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Incident Infectious and Malignant Adverse Event Risk is Lower Using Methotrexate Compared to Thiopurines in Crohn’s disease.

Chen DD, Waljee AK, Govani SM, Higgins P, Stidham RW. Incident Infectious and Malignant Adverse Event Risk is Lower Using Methotrexate Compared to Thiopurines in Crohn’s disease. Poster session presented at: Digestive Disease Week Annual Conference; 2015 May 16; Washington, DC.


Incident Infectious and Malignant Adverse Event Risk is Lower Using Methotrexate Compared to Thiopurines in Crohn's disease View Session Detail Presentation Number: Sa1128 Author Block: Dennis D. Chen2 , Akbar K. Waljee3,1 , Shail M. Govani1,3 , Peter Higgins1 , Ryan W. Stidham1 1 Internal Medicine, Division of Gastroenterology and Hepatology, University of Michigan, Ann Arbor, Michigan, United States; 2 Internal Medicine, University of Michigan, Ann Arbor, Michigan, United States; 3 Health Services Research and Development Center for Clinical Management Research, Veteran Affairs Medical Center, Ann Arbor, Michigan, United States Abstract: BACKGROUND: Immunomodulators are implicated in increasing the risks of several adverse events (AE), including reactivation of latent viruses, malignancy and idiosyncratic medication-related pancreatitis. Methotrexate (MTX) is infrequently used as a primary immunomodulator in the United States. Due to mechanistic differences, we hypothesize that MTX use may be associated with less risk of medication-related adverse events compared to thiopurines. METHODS: We conducted a retrospective record review at a large tertiary medical center, identifying adults with Crohn's disease (CD, ICD9 555.x) using thiopurine or MTX monotherapy from 1996-2012. Inclusion criterial included a minimum of 2 years follow up and annual gastroenterology clinic visit after medication start. Subjects using concurrent anti-TNF therapy or chronic prednisone were excluded. Medication timing data and AE data, including varicella zoster (VZV), squamous cell carcinoma (SCC), non-dermatologic malignancy (including lymphoma), and drug-induced pancreatitis, were extracted from electronic medical records. Chi-squared and Fisher's exact tests were used with logistic regression for data analysis in SAS 9.3. RESULTS: The study population included 852 subjects; 189 (21.43%) using MTX and 693 (78.57%) using thiopurine monotherapy. Subjects were 50.23% male (p = 0.624) with a mean age of 44.27 15.13 years (p = 0.751). Mean MTX duration of use was 3.37 5.02 years, compared to thiopurine duration of 4.21 4.07 years. A total of 105 (11.95%) incident AE were comprised of 50 VZV reactivations, 14 SCC, 15 non-dermatologic malignancies, and 26 pancreatitis episodes. Complications were less frequent among MTX users (10/189, 5.29%) compared to thiopurine users (95/690, 13.77%). Adjusting for gender, age, and duration of use, the odds of incident AE were lower in MTX users (OR = 0.354, 95%CI 0.177, 0.711, p = 0.0035) relative to thiopurine users. Additionally, when adjusting for prior thiopurine exposure, methotrexate demonstrated further reduction in the odds of AE (OR = 0.281, 95%CI 0.134, 0.593, p = 0.0008) While this retrospective cohort is underpowered for analysis of individual AE, methotrexate use was protective against drug-induced pancreatitis compared to thiopurines (OR = 0.114, 95%CI 0.015, 0.856, p = 0.0348). No significant differences in the risk of VZV or non-dermatologic malignancy were observed between the MTX and thiopurine groups. CONCLUSIONS: Methotrexate may offer a safety advantage compared to thiopurines and could be considered the first line immunomodulator in males with Crohn's disease. The analysis could not reliably account for active smoking which may represent an important covariate. Larger cohorts may be able to detect the carry over risk attributable to prior thiopurine exposure, potentially unmasking further relative risk reduction of adverse events in methotrexate users.

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