Initiation Of Azathioprine Therapy Research Articles

Precision medicine for rheumatologists: lessons from the pharmacogenomics of azathioprine.

Precision medicine aims to personalize treatment for both effectiveness and safety. As a critical component of this emerging initiative, pharmacogenomics seeks to guide drug treatment based on genetics. In this review article, we give an overview of pharmacogenomics in the setting of an immunosuppressant frequently prescribed by rheumatologists, azathioprine. Azathioprine has a narrow therapeutic index and a high risk of adverse events. By applying candidate gene analysis and unbiased approaches, researchers have identified multiple variants associated with an increased risk for adverse events associated with azathioprine, particularly bone marrow suppression. Variants in two genes, TPMT and NUDT15, are widely recognized, leading drug regulatory agencies and professional organizations to adopt recommendations for testing before initiation of azathioprine therapy. As more gene-drug interactions are discovered, our field will continue to face the challenge of balancing benefits and costs associated with genetic testing. However, novel approaches in genomics and the integration of clinical and genetic factors into risk scores offer unprecedented opportunities for the application of pharmacogenomics in routine practice. Key Points • Pharmacogenomics can help us understand how individuals' genetics may impact their response to medications. • Azathioprine is a success story for the clinical implementation of pharmacogenomics, particularly the effects of TPMT and NUDT15 variants on myelosuppression. • As our knowledge advances, testing and dosing recommendations will continue to evolve, with our field striving to balance costs and benefits to patients. • As we aim toward the goals of precision medicine, future research may integrate increasingly individualized traits-including clinical and genetic characteristics-to predict the safety and efficacy of particular medications for individual patients.

57-Year-Old Man With Hip Pain and Lytic Bone Lesions

57-year-old man presented to his primary care physician with a 2-year history of progressive right hip pain. His medical history was notable for hyperlipidemia. He was up-to-date on sex- and agespecific cancer screening. The patient had no history of chest pain, palpitations, shortness of breath, cough, or other cardiac, respiratory, neurologic, or visual symptoms. He had no recent travel history or occupational or social contact with persons who were ill. Physical examination revealed an obese man (body mass index [calculated as weight in kilograms divided by height in meters squared], 40.34 kg/m 2 ) with normal vital signs and unremarkable findings on cardiac, respiratory, abdominal, neurologic, and lymphatic examination. No pain or tenderness was elicited on examination. He was treated initially with nonopioid pain medications. Sacroiliac corticosteroid injections were minimally beneficial. Results of a complete blood cell count (CBC) and electrolyte panel were normal with the exception of an elevated serum calcium level of 11.7 mg/dL (reference range, 8.9-10.1 mg/dL). Ultimately, magnetic resonance imaging (MRI) of his lumbar spine revealed numerous punched-out lytic lesions in the lumbar vertebra and pelvis. He underwent computed tomography (CT) of his chest, abdomen, and pelvis that identified further lytic lesions as well as multiple splenic lesions concerning for metastases. Two separate CT-guided bone biopsy samples of the lytic lesions in the lumbar vertebra did not elicit an etiology of the lesions.

The Use of Low-Dose Azathioprine in Patients with Vogt-Koyanagi-Harada Disease

Purpose: To evaluate treatment outcomes with low-dose azathioprine in Vogt-Koyanagi-Harada (VKH) disease patients. Design: Retrospective case series. Methods: Medical records of consecutive patients with VKH disease were reviewed. Azathioprine was administered in cases with corticosteroid intolerance or uncontrolled inflammation. Corticosteroid sparing effect, visual acuity, corticosteroid dose, and complication rates were evaluated. Results: Sixteen of 34 VKH patients included in this study underwent azathioprine therapy with systemic corticosteroid. Six patients received azathioprine in the acute uveitic phase and 10 patients in the chronic recurrent phase. A corticosteroid sparing effect was achieved in 86.5% of patients given azathioprine in the acute uveitic phase and 90.0% of patients given in the chronic recurrent phase. Median time to corticosteroid sparing effect was 3.5 months. Twelve of 16 patients showed improved activity in 1 month after initiation of azathioprine therapy. Conclusion: Low-dose azathioprine therapy may be effective as corticosteroid sparing agent in VKH disease.

Allelic variants of the thiopurine s-methyltranferase deficiency in patients with ulcerative colitis and in healthy controls

OBJECTIVE: Thiopurine S-methyltransferase (TPMT) is a cytosolic enzyme that catalyzes the inactivation of mercaptopurine, azathioprine, and thioguanine. The genetic polymorphisms in the TPMT gene that regulate TPMT activity are inherited as an autosomal recessive trait and patients with genetically determined low levels of TPMT activity develop severe myelosupression when treated with standard doses of the above-mentioned drugs. We have analyzed the frequencies of the allelic variants of the TPMT gene in a white European population of healthy blood donors from Spain and The Netherlands, and in a group of patients suffering from ulcerative colitis (UC) with a similar genetic background. METHODS: Two hundred and thirteen unrelated healthy individuals (HC) and 146 UC patients were typed for the polymorphic sites at positions 460 (G → A) and 719 (A → G) of the TPMT gene using specific polymerase chain reaction-restriction fragment-length polymorphism (PCR-RFLP) methods. RESULTS: There were no significant differences between the allele frequencies observed in the group of UC patients and those of the control group (10% of cases were heterozygous carriers of a TPMT mutant allele). The most frequent mutant allele in both UC and HC groups was TPMT3A (A 460 → G 719) (60% of carriers). TPMT3B (A 460 → A 719) and TPMT3C (G 460 → G 719) alleles were more often found in our study than in previously reported studies, reflecting the different genetic backgrounds of the European populations analyzed. CONCLUSIONS: Genotyping methods provide a simple and reliable screening to identify patients with a high risk of developing severe bone marrow toxicity if treated with thiopurine drugs. In UC patients, TPMT genotype should be determined before the initiation of azathioprine therapy.

Reversible cholestasis with bile duct injury following azathioprine therapy. A case report

A 67-year-old patient, with primary polymyositis and without previous evidence of liver disease, developed clinical and biochemical features of severe cholestasis 3 months after initiation of azathioprine therapy. Liver biopsy showed cholestasis with both cytological and architectural alterations of interlobular bile ducts. Azathioprine withdrawal resulted after 7 weeks in the resolution of clinical and biochemical abnormalities. It is believed that this is the first reported case of reversible azathioprine-induced cholestasis associated with histological evidence of bile duct injury.

Azathioprine and the liver: Evidence favoring idiosyncratic, mixed cholestatic-hepatocellular injury in humans

A patient with systemic lupus erythematosus developed jaundice and biochemical evidence of hepatic dysfunction 3 wk after initiation of azathioprine therapy. A liver biopsy specimen was obtained, and it showed canalicular cholestasis and centrilobular ballooning of hepatocytes. Clinical and serologic assessment excluded other causes of hepatic dysfunction, such as viral hepatitis, administration of other drugs, or worsening of the collagen disease and the patient was improved 2 wk after azathioprine was discontinued. This case adds further evidence that azathioprine is an idiopathic hepatotoxin with the potential for combined cholestatic and hepatocellular injury in humans.