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Does long term treatment with azathioprine predispose to malignancy and death in patients with systemic lupus erythematosus?
  1. P Nero1,
  2. A Rahman2,
  3. D A Isenberg2
  1. 1Unidade de Reumatologia, Hospital de Egas Moniz, Lisboa, Portugal
  2. 2Centre for Rheumatology, Department of Medicine, University College London, London, UK
  1. Correspondence to:
    Dr P Nero
    Hospital de Egas Moniz, R. da Junqueira, 126 Lisboa 1349-019, Portugal;

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The treatment of patients with rheumatic diseases with second line agents has expanded in the past three decades. However, such drugs have been linked with the development of malignancy, particularly in patients with rheumatoid arthritis.1 Azathioprine is used to treat patients with systemic lupus erythematosus (SLE) with renal disease, or as a steroid-sparing agent.2 We have assessed the risk that azathioprine treatment predisposes to the development of malignancies and death in patients with SLE.

We carefully reviewed the case notes of 358 patients with SLE receiving long term follow up in the Lupus Clinic at University College London, between 1978 and 2002, and assessed their treatment. Three hundred and twenty six (91.1%) patients were female and 32 (8.9%) male. One hundred and forty eight (41.3%) were treated at any time with azathioprine, while 210 (58.7%) never used this second line agent. The mean (SD) ages of the users and non-users were similar (40.5 (12.7) v 45.3 (13.2), respectively, which is not significant by χ2 test with 95% confidence intervals). The mean (SD) duration of azathioprine treatment was 3.8 (3.9) years (minimum of 6 months and maximum of 18 years). Most patients are alive (83.2%) and only a minority were lost to follow up (3.1%). Forty nine (13.7%) of our patients have died: 27/148 (18%) had received azathioprine and 22/210 (10%) had not. Eight of our patients prescribed azathioprine developed a malignancy (none had a lymphoma), whereas 14 not given azathioprine have done so (three had lymphomas: one non-Hodgkin and two Hodgkin). These differences are not statistically significant (χ2 test). However, the number of deaths in the azathioprine group which is almost double that in the other group does raise concerns, although it may simply be identifying a subgroup with more serious disease.

Table 1 shows the number of malignancies and death in patients with SLE treated with azathioprine, according to the duration of treatment.

Five of the patients who died were receiving azathioprine for <1 year, 10 for between 1 and 4 years, 11 for between 5 and 9 years, and 1 for >10 years. Five patients who developed malignancy were receiving azathioprine for between 1 and 4 years and 3 for between 5 and 9 years. The two patients lost to follow up had been receiving azathioprine treatment for 3 and 4 years at that time.

We have been unable to locate any publications examining azathioprine related complications in the treatment of patients with SLE. In rheumatoid arthritis and in Sjögren’s syndrome, however, it has been linked with lymphoma development.1 3 4

We conclude that although azathioprine seems to be a safe second line agent for the treatment of patients with SLE larger and longer term studies are needed to confirm these findings.

Table 1

Number of deaths and malignancy in patients with SLE treated with azathioprine

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