our findings showed a lower rate of AZA side effects in enrolled patients that might be due to the administration of the minimum dosage of the drug to control the patients' ocular manifestations. Besides, patients were followed up meticulously in our study that helped to adjust drug dosage and consumption by patients considering the patients' signs and symptoms and ceasing it after resolving the disease.
A previous multi-center study in 145 patients starting AZA for non-infectious ocular inflammation found that AZA is a relatively effective therapy in patients with active ocular inflammation who need a corticosteroid-sparing agent; however, some patients will not respond to treatment or develop side effects at a rate of 0.16/person-year. Treatment-limiting side effects seen in around one-fourth of patients within one year, but usually were modifiable, which is more than our study. .
We did not observe all potential side effects of AZA in the present study. Previously mentioned adverse events in the literature included gastrointestinal upset, bone marrow suppression, elevated liver enzymes, infection, and allergy . Myelosuppression is a potentially lethal complication in treatment with AZA . A blood profile has been reviewed in all of our ocular Behçet’s patients. Whereas, Serum hemoglobin levels, leukocyte, and platelet counts were monitored before and after the onset of therapy. We observed severe leukopenia in only two patients (WBC count < 3 * 106/ml) without clinical symptoms such as infections. The leukocyte count was corrected after the temporary discontinuation of AZA in both patients, while other patients exhibited average levels for leukocyte count. The recently described leukopenia might be the effect of AZA; however, it might also be related to decreased disease activity or dosage of concomitant drugs. None of our patients represented thrombocytopenia during AZA therapy. Colombel and his team  found that myelosuppression during azathioprine therapy seen in twenty – seven percent of patients who had mutant alleles of the thiopurine methyltransferase (TPMT) gene but more often caused by other factors.
A complex multi-step pathway is involved in the metabolism of thiopurines. The key enzyme in this pathway is TPMT, which participates in the inactivation of thiopurines. Genetic heterogeneity of the TPMT enzyme leads to low/absent enzyme activity in 0.3% of individuals and intermediate activity in 10% of individuals . It was not possible for us to test patients for TPMT activity before starting treatment with thiopurines. We suggest checking the blood profile and liver enzyme tests before starting the AZA and repeating both in a period of treatment to minimizing the adverse effects of the drug such as the risk of leukopenia and liver injury. The regular laboratory tests could be applied in patients who suffer primary hematological disorders or hepatic diseases and have an altered level of the blood cells or liver enzymes, in addition to patients who have had previously consumed other immunosuppressive agents. Moreover, the role of TPMT in other adverse effects is yet to be known, and myelosuppression is commonly caused by other factors .
Previous studies implicated the potential role of AZA in the induction of malignancies. The role of Thiopurines has been confirmed in the occurrence of malignant lymphoma and non-Hodgkin lymphoma in patients with rheumatoid arthritis, solid organ transplantation, and IBD [17–19]. In the present study, a case of basal cell carcinoma was observed. Lewis and his team confirmed that the benefits of AZA in IBD patients outweigh the possible risk of lymphoma . Altogether, whether or not AZA poses the risk of neoplasia, remains controversial due to the doses used to treat IBD or other diseases .
Reports of fever, rigors, arthralgias, and myalgias are recorded in patients with cardiac transplants in whom Azathioprine has been recently initiated . Here we reported two cases of high fever, chills, nausea, and arthralgia after Azathioprine administration. A hypothesis by Korteliz et al  described that some concomitant drugs might interfere with AZA. Corticosteroids decrease allergy-based adverse effects; however, they prevent leucopenia.
Our study was of some limitations. First, we could not evaluate the interaction of the different concomitant medications on the development of AZA side effects, which might have led to a bias in our observations. Second, we did not have a control group to compare the outcomes of the patients between groups.