Thiopurines related malignancies in inflammatory bowel disease: local experience in Granada, Spain

Abstract

Aim: To investigate the incidence of neoplasms in inflammatory bowel disease (IBD) patients and the potential causative role of thiopurines.

Methods: We performed an observational descriptive study comparing the incidence of malignancies in IBD patients treated with thiopurines and patients not treated with these drugs. We included 812 patients which were divided in two groups depending on whether they have received thiopurines or not. We have studied basal characteristics of both groups (age when the disease was diagnosed, sex, type of IBD, etc.) and treatments received (Azathioprine, mercaptopurine, infliximab, adalimumab or other immunomodulators), as well as neoplasms incidence. Univariate analysis was performed with the student t test, χ(2) test or Wilcoxon exact test as appropriate. A logistic regression analysis was performed as multivariate analysis. Statistical significance was establish at P values of less than 0.05, and 95%CI were used for the odds ratios.

Results: Among 812 patients included, 429 (52.83%) have received thiopurines: 79.5% azathioprine, 14% mercaptopurine and 6.5% both drugs. 44.76% of patients treated with thiopurines and 46, 48% of patients who did not receive this treatment were women (P > 0.05). The proportion of ulcerative colitis patients treated with thiopurines was 30.3% compare to 66. 67% of patients not treated (P < 0.001). Mean azathioprine dose was 123.79 ± 36.5 mg/d (range: 50-250 mg/d), mean usage time was 72.16 ± 55.7 mo (range: 1-300 mo) and the accumulated dose along this time was 274.32 ± 233.5 g (1.5-1350 g). With respect to mercaptopurine, mean dose was 74.7 ± 23.9 mg/d (range: 25-150 mg/d), mean usage time of 23.37 ± 27.6 mo (range: 1-118 mo), and the accumulated dose along this time was 52.2 ± 63.5 g (range: 1.5-243 g). Thiopurine S-methyltransferase activity was tested in 66% of patients treated with thiopurines, among which 98.2% had an intermediate or high activity. Among the patients treated with thiopurines, 27.27% (112 patients) and 11.66% (50 patients) received treatment with Infliximab and Adalimumab respectively, but only 1.83% (7 patients) and 0.78% (3 patients) received these drugs in the group of patients who did not received thiopurines (P < 0.001 and P < 0.001 respectively). Finally, 6.8% (29 patients) among those treated with thiopurines have received other immunosuppressants (Methotrexate, Tacrolimus, Cyclosporin), compare to 1% (4 patients) of patients not treated with thiopurines (P < 0.001). Among patients treated with thiopurines, 3.97% developed a malignancy, and among those not treated neoplasms presented in 8.1% (P = 0.013). The most frequent neoplasms were colorectal ones (12 cases in patients not treated with thiopurines but none in treated, P < 0.001) followed by non-melanoma skin cancer (8 patients in treated with thiopurines and 6 in not treated, P > 0.05).

Conclusion: In our experience, thiopurine therapy did not increase malignancies development in IBD patients, and was an effective and safe treatment for these diseases.

Keywords: Azathioprine; Crohn’s disease; Inflammatory bowel disease; Malignancy; Mercaptopurine; Neoplasm; Thiopurines; Ulcerative colitis.

Figure 1

Types of neoplasms (n = 53). The most frequent neoplasms were non-melanoma skin cancer, colorectal cancer and haematological (lymphomas and leukaemia).

Figure 2

All the neoplasms, except for non-melanoma skin cancer, lymphomas and prostate, have been more common in patients not treated with thiopurines, however, significant differences have only been identified in colorectal and breast cancer. Non thiopurines vs thiopurines, ^bP value < 0.01 (OR = 0.96, 95%CI: 0.94-0.98); P value = 0.05 (OR = 0.99, 95%CI: 0.98-1).

Figure 3

There seem to be no statistically significant differences in the appearance of neoplasms in any of the locations, behaviours or ages of diagnosis of the patients with Crohn’s disease and ulcerative colitis in relation to thiopurines intake. A: Percentage of neoplasms according to Crohn’s disease (CD) subtype; B: Percentage of neoplasms according to ulcerative colitis (UC) subtype.