Concomitant use of immunomodulators with anti-TNF in Crohn's disease: yes or no?
ABSTRACT Today up to 40% of Crohn's disease patients receive a concomitant therapy of TNF blockers in combination with thiopurines or methotrexate. Although data of prospective controlled trails are rare, some recently published studies indicate a more rapid onset of remission and increased mucosal healing following concomitant therapy in short term. However, data confirming the need or benefit of concomitant immunosuppressive therapy once remission has been reached remains unknown. Concomitant therapy lowers TNF-alpha induced immunogenicity, but the question of whether ATI formation also lowers the efficiency of TNF-alpha antagonists has not yet been answered to a level that would justify the use of concomitant immunosuppression. Knowing that immunosuppression increases the risk for opportunistic infections and lymphomas the potential risks and of concomitant therapy must be well balanced against the benefit. This article aims to interpret the available data on the efficiency, immunogenicity, and safety of concomitant therapy in patients under anti-TNF therapy.
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ABSTRACT: Background The association of concomitant immunosuppressant use with infliximab (IFX) and therapeutic outcomes in correlation with pharmacokinetic properties in ulcerative colitis (UC) remains unclear. AimsTo assess the effect of concomitant immunosuppressant use on the duration of IFX therapy, and the pharmacokinetic properties of IFX in patients with UC. MethodsA retrospective analysis of UC patients treated with IFX. Duration of efficacious IFX therapy, and serum IFX and antibody-to-IFX (ATI) levels were compared between those receiving IFX as monotherapy or in combination with an immunosuppressant. ResultsAmong the 85 UC patients who received IFX, 46 (54.1%) received concomitant immunosuppressants, and 38 (45.9%) received IFX monotherapy. Concomitant immunosuppressant use was associated with increased duration of IFX therapy as 90% of patients receiving immunosuppressants remained on therapy at 1 year versus 61% of patients on monotherapy (Log-rank, P = 0.016). Concomitant immunosuppressant use, as compared to monotherapy, was associated with greater IFX levels (20.4 mg/L vs.10.5 mg/L, P = 0.025) and less frequent ATI formation (4.5% vs.33.3%, P = 0.031). Patients receiving greater than 2.0 mg/kg of azathioprine had greater IFX levels than those receiving less than 2.0 mg/kg (26.0 vs.10.6 mcg/ml, P = 0.03) and those receiving IFX monotherapy (26.0 vs.11.2 mcg/ml, P = 0.03). The duration of IFX therapy among patients receiving less than 2.0 mg/kg azathioprine was indistinguishable from patients on IFX monotherapy (Log-rank, P = 0.95). Conclusion Concomitant immunosuppressant therapy with IFX improves outcomes in UC as shown by increased duration of therapy, decreased immunogenicity against IFX, and increased blood levels of IFX. Our data suggest that this benefit may be dependent on the dose of concomitant immunosuppression.Journal of Gastroenterology and Hepatology 06/2014; · 3.33 Impact Factor
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ABSTRACT: The objective of this study was to contribute long-term safety data for infliximab and other therapies in Crohn's disease (CD). We prospectively evaluated CD patients enrolled in the large, observational Crohn's Therapy, Resource, Evaluation, and Assessment Tool registry, established to compare infliximab safety with conventional nonbiological medications in CD. A total of 6,273 patients were enrolled and evaluated on or before 23 February 2010; 3,420 received infliximab (17,712 patient-years; 89.9% received ≥2 infusions) and 2,853 received other-treatments-only (13,251 patient-years). Mean length of patient follow-up was 5.2 years. More infliximab- than other-treatments-only-treated patients had moderate-to-severe (30.6% vs. 10.7%) or severe-to-fulminant (2.5% vs. 0.6%) disease severity (P<0.001). In the year before enrollment, more infliximab- than other-treatments-only-treated patients required surgical intervention (17.4% vs. 13.6%), medical hospitalization (14.2% vs. 8.8%), prednisone (47.8% vs. 31.4%), immunomodulators (52.0% vs. 32.1%), and narcotic analgesics (17.3% vs. 9.1%). Patient mortality was similar for infliximab- and other-treatments-only-treated patients (0.58 vs. 0.59/100 patient-years). In multivariate logistic regression analyses, treatment with prednisone (hazard ratio (HR)=2.14, 95% confidence interval (CI)=1.55, 2.95; P<0.001) or narcotic analgesics (HR=1.79, 95% CI=1.29, 2.48; P<0.001) and age (HR=1.08, 95% CI=1.07, 1.09; P<0.001) were associated with increased mortality risk. Neither infliximab nor immunomodulator treatment was associated with increased mortality risk. Factors independently associated with serious infections included moderate-to-severe disease activity (HR=2.24, 95% CI=1.57, 3.19; P<0.001), narcotic analgesic treatment (HR=1.98, 95% CI=1.44, 2.73; P<0.001), prednisone therapy (HR=1.57, 95% CI=1.17, 2.10; P=0.002), and infliximab treatment (HR=1.43, 95% CI=1.11, 1.84; P=0.006). Mortality was similar between infliximab- and other-treatments-only-treated CD patients. An increased risk of serious infection with infliximab was observed, although CD severity and use of prednisone or narcotic analgesics carried higher risks.The American Journal of Gastroenterology 08/2012; 107(9):1409-22. · 9.21 Impact Factor
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ABSTRACT: & Aims: Effectiveness of early treatment with biologics and immunomodulator therapy on healthcare utilization remains poorly defined. We assessed rates of hospitalization and surgery within 1 y following initiation of infliximab and/or immunomodulator therapy in a US cohort of patients with IBD. We conducted a retrospective, observational cohort study of Veterans with Crohn's disease or ulcerative colitis using administrative data from 176 Department of Veteran Affairs facilities (October 1, 2001 through September 30, 2009). Inpatient, outpatient, and death records were linked longitudinally with prescription fill data. Each person-day of follow up was assessed for treatment with infliximab, immunomodulators, both (dual therapy), or neither. We calculated drug exposure time and used Poisson and logistic regression analyses to assess outcomes. The cohort of 20,474 patients included 8042 patients with Crohn's disease and 12,432 with ulcerative colitis (93.9% male; 72.5% white; mean age, 60.9±14.5 y) prescribed infliximab (0.17%), immunomodulator (1.3%), or dual therapy (1.5%). Adjusted models revealed 50% relative reductions in hospitalization among patients who received 9.2 months of immunomodulator monotherapy, 8 months of infliximab, or 7.7 months of dual therapy. A 50% relative reduction in surgery was observed among patients receiving 7 months of infliximab or 5 months of dual therapy. Analysis of dose-response data revealed 73.1% and 92% reductions in risk of hospitalization and surgery, respectively, after 9 months of dual therapy. Based on a retrospective cohort study, dual therapy with infliximab and an immunomodulator for <8 months is associated with significant reductions in hospitalization and surgery within 1 y of the start of therapy. These findings indicate that patients with IBD are more likely to benefit if dual therapy is initiated earlier in their first year of therapy.Clinical gastroenterology and hepatology: the official clinical practice journal of the American Gastroenterological Association 06/2013; · 5.64 Impact Factor