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


CONCLUSIONS
In our experience, thiopurine therapy did not increase malignancies development in IBD patients, and was an effective and safe treatment for these diseases.
Inflammatory Bowel Disease Unit, Department of Gastroenterology, University Hospital Virgen de Las Nieves, 18014 Granada, Spain. mmrosarioes@yahoo.es
María
M
Gómez-García
Maria José
MJ
Cabello-Tapia
Antonio Damián
AD
Sánchez-Capilla
Javier
J
De Teresa-Galván
Eduardo
E
Redondo-Cerezo
D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000893:Anti-Inflammatory Agents / Q000009:adverse effects*; D001379:Azathioprine / Q000009:adverse effects*; D016009:Chi-Square Distribution; D002648:Child; D002675:Child, Preschool; D004359:Drug Therapy, Combination; D005260:Female; D005765:Gastrointestinal Agents / Q000009:adverse effects*; D006785:Hospitals, University; D006801:Humans; D015994:Incidence; D015212:Inflammatory Bowel Diseases / Q000188:drug therapy* / Q000453:epidemiology; D016015:Logistic Models; D008297:Male; D015122:Mercaptopurine / Q000009:adverse effects*; D008875:Middle Aged; D015999:Multivariate Analysis; D009369:Neoplasms / Q000139:chemically induced* / Q000453:epidemiology; D016017:Odds Ratio; D012189:Retrospective Studies; D018570:Risk Assessment; D012307:Risk Factors; D013030:Spain / Q000453:epidemiology; D055815:Young Adult
D000893:Anti-Inflammatory Agents; D005765:Gastrointestinal Agents; D015122:Mercaptopurine; D001379:Azathioprine
Azathioprine; Crohn’s disease; Inflammatory bowel disease; Malignancy; Mercaptopurine; Neoplasm; Thiopurines; Ulcerative colitis