Azathioprine induced pancytopenia: A serious complication
V Hadda, BD Pandey, R Gupta, A Goel
Department of Medicine, All India Institute of Medical Sciences, New Delhi - 110 029, India
Department of Medicine, All India Institute of Medical Sciences, New Delhi - 110 029
Azathioprine is commonly used for treatment of lupus nephritis. Myelosuppression is known to occur with azathioprine, but severe pancytopenia is uncommon. A 23-year-old man with lupus nephritis was initially treated with intravenous cyclophosphamide pulses and oral prednisolone along with enalapril and frusemide. Following six months of cyclophosphamide, he was initiated on oral azathioprine as maintenance therapy. He subsequently returned with febrile neutropenia and severe bone marrow suppression. Fever responded to broad spectrum antibiotics and his counts gradually improved following granulocyte-macrophage colony stimulating factor. When last seen in October, he was symptom free and disease activity in control. We suggest that physicians remain sensitive to possibility of azathioprine induced severe bone marrow suppression. Frequent monitoring of blood counts is probably the best way to avoid this complication specially, where testing for thiopurine methyltransferase is not available.
|How to cite this article:|
Hadda V, Pandey B D, Gupta R, Goel A. Azathioprine induced pancytopenia: A serious complication.J Postgrad Med 2009;55:139-140
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Hadda V, Pandey B D, Gupta R, Goel A. Azathioprine induced pancytopenia: A serious complication. J Postgrad Med [serial online] 2009 [cited 2023 Oct 4 ];55:139-140
Available from: https://www.jpgmonline.com/text.asp?2009/55/2/139/52849
A 23-year-old man, presented with low grade fever, polyarthritis, oral ulcers, and alopecia for six months. Subsequently, he developed edema feet and a decrease in urine output. On examination, he was pale with a blood pressure of 156/96 mm of Hg. He had active synovitis and ascites. There was no skin rash or joint deformity. A presumptive diagnosis of active SLE was further supported by raised erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), and anti dsDNA antibodies. Blood urea and creatinine were normal. Urine showed 30-40 RBCs per high power field with 50% dysmorphic RBCs. Renal biopsy revealed membranous lupus nephritis with focal segmental proliferation (WHO class Vc). The patient received pulsed cyclophosphamide therapy along with oral prednisolone, enalapril, and frusemide.
Following six months of cyclophosphamide he was initiated on oral azathiaprine (100 mg/day) in the second week of January this year. He came back after 3 weeks with high-grade fever, dry cough, and headache. On examination, he was febrile. He had tachycardia and blood pressure was normal (122/80 mm of Hg). There was no lymphadenopathy, skin rash or external bleed. Blood investigations revealed severe pancytopenia [Table 1]. ESR was 80 mm in first hour by Westergren's method. His renal functions were deranged with urea of 87 mg/dl and creatinine of 1.8 mg/dl. Liver functions were normal. CRP, anti dsDNA antibodies, and urine examination did not indicate a flare of SLE activity. His bone marrow was found hypocellular with 10% cellularity. He was given broad spectrum antibiotics for neutropenic fever and azathioprine was discontinued. He received three doses of GM-CSF. Fever responded to treatment within a week and his counts gradually improved [Table 1]. After 19 days of hospitalization, he was discharged on prednisolone (20 mg/day), hydroxychloroquin, enalapril, losartan, amlodipine, and atenolol. In July, his blood counts were normal but active sediments in urine prompted us to initiate mycophenolate mofetil (500 mg twice daily). When last seen in October, he remains symptom free with disease activity in control.
Azathioprine is commonly used for management of lupus nephritis. Mild myelotoxicity is a common side effect of azathioprine, however, severe myelosuppression leading to pancytopenia is uncommon. In patients with inflammatory bowel disease, it is reported in 0.4-2% cases treated with azathioprine.  Bone marrow suppression by azathioprine have also been reported in other autoimmune disorders. , Others have reported cases presenting with pancytopenia within weeks to months of azathioprine, used in the range of 1-2 mg/kg/day. ,
The metabolism of azathioprine is now better understood. In vivo , it is converted, non-enzymatically, to 6-mercaptopurine. Further metabolism of this drug involves various enzymes like, hypoxanthine guanine phosphoribosyl transferase (HGPRT), thiopurine methyltransferase (TPMT), and xanthine oxidase (XO). HGPRT is responsible for its bio-activation and converts it to 6-thioinosine 5-monophosphate which is further metabolized to 6-thioguinine nucleotides (6-TGNs). 6-GTNs get incorporated into DNA and RNA and are possibly, responsible for cytotoxic effect. Another mechanism suggested involve 6-GTNs binding to GTPase Rac 1 leading to activation of mitochondrial pathway of apoptosis in CD3 and CD28 co-stimulated T-cells.  Both XO and TPMT are catabolic enzymes involved in clearance of thiopurines. Xanthine oxidase is inhibited by allopurinol and concurrent administration of both allopurinol and azathioprine can lead to enhanced azathioprine toxicity. TPMT-dependent catabolism is critical, as low TPMT activity may lead to enhanced cytotoxicity. TPMT is governed by a genetic polymorphism and is responsible for the differential susceptibility to myelosupression. , Patients with TPMT allele homozygous for the low activity are extremely susceptible to acute myelotoxicity with thiopurine drugs. Researchers have shown that 0.3-0.45% of subjects with varied medical conditions have low or undetectable erythrocyte TPMT. , Konstantopoulou et al. , subsequently, described azathioprine induced pancytopenia related to deficiency of TPMT.  Gardiner and colleagues could avoid myelosuppression by decreasing dose (25 mg/day) of azathioprine in TPMT deficient patient and they advocated TPMT screening prior to therapy.  TPMT screening has been advocated by other authors also.  However, it has been shown that TPMT mutations may not predict all cases of myelosupression.  Furthermore, in absence of data regarding levels of TPMT in our population making inference regarding activity would be hazardous. Kham et al. described that 0.8% of Indian children with acute lymphoblastic leukemia were carrying TPMT*3C mutations, associated with low activity of enzyme.  However, TPMT status in normal subjects and those with SLE is not yet known. Screening of every patient for TPMT mutations before starting azathioprine may be recommended in developed nations where prevalence of mutations are high and facility for testing is easily available. Notwithstanding the suggestion that as the estimated cost of management of patients with pancytopenia during hospital stay may be quite high (£9100), good for at least 430 tests for TPMT enzyme activity (~ £21 each), it would be justified to offer testing to every patient before starting azathioprine,  it may still not be applied to our population not only because the facility remains routinely unavailable (as in our case) but also the status of this mutation among Indian population is not known. Furthermore, certain drugs like diuretics (frusemide), non-steroidal anti-inflammatory drugs, angiotensin-converting enzyme inhibitors, etc. may inhibit TPMT activity and may contribute to enhanced toxicity of azathioprine. , Also, genetic variation of other enzymes metabolizing thiopurines is also likely to be important for toxicity. Monitoring of levels of these metabolites, e.g. 6-GTN, may be proposed, however, facility is limited. Therefore, frequent blood counts monitoring is cheap and probably the best way to avoid this complication. We monitor patients with blood counts every 2 weeks until dose is stabilized and then 1-3 monthly as suggested by Indian Rheumatology Association. 
Our patient represents a probable case of azathioprine induced severe myelosuppression with adverse drug reaction probability score of six.  Physicians should remain sensitive to the possibility of severe bone marrow suppression when initiating immunosupprssion with azathiaprine. It is possible to predict bone marrow suppression using TPMT testing, however, this facility is limited. Therefore, frequent monitoring of blood counts is the best way to avoid this complication in our setting.
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