Efficacy of High-Dose Versus Low-Dose Methotrexate in Combination Therapy for Inflammatory Bowel Disease

Abstract

Introduction: Methotrexate (MTX) is frequently used as part of combination therapy for the treatment of inflammatory bowel disease (IBD). Despite this frequency, optimal MTX dosing regimens for combination therapy have not been established. This study compared efficacy of low-dose and high-dose MTX treatment regiments among patients prescribed MTX and a biologic medication. Methods: A retrospective cohort study was completed. Using the electronic health records system of a cohort of MTX-prescribed IBD patients at our center between 2010 and 2013. Low-dose (LD) MTX was defined as ≤12.5 mg/week and high-dose (HD) MTX as 15-25 mg/week. Patients who met the criteria for clinical remission (Harvey-Bradshaw index (HBI) ≤4, simple clinical colitis activity index (SCCAI) ≤2 or by clinical report) at baseline were followed for up to 42 months. Standardized chart review occurred in 6 month intervals. The primary outcome measure was consecutive months in remission prior to relapse. Secondary outcomes included non-standardized indicators of worsening disease (indicated by endoscopic inflammation, steroid use, therapy escalation, addition or escalation of concomitant therapy, or surgery), and the presence of side effects. Regression analysis and Kaplan-Meier survival analysis were completed. Results: Eighty-eight MTX-prescribed IBD patients, including 73 (83%) dual-therapy patients were identified. Thirty-two LD and 14 HD individuals met inclusion criteria. When compared with HD patients, LD patients were more likely to relapse (log-rank test, p<0.01). In addition, patients prescribed LD MTX had a greater degree of worsening disease by non-standardized secondary indicators, but this difference was not significant. Secondary outcomes occurred during 34.4% of LD review periods compared with 31.4% of HD review periods (p=0.67). Of the patients, 4/32 (13%) LD patients and 2/14 (14%) HD patients altered or terminated MTX therapy due to adverse events, (nausea (n=4) increased liver enzymes (n=2), fatigue (n=1), and/or headache (n=1)).Figure 1: Kaplan-Meier analysis of LD vs. HD MTX therapy.Conclusion: When combined with anti-TNF therapy, MTX prescribed at doses of >12.5 mg/week were more effective at maintaining clinical remission than lower doses, but did not affect overall steroid use, anti-TNF dosing, surgery or endoscopic inflammation. A prospective study is warranted.