Crohn's Disease: Immunomodulators With Anti-Tumor Necrosis Factor Agents
Background & Aims: There is no consensus on the appropriateness of concomitant immunomodulators with anti– tumor necrosis factor (TNF) therapy for Crohn's disease. Some patients benefit from concomitant immunomodulators, but concerns related to infections and lymphoma risk have dampened enthusiasm for this approach. We applied the RAND/University of California Los Angeles Appropriateness Method toward establishing appropriateness of concomitant immunomodulators and anti-TNF therapies for Crohn's disease.
Methods: A literature review was conducted regarding efficacy and safety of concomitant immunomodulators in the setting of anti-TNF therapy for Crohn's disease and presented to the Building Research in Inflammatory Bowel Disease Globally group, a globally diverse panel of 13 gastroenterologists clinically experienced in inflammatory bowel disease. A total of 134 scenarios were constructed using several clinical variables. Panelists used a modified Delphi method to rate the appropriateness of concomitant immunomodulators, and met to discuss and re-rate appropriateness. Disagreement was assessed using a validated index.
Results: Concomitant immunomodulators were generally rated appropriate for 63 scenarios, uncertain for 60 scenarios, and inappropriate for 11 scenarios. In general, concomitant immunomodulators were appropriate for those with extensive disease, shorter duration of disease, perianal involvement, prior surgery, females, and older patients (>26 y). Concomitant immunomodulators were generally rated inappropriate for young males, and in some scenarios involving uncomplicated disease. Smoking and the particular anti-TNF medication did not influence ratings. Disagreement was observed in 6 of 134 scenarios.
Conclusions: The appropriateness of concomitant immunomodulators with anti-TNF therapy for Crohn's disease was determined through a modified Delphi panel approach based on expert interpretation of the available literature. Clinicians should consider multiple factors when considering concomitant immunomodulators with anti-TNF treatment.
The treatment of Crohn's disease was revolutionized in the late 1990s with the introduction of infliximab, an anti–tumor necrosis factor (TNF) monoclonal antibody. Since then, clinicians have faced uncertainty regarding the optimization of efficacy and safety of anti-TNF therapy. The use of immunomodulators such as 6-mercaptopurine, azathioprine, and methotrexate concurrently with anti-TNF therapy may increase response rates by decreasing immunogenicity against the anti-TNF compounds or through synergy by administering 2 effective medications. The Study of Biologic and Immunomodulator Naive Patients in Crohn's Disease (SONIC) trial found that in immunomodulator-naive patients induced and maintained with infliximab, concomitant azathioprine allowed for significantly more patients to achieve remission at 6 months, as compared with those treated with either infliximab alone or azathioprine alone. In contrast, the Combination of Maintenance Methotrexate-Infliximab Trial (COMMIT) did not show a difference in treatment success among patients induced with prednisone and infliximab, randomized to receive methotrexate or placebo. Thus, the efficacy of combination therapy is unclear. Furthermore, serious adverse events may occur more often when prescribing 2 immune-suppressant medications, including serious infections, non-Hodgkin's lymphoma, and hepatosplenic T-cell lymphoma. However, it remains unknown whether exposure to an immunomodulator in addition to anti-TNF therapy increases these risks relative to those treated with anti-TNF or immunomodulators alone.
Given the potential for improved efficacy but increased risk from concomitant immunomodulators, clinicians prescribing anti-TNF agents carefully must evaluate the pros and cons of combination therapy for the individual patient. We used the RAND appropriateness methodology, an evidence-based process, to assess the appropriateness of concomitant immunosuppressive therapy with anti-TNF use in a range of patients with moderate-to-severe Crohn's disease.
Abstract and Introduction
Abstract
Background & Aims: There is no consensus on the appropriateness of concomitant immunomodulators with anti– tumor necrosis factor (TNF) therapy for Crohn's disease. Some patients benefit from concomitant immunomodulators, but concerns related to infections and lymphoma risk have dampened enthusiasm for this approach. We applied the RAND/University of California Los Angeles Appropriateness Method toward establishing appropriateness of concomitant immunomodulators and anti-TNF therapies for Crohn's disease.
Methods: A literature review was conducted regarding efficacy and safety of concomitant immunomodulators in the setting of anti-TNF therapy for Crohn's disease and presented to the Building Research in Inflammatory Bowel Disease Globally group, a globally diverse panel of 13 gastroenterologists clinically experienced in inflammatory bowel disease. A total of 134 scenarios were constructed using several clinical variables. Panelists used a modified Delphi method to rate the appropriateness of concomitant immunomodulators, and met to discuss and re-rate appropriateness. Disagreement was assessed using a validated index.
Results: Concomitant immunomodulators were generally rated appropriate for 63 scenarios, uncertain for 60 scenarios, and inappropriate for 11 scenarios. In general, concomitant immunomodulators were appropriate for those with extensive disease, shorter duration of disease, perianal involvement, prior surgery, females, and older patients (>26 y). Concomitant immunomodulators were generally rated inappropriate for young males, and in some scenarios involving uncomplicated disease. Smoking and the particular anti-TNF medication did not influence ratings. Disagreement was observed in 6 of 134 scenarios.
Conclusions: The appropriateness of concomitant immunomodulators with anti-TNF therapy for Crohn's disease was determined through a modified Delphi panel approach based on expert interpretation of the available literature. Clinicians should consider multiple factors when considering concomitant immunomodulators with anti-TNF treatment.
Introduction
The treatment of Crohn's disease was revolutionized in the late 1990s with the introduction of infliximab, an anti–tumor necrosis factor (TNF) monoclonal antibody. Since then, clinicians have faced uncertainty regarding the optimization of efficacy and safety of anti-TNF therapy. The use of immunomodulators such as 6-mercaptopurine, azathioprine, and methotrexate concurrently with anti-TNF therapy may increase response rates by decreasing immunogenicity against the anti-TNF compounds or through synergy by administering 2 effective medications. The Study of Biologic and Immunomodulator Naive Patients in Crohn's Disease (SONIC) trial found that in immunomodulator-naive patients induced and maintained with infliximab, concomitant azathioprine allowed for significantly more patients to achieve remission at 6 months, as compared with those treated with either infliximab alone or azathioprine alone. In contrast, the Combination of Maintenance Methotrexate-Infliximab Trial (COMMIT) did not show a difference in treatment success among patients induced with prednisone and infliximab, randomized to receive methotrexate or placebo. Thus, the efficacy of combination therapy is unclear. Furthermore, serious adverse events may occur more often when prescribing 2 immune-suppressant medications, including serious infections, non-Hodgkin's lymphoma, and hepatosplenic T-cell lymphoma. However, it remains unknown whether exposure to an immunomodulator in addition to anti-TNF therapy increases these risks relative to those treated with anti-TNF or immunomodulators alone.
Given the potential for improved efficacy but increased risk from concomitant immunomodulators, clinicians prescribing anti-TNF agents carefully must evaluate the pros and cons of combination therapy for the individual patient. We used the RAND appropriateness methodology, an evidence-based process, to assess the appropriateness of concomitant immunosuppressive therapy with anti-TNF use in a range of patients with moderate-to-severe Crohn's disease.
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