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Summary

  1. Top of page
  2. Summary
  3. introduction
  4. Methods
  5. Results
  6. Discussion
  7. References

Background and aim : Data from renal transplant and rheumatoid arthritis patients suggest that there is an increased risk of malignancy after treatment with azathioprine. Whether this is true for patients with inflammatory bowel disease remains uncertain.

Method : A retrospective review of clinical notes was performed.

Results : Azathioprine was given to 626 of 2204 patients (855 with Crohn's disease and 1349 with ulcerative colitis). The mean total duration of azathioprine use was 27 months. The mean follow-up from diagnosis was 13.7 years and the mean follow-up from the start of azathioprine treatment was 6.9 years. Thirty-one cancers were observed in 30 patients treated with azathioprine (4.5%) and 77 cancers were observed in 70 patients not treated with azathioprine (4.5%; P=N.S.). Logistic regression analysis (including in the model the age, sex, diagnosis and extent of disease) showed that treatment with azathioprine did not significantly affect the risk of the development of cancer. Eight patients had lymphoma; three had been given azathioprine (P=N.S.). For patients with ulcerative colitis, the number of colorectal cancers (including high-grade dysplasia) in patients given azathioprine was eight of 355 (2.2%), compared with 28 of 994 (2.8%) for patients not given azathioprine (P=N.S.). The cumulative risk of colorectal cancer or dysplasia/dysplasia-associated lesion or mass (adjusted to exclude post-colectomy patients) after 10, 20, 30 and 40 years ofulcerative colitis was 0.4%, 1.3%, 9%and 15.5%, respectively.

Conclusion : No increased risk of cancer diagnosis following azathioprine treatment was observed.


introduction

  1. Top of page
  2. Summary
  3. introduction
  4. Methods
  5. Results
  6. Discussion
  7. References

Azathioprine and the metabolite 6-mercaptopurine have been widely used for both Crohn's disease and ulcerative colitis since the 1960s.1–3 These drugs are now being used more frequently for both types of inflammatory bowel disease and for an increasing duration. Azathioprine is effective for maintaining remission for at least 4 years,4 but enthusiasm for a longer treatment duration is tempered by the uncertainty regarding the risk of inducing malignant disease.

Follow-up data from renal transplant recipients suggest an increased risk of malignancy. This is most apparent for skin cancers, but has also been observed for non-Hodgkin's lymphoma and other solid tumours.5 The Australian and New Zealand renal transplant registry has reported a 10 times relative risk of lymphoma (confidence interval (CI), 6.7–11.0).5 The incidence of tumours appears to increase significantly after 10 years of azathioprine treatment (3.9% at 10 years, increasing to 13.9% at 20 years).6 This increase in malignancy is predominantly due to an increased incidence of skin cancers. In one study, the relative risk of developing skin cancers, but not other malignancies, increased from 6.6 at 5 years to 20 after > 15 years.7

There have been several large follow-up studies of patients with rheumatoid arthritis treated with immunosuppressive drugs which have shown an increased risk of malignancy, particularly lymphoma.8–10 A matched cohort study showed a small increase in mortality in patients who had been exposed to immunosuppressive treatment compared to the unexposed cohort. Most of the excess deaths were due to malignancy. The relative risk of developing malignancy was 1.5 (95% CI, 0.9–2.3). The relative risk of developing lymphoma in the immunosuppressive-exposed group was 7.0 (95% CI, 0.9–56.5).8 A study of 1773 patients with rheumatoid arthritis from 15 European countries treated with immunosuppressive drugs, with 12 266 person-years of follow-up, showed an age- and sex-adjusted relative risk of 3.74 (CI, 1.5–9.5) for developing a neoplasm of the immune system, skin and bladder. A similar pattern was seen when the analysis was confined to azathioprine.9 A study of 1600 patients with rheumatoid arthritis treated with azathioprine showed six cases of non-Hodgkin's lymphoma compared with an expected number of 0.55.10

Only two hospital clinics have published long-term follow-up data of inflammatory bowel disease patients treated with azathioprine or the metabolite 6-mercaptopurine to determine the risk of malignancy. In a study of 755 patients followed for a median of 9 years from the start of azathioprine treatment, 31 malignancies were observed compared with an expected number of 24.3 (predicted by national mortality rates for the same age and sex distribution).11 The median duration of azathioprine treatment was 12.5 months. The excess of malignancies was accounted for by the known increased risk of colorectal cancer in ulcerative colitis (13 colorectal and two anal tumours compared to an expected number of 2.27; this difference was highly significant). In an extension to this study, 86 patients with total colitis diagnosed for over 10 years, who had been exposed to azathioprine, were compared with 180 disease-matched controls. There was no increased risk of colorectal malignancy for patients treated with azathioprine (the relative risk was 30.8 in the azathioprine-treated patients and 23.8 in non-treated patients). The conclusion from this study was that the colorectal cancer risk was related to the duration of disease but not to the use of azathioprine. In a study of 550 patients treated with 6-mercaptopurine for a mean of 5 years (range, 5 months to 22 years), 25 developed a neoplasm; eight were colorectal cancers.12 Two patients with Crohn's disease developed non-Hodgkin's lymphoma and one patient was diagnosed with leukaemia.

The aim of this study was to extend our knowledge of the potential risk of malignancy from treatment with azathioprine by studying a large, stable, clinic population. The unexposed inflammatory bowel disease clinic population was chosen as the most relevant control group.

Methods

  1. Top of page
  2. Summary
  3. introduction
  4. Methods
  5. Results
  6. Discussion
  7. References

The notes of patients attending the Inflammatory Bowel Disease Clinic at the John Radcliffe Hospital were reviewed. The information was recorded directly into an Access database. Patients were excluded if referred for a tertiary opinion or referred with the intention of early surgery. Patients were included only if they had attended the Inflammatory Bowel Disease Clinic for routine follow-up for at least 1 year. Patients with cancer diagnosed before azathioprine was given were included in the ‘azathioprine not given’ group. Patients with high-grade dysplasia or dysplasia-associated lesion or mass were included in the colorectal cancer data because of their high risk of developing cancer. Left-sided colitis was defined as colitis extending beyond the rectum but not past the splenic flexure. Total colitis was defined as colitis extending beyond the hepatic flexure. Data for colitis beyond the splenic flexure but not beyond the hepatic flexure were combined with ‘total colitis’ for some analyses. The extent of disease was defined as the maximum recorded macroscopic extent at colonoscopy. For the life-table analysis of the cumulative risk of colorectal cancer, patients who had undergone a colectomy were excluded from further follow-up analysis given that the risk of developing colorectal cancer had been eliminated.

Statistical analysis was performed using SAS version 8.1; t-tests and chi-squared tests were used to investigate the differences in demographics and diagnoses between patients who had or had not received azathioprine. Logistic regression was used to investigate the differences in the proportions of patients diagnosed with cancer (all cancers and specific cancers) between patients who had or had not received azathioprine. The age at diagnosis of inflammatory bowel disease, time since diagnosis, type of inflammatory bowel disease and gender were included in the model. For all cancers, and also for colorectal cancer, further separate logistic regressions were performed on patients with ulcerative colitis and Crohn's disease (in particular, to investigate the effect of the site/extent of the disease). The influence of the duration of azathioprine treatment on the risk of developing cancer was assessed by the Mann–Whitney U-test. The influence of azathioprine and other variables (gender, extent of disease) on the time to the development of colorectal cancer was examined by the Cox proportional hazards model.

Results

  1. Top of page
  2. Summary
  3. introduction
  4. Methods
  5. Results
  6. Discussion
  7. References

The clinical notes of 2204 patients were reviewed. Azathioprine treatment had been given to 626 patients (Crohn's disease, 271 patients; ulcerative colitis, 355 patients; Table 1). The mean follow-up from diagnosis was 13.5 ± 9.3 years (8423 patient-years), and the mean duration of follow-up from the start of azathioprine treatment was 6.9 ± 5.5 years (4319 patient-years). The mean total duration of treatment was 27.1 ± 32.1 months (range, 1–222 months). The patients given azathioprine are compared with those not given azathioprine in Table 1. Azathioprine was more likely to have been given for colonic Crohn's disease rather than small bowel disease and for ulcerative colitis beyond the splenic flexure rather than left-sided colitis. Patients given azathioprine had a younger age at diagnosis. The follow-up duration for the treated and untreated groups was not significantly different.

Table 1.  Disease type, disease distribution and follow-up data for patients who had or had not received azathioprine
 Azathioprine givenNot givenSignificance
  • *

    Ten patients not able to be classified according to disease site.

Male : female292 : 335741 : 837N.S.
Diagnosis
 Crohn's disease271 (43%)584 (37%) 
 Ulcerative colitis355 (57%)994 (63%)0.006
Mean age at diagnosis (years)31.9 ± 14.935.1 ± 15.40.0001
Mean duration of follow-up (years)13.513.7N.S.
Crohn's disease
 Colon ± small bowel168 (62%)294* (52%) 
 Small bowel only103 (38%)280 (48%)0.0001
Ulcerative colitis
 Colitis beyond splenic flexure134 (38%)294 (30%)0.0001
 Left-sided colitis165 (46%)332 (33%) 
 Rectum56 (16%)368 (37%) 

The main cancer subgroups for azathioprine-treated and untreated patients are shown in Table 2 stratified according to age group. The details of the cancer diagnoses classified as ‘other’ are listed in Table 3. Six patients had a cancer diagnosis prior to starting azathioprine and were included in the untreated group. The types of malignancy were similar in the treated and untreated patients (Tables 2 and 3). Thirty-one cancers were observed in 30 patients treated with azathioprine (4.5%) and 77 cancers were observed in 70 patients not treated with azathioprine (4.5%; P = N.S.). Logistic regression analysis (including age at diagnosis, time since diagnosis, sex, disease type and location) showed that there was no effect of azathioprine treatment on the rate of all cancers (P = 0.2) or on the rate of any of the cancer subgroups (colorectal cancer, bronchial cancer, breast cancer and lymphoma; P = 0.8, 0.9, 0.5, 0.5, respectively). The analysis for colorectal cancer was performed separately for ulcerative colitis and Crohn's disease. There was no evidence that azathioprine treatment caused any difference in the proportion of patients with colorectal cancer (ulcerative colitis, P = 0.4; Crohn's disease, P = 0.5).

Table 2.  Main types of cancer diagnosis according to treatment given and stratified by age at cancer diagnosis
 CRCDysplasia/DALMBreastLymphomaBronchialSkinRenal Other* 
Age groupANAANAANAANAANAANAANAANATotal
  1. CRC, colorectal cancer; DALM, dysplasia-associated lesion or mass; A, azathioprine given; NA, azathioprine not given.

  2. * Cancer subtypes included in the ‘other’ category are shown in Table 3 .

15–19      1        12
20–24                0
25–29  1    1       13
30–341      1        2
35–39 21           216
40–44 4 1 21        412
45–4922 113   1 1   415
50–54 1 21211   12   11
55–59131 1       1   7
60–6413 3 2 1   11 2216
65–69151    1 2 1  1113
70–7411 11   1 12   210
75–79 2 11          610
80–84                0
85+              1 1
Total723495935131640622108
Table 3.  Other types of cancer not included in Table 2
 Azathioprine givenAzathioprine not given
Astrocytoma 1
Bladder 1
Chronic lymphatic leukaemia 1
Cholangiocarcinoma14
Gastric 1
Laryngeal 2
Mucoepidermal1 
Myelodysplasia 2
Ovarian2 
Pancreas 3
Prostate1 
Sarcoma 3
Squamous cell — oral cavity11
Testis 2
Thymic 1
Total622

The cancer diagnoses according to the duration of azathioprine treatment are shown in Table 4. The duration of azathioprine treatment was not significantly different between patients with or without a diagnosis ofmalignancy (Mann–Whitney U-test, P = 0.46). There were five cancers in the 80 patients treated with azathioprine for more than 5 years. One patient developed a colorectal cancer after 31 years of colitis. One patient developed a renal cell cancer after 5 years of treatment and a 76-year-old woman developed breast cancer after 10 years of treatment. Two other patients had lymphoma and are described in more detail in Table 5 (patients 1 and 3). There were four patients with renal cell carcinoma (Table 2). All of these patients had received azathioprine (durations of treatment for these four patients were 4, 12, 49 and 67 months). There was no excess of skin tumours. Eight patients had malignancy of the immune system. The details of these patients are outlined in Table 5.

Table 4.  Cancer diagnosis related to the duration of azathioprine treatment. There was no significant difference in the rate of cancer diagnosis according to the duration of treatment
 Duration of azathioprine treatment 
 0–24 months25–60 months> 60 monthsTotal
  • *

    Six patients were excluded from the analysis as azathioprine was given after cancer diagnosis.

Cancer diagnosis19 (5.3%)7 (4.4%)5 (6.6%)31 (in 30 patients)
No cancer diagnosis35815775590
Total37616480620*
Table 5.  Clinical details of eight patients with a diagnosis of lymphoma
PatientAge (years) at diagnosis of IBDSexType of IBDAzathioprine givenDuration of treatment (months)Age (years) at diagnosis of lymphomaHistologyNotes /Follow-up
  • C, Crohn's disease; IBD, inflammatory bowel disease; MALToma, tumour of ‘mucosa-associated lymphoid tissue’; RA, rheumatoid arthritis; UC, ulcerative colitis.

  • *

    Diagnosis of lymphoma prior to diagnosis of ulcerative colitis.

132MUCYes7243MALToma of the sigmoid colonAlso had RA; sigmoid colectomy – no recurrence after 5 years
215MUCYes419Hodgkin'sDied during treatment
331FUCYes9452Follicular  lymphomaCompleted chemotherapy
431MUCNo 26*Hodgkin'sDied from anaplastic sarcoma 21 years later
553FUCNo 63Non-Hodgkin'sDied from recurrent disease 14 years later
650MCNo 69Lymphoma  (type not known)Alive after 10 years of follow-up
717MUCNo 31Hodgkin'sDied from cholangiocarcinoma  15 years later
825MUCNo 54Non-Hodgkin's  (low-grade)Remission on  chlorambucil  (follow-up 3 years)

For patients with ulcerative colitis who had been given azathioprine, the observed numbers of colorectal cancers (including patients with dysplasia-associated lesion or mass and high-grade dysplasia) were four of 134 (3.0%) for colitis beyond the splenic flexure and four of 165 (2.4%) for left-sided colitis. For patients who had not been given azathioprine, the observed numbers of colorectal cancers were 18 of 294 (6.1%) and 10 of 333 (3.0%) for colitis beyond the splenic flexure and left-sided colitis, respectively (Table 6). No cancers were observed in patients with proctitis only. Azathioprine treatment was not a significant covariate for the risk of colorectal cancer (Figure 1). The risk of colorectal cancer was higher for males (P = 0.004). The cumulative risks of colorectal cancer (including dysplasia and dysplasia-associated lesion or mass) after 10, 20, 30 and 40 years of colitis were 0.5%, 1.3%, 2.4% and 7.6%, respectively. The cumulative colectomy rates at 10, 20, 30 and 40 years were 9.5%, 16%, 27% and 34%, respectively. After adjusting to exclude patients from the analysis after a colectomy, the cumulative risks were 0.4%, 1.3%, 9% and 15.5% at 10, 20, 30 and 40 years, respectively.

Table 6.  Colorectal cancer (including high-grade dysplasia and dysplasia-associated lesion or mass) for patients with ulcerative colitis according to extent of disease
 Azathioprine givenAzathioprine not given
 CancerDysplasiaTotalCancer/dysplasia (%)CancerDysplasiaTotalCancer/dysplasia (%)
  • *

    There was no significant difference in the proportion of patients with colorectal cancer (including dysplasia) between those who did and did not receive azathioprine.

Colitis beyond221343.01172946.1
 splenic flexure
Left-sided221652.4823323.0
Rectum00560003680
Total443552.2*1999942.8*
image

Figure 1. The proportion of patients with inflammatory bowel disease (IBD) (data for ulcerative colitis and Crohn's disease combined) without colorectal cancer or high-grade dysplasia/dysplasia-associated lesion or mass related to the duration of disease. There was no significant difference in the risk of colorectal cancer between patients who had or had not received azathioprine. Treatment: dotted line, azathioprine given; dashed line, azathioprine not given.

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Seven patients with Crohn's disease had colorectal cancer; three had been given azathioprine prior to cancer diagnosis. All patients had colonic Crohn's disease. The sites of colorectal cancer were the rectum (four patients; only one had severe peri-anal disease), splenic flexure, hepatic flexure and caecum. When compared with ulcerative colitis, the risk of developing colorectal cancer was significantly lower for Crohn's disease (P = 0.02). The risk of developing colorectal cancer for Crohn's disease patients with extensive colonic involvement (patients with ‘proctitis only’ or ‘ileo-caecal involvement only’ excluded from the analysis) was not significantly different from that for patients with ulcerative colitis (P = 0.11).

Discussion

  1. Top of page
  2. Summary
  3. introduction
  4. Methods
  5. Results
  6. Discussion
  7. References

This is a hospital-based retrospective review of malignancy and inflammatory bowel disease. The potential selection bias of a hospital-based study was reduced by only including patients who were attending the clinic as their primary point of follow-up. The advantage of this study is the use of the non-treated inflammatory bowel disease patients as a control group. The potential effects of age at diagnosis, age at follow-up, type of inflammatory bowel disease and the extent and location of disease were adjusted for using logistic regression analysis. Our data are similar to the results of two other large clinical-based series that have shown no increased risk of malignancy for patients treated with azathioprine or 6-mercaptopurine.11, 12 This series is unique given the large number of patients with ulcerative colitis treated with azathioprine. This study, and the two others, have also shown that there is no increase in the risk of developing colorectal cancer for patients with ulcerative colitis after exposure to azathioprine.11, 12 The mean duration of treatment in this study was 27 months; conclusions cannot be made on the cancer risk for longer mean durations of treatment.

Colorectal cancer made up 38% of the total malignancies observed. The risk of developing colorectal cancer increases with the duration of disease, but is not affected by azathioprine treatment (Figure 1). The overall risk of colorectal cancer in this study is low compared with many other series, although there is a wide range in the reported cumulative risk for colorectal cancer.13 Studies from many different regions have all shown no increased risk of colorectal cancer for patients with proctitis.14 An earlier study from Oxford of 624 ulcerative colitis patients who were seen between 1938 and 1962 reported 22 colorectal cancers.15 This overall incidence is similar to that of this series, with 23 colorectal cancers in 926 patients with ulcerative colitis (proctitis excluded). The Oxford data have also been reported combined with data from Birmingham and Stockholm. Patients with a cancer diagnosis within 1 year of referral were excluded in an attempt to correct for referral bias. The cumulative cancer rate for the three centres for ‘extensive colitis’ was 7.2% at 20 years and 16.5% at 30 years.16

The risk of cancer in colonic Crohn's disease has been debated. Our study, and also two recent studies, suggest that the risk of colorectal cancer is similar to that of ulcerative colitis if an appropriate comparison is made.17–19 Gillen et al. studied 125 patients with extensive Crohn's colitis compared with 486 patients with extensive ulcerative colitis. The cumulative risk of colorectal cancer was 8% at 22 years for Crohn's disease and 7% at 20 years for ulcerative colitis.17 The risk of colorectal cancer was not increased by azathioprine treatment, although the numbers were too small to make a definite conclusion. Goldstein et al. reviewed 151 patients with extensive Crohn's colitis of more than 10 years' duration, who had been treated with at least 1 month of 6-mercaptopurine. They found only two colorectal cancers (1.4%).19

There is increasing interest in the inherent risk of lymphoma with inflammatory bowel disease and the potential impact of immunosuppressive treatment including azathioprine (and, more recently, treatment with chimeric antitumour necrosis factor antibodies). Studies of the risk of lymphoma in patients with inflammatory bowel disease have given mixed results.20–22 A large study from the UK using general practice databases has shown no increased risk.20 A study of five large inflammatory bowel disease clinics in North America found five patients with lymphoma.21 This gave an observed incidence of 104 per 100 000 compared with an expected incidence of 15.5 per 100 000. They were all extra-intestinal non-Hodgkin's lymphomas, but none of the patients had received immunomodulatory treatment. An Italian study has shown an increased risk of Hodgkin's disease in patients with ulcerative colitis (standardized incidence ratio of 8.6; CI, 2.8–20.1), but no difference in the risk of developing non-Hodgkin's disease.22 There are very few data on the possible increased risk of lymphoma with azathioprine treatment. This study did not show any increased risk of lymphoma with treatment. Data from two other large clinic-based studies showed no lymphomas in 755 azathioprine-treated patients and two lymphomas in 550 patients treated with 6-mercaptopurine.11, 12 A study of 782 patients with inflammatory bowel disease from Ireland showed four patients with lymphoma, all of whom had received immunosuppressive treatment.23 A 15-year review from the Mayo Clinic found 18 patients with lymphoma. In situ hybridization was performed using DNA probes specific for Epstein–Barr virus genomes. Five of the seven lymphomas positive for Epstein–Barr virus were found in patients treated with azathioprine or 6-mercaptopurine. The authors concluded that there may be a small increased risk of Epstein–Barr virus-positive lymphomas in treated patients.24 The number of cases with lymphoma in all of these studies is too small to make definite conclusions regarding the underlying risk of lymphoma with inflammatory bowel disease and the effect of immunosuppressive treatment.

In summary, no increase in the risk of cancer (colorectal cancer or other tumours) was observed with azathioprine treatment given to patients with ulcerative colitis or Crohn's disease.

References

  1. Top of page
  2. Summary
  3. introduction
  4. Methods
  5. Results
  6. Discussion
  7. References
  • 1
    Present DH, Korelitz BI, Wisch N, et al. Treatment of Crohn's disease with 6-mercaptopurine. A long-term randomised double-blind study. N Engl J Med 1980; 402: 9817.
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    Pearson DC, May GR, Fick GH, Sutherland LR. Azathioprine and 6-mercaptopurine in Crohn's disease. A meta-analysis. Ann Intern Med 1995; 123: 13242.
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    Present DH, Meltzer SJ, Krumholtz MP, Wolke A, Korelitz BI. 6-Mercaptopurine in the management of inflammatory bowel disease: short and long-term toxicity. Ann Intern Med 1989; 111: 6419.
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    Gyde SN, Prior P, Allan RN, et al. Colorectal cancer in ulcerative colitis: a cohort study of primary referrals from three centres. Gut 1988; 29: 20617.
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    Gillen CD, Walmsley RS, Prior P, et al. Ulcerative colitis and Crohn's disease: a comparison of the colorectal cancer risk in extensive colitis. Gut 1994; 35: 15902.
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    Ekbom A, Helmick C, Zack M, Adami HO. Increased risk of large bowel cancer in Crohn's disease with colonic involvement. Lancet 1990; 336: 3579.
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    Goldstein ES, Marion JF, Wheeler S, Present DH. 6-mercaptopurine: does it increase or decrease the risk of colon cancer in Crohn's disease. Gastroenterology 1998; 114: A986 (Abstract).
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    Lewis JD, Billker WB, Brensinger C, Deren JJ, Vaughn DJ, Strom BL. Inflammatory bowel disease is not associated with an increased risk of lymphoma. Gastroenterology 2001; 121: 123942.
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    Masel SL, Hanauer SB. Increased association of lymphoma and inflammatory bowel disease. Gastroenterology 2000; 118(Suppl. 2): A119(Abstract).
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    Palli D, Trallori G, Bagnoli S, et al. Hodgkin's disease risk is increased in patients with ulcerative colitis. Gastroenterology 2000; 119: 64753.
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    Farrell RJ, Ang Y, Kileen P, et al. Increased incidence of non-Hodgkin's lymphoma in inflammatory bowel disease patients on immunosuppressive therapy but overall risk is low. Gut 2000; 47: 5149.
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    Dayharsh GA, Loftus EV, Sandborn WJ, et al. Epstein–Barr virus positive lymphoma in patients with inflammatory bowel disease treated with azathioprine or 6-mercaptopurine. Gastroenterology 2002; 122: 727.