Immunomodulators with Anti–Tumor Necrosis Factor Agents: One Size does not Fit All
Gil Y. Melmed; Brennan M. Spiegel; Brian Bressler; Adam S. Cheifetz; Shane M. Devlin; Laura E. Harrell; Peter M. Irving; Jennifer Jones; Gilaad G. Kaplan; Patricia L. Kozuch; Fernando S. Velayos; Leonard Baidoo; Miles P. Sparrow; Corey A. Siegel
Posted: 09/07/2010; Clin Gastroenterol Hepatol. 2010;8(8):655-659. © 2010 AGA Institute
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.[1–3] 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.[4] 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,[5–7] and hepatosplenic T-cell lymphoma.[8,9] 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.[6]
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.
Methods
Study Overview
The RAND/University of California Los Angeles appropriateness method uses a modified Delphi panel approach, which is a widely used, iterative, evidence-based process that combines the best available evidence with the expert opinion of the available literature to determine the appropriateness of processes of care in medicine.[10]
Literature Review
We conducted a systematic literature search in September 2008 to identify controlled trials that evaluated the longterm safety and/or efficacy of concomitant immunomodulator therapy in patients with Crohn's disease treated with anti-TNF therapy. We also conducted reviews for the following topics: (1) summary and analysis of the SONIC[4] and COMMIT[11] trials; (2) pharmacokinetics of anti-TNF therapy and concomitant immunomodulators; (3) predictors of response to anti-TNF therapy; (4) efficacy and safety of concomitant immunomodulators in the rheumatology literature; and (5) lymphoma risk with immunomodulators and anti-TNF therapy. The summary document was distributed to all panelists for review before the first round of ratings (Supplementary Material).
Clinical Scenarios and Definitions
We created clinical scenarios using variables that might influence the decision to use immunomodulators with anti-TNF therapy, and sought input from opinion leaders for additional variables. Scenarios were arranged in 5 chapters, as follows: Chapter 1: Steroid and immunomodulator-naive, starting an anti-TNF (similar to the SONIC[4] population); Chapter 2: Steroid-induced, starting an anti-TNF concurrently for maintenance (similar to the COMMIT[11] population); Chapter 3: Failing immunomodulators and starting anti-TNF therapy (similar to many subjects enrolled in anti-TNF pivotal trials);[12–16] Chapter 4: Clinical attenuation to monotherapy with anti-TNF therapy, switching to a second anti-TNF; and Chapter 5: In remission for 6 months or longer on anti-TNF therapy with a concomitant immunomodulator (similar to the population in the report by Van Assche et al[17]).
Within each chapter, scenarios were constructed using the following variables: sex, age, disease duration, disease extent, presence or absence of perianal involvement, and surgical history. A total of 134 scenarios were created. Definitions of terms used to construct the scenarios are listed in Supplementary Table 1.
Appropriateness was rated on a scale of 1 to 9 for each scenario (1–3, inappropriate; 4–6, uncertain; and 7–9, appropriate[10]). An immunomodulator was considered appropriate when the expected benefits exceeded the expected negative consequences by a sufficiently wide margin to justify prescribing the immunomodulator. Additional questions were posed, as follows. First, is the decision to use concomitant immunomodulator therapy influenced by specific anti-TNF medications? Second, does active smoking status increase the likelihood of prescribing an immunomodulator? Third, in an older patient, does gender influence the likelihood of prescribing an immunomodulator? Fourth, is the decision to use an immunomodulator influenced by a patient being older than 60 years old?
Appropriateness Panel
The panel consisted of 13 members of the Building Research in Inflammatory Bowel Disease (IBD) Globally (BRIDGe) group, composed of gastroenterologists engaged in IBD research (www.BRIDGeIBD.com). The group is diverse, with representation from the United States, Canada, Australia, and the United Kingdom, and from both university and private practice settings. After receiving the literature summary, panelists confidentially rated the scenarios and convened 2 weeks later at a moderated in-person meeting (January 2009, Dallas, TX). During this meeting scenarios were discussed in detail, after which panelists confidentially re-rated each scenario; agreement was not required.
Analysis
Median scores were calculated and rounded up, so that a median score of 3.5 was rated as uncertain whereas a median score of 6.5 was rated as appropriate. To quantify the level of agreement, a RAND/UCLA disagreement index was calculated.[16] A disagreement index greater than 1.0 indicates extreme variation whereas disagreement index values less than 1.0 reflect increasing agreement. The disagreement index is calculated using a standard published equation.[8,16]
Gil Y. Melmed; Brennan M. Spiegel; Brian Bressler; Adam S. Cheifetz; Shane M. Devlin; Laura E. Harrell; Peter M. Irving; Jennifer Jones; Gilaad G. Kaplan; Patricia L. Kozuch; Fernando S. Velayos; Leonard Baidoo; Miles P. Sparrow; Corey A. Siegel
Posted: 09/07/2010; Clin Gastroenterol Hepatol. 2010;8(8):655-659. © 2010 AGA Institute
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.[1–3] 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.[4] 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,[5–7] and hepatosplenic T-cell lymphoma.[8,9] 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.[6]
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.
Methods
Study Overview
The RAND/University of California Los Angeles appropriateness method uses a modified Delphi panel approach, which is a widely used, iterative, evidence-based process that combines the best available evidence with the expert opinion of the available literature to determine the appropriateness of processes of care in medicine.[10]
Literature Review
We conducted a systematic literature search in September 2008 to identify controlled trials that evaluated the longterm safety and/or efficacy of concomitant immunomodulator therapy in patients with Crohn's disease treated with anti-TNF therapy. We also conducted reviews for the following topics: (1) summary and analysis of the SONIC[4] and COMMIT[11] trials; (2) pharmacokinetics of anti-TNF therapy and concomitant immunomodulators; (3) predictors of response to anti-TNF therapy; (4) efficacy and safety of concomitant immunomodulators in the rheumatology literature; and (5) lymphoma risk with immunomodulators and anti-TNF therapy. The summary document was distributed to all panelists for review before the first round of ratings (Supplementary Material).
Clinical Scenarios and Definitions
We created clinical scenarios using variables that might influence the decision to use immunomodulators with anti-TNF therapy, and sought input from opinion leaders for additional variables. Scenarios were arranged in 5 chapters, as follows: Chapter 1: Steroid and immunomodulator-naive, starting an anti-TNF (similar to the SONIC[4] population); Chapter 2: Steroid-induced, starting an anti-TNF concurrently for maintenance (similar to the COMMIT[11] population); Chapter 3: Failing immunomodulators and starting anti-TNF therapy (similar to many subjects enrolled in anti-TNF pivotal trials);[12–16] Chapter 4: Clinical attenuation to monotherapy with anti-TNF therapy, switching to a second anti-TNF; and Chapter 5: In remission for 6 months or longer on anti-TNF therapy with a concomitant immunomodulator (similar to the population in the report by Van Assche et al[17]).
Within each chapter, scenarios were constructed using the following variables: sex, age, disease duration, disease extent, presence or absence of perianal involvement, and surgical history. A total of 134 scenarios were created. Definitions of terms used to construct the scenarios are listed in Supplementary Table 1.
Appropriateness was rated on a scale of 1 to 9 for each scenario (1–3, inappropriate; 4–6, uncertain; and 7–9, appropriate[10]). An immunomodulator was considered appropriate when the expected benefits exceeded the expected negative consequences by a sufficiently wide margin to justify prescribing the immunomodulator. Additional questions were posed, as follows. First, is the decision to use concomitant immunomodulator therapy influenced by specific anti-TNF medications? Second, does active smoking status increase the likelihood of prescribing an immunomodulator? Third, in an older patient, does gender influence the likelihood of prescribing an immunomodulator? Fourth, is the decision to use an immunomodulator influenced by a patient being older than 60 years old?
Appropriateness Panel
The panel consisted of 13 members of the Building Research in Inflammatory Bowel Disease (IBD) Globally (BRIDGe) group, composed of gastroenterologists engaged in IBD research (www.BRIDGeIBD.com). The group is diverse, with representation from the United States, Canada, Australia, and the United Kingdom, and from both university and private practice settings. After receiving the literature summary, panelists confidentially rated the scenarios and convened 2 weeks later at a moderated in-person meeting (January 2009, Dallas, TX). During this meeting scenarios were discussed in detail, after which panelists confidentially re-rated each scenario; agreement was not required.
Analysis
Median scores were calculated and rounded up, so that a median score of 3.5 was rated as uncertain whereas a median score of 6.5 was rated as appropriate. To quantify the level of agreement, a RAND/UCLA disagreement index was calculated.[16] A disagreement index greater than 1.0 indicates extreme variation whereas disagreement index values less than 1.0 reflect increasing agreement. The disagreement index is calculated using a standard published equation.[8,16]
