Clinical Gastroenterology and Hepatology
Volume 8, Issue 8 , Pages 655-659, August 2010

The Appropriateness of Concomitant Immunomodulators With Anti–Tumor Necrosis Factor Agents for Crohn's Disease: One Size Does Not Fit All

  • Gil Y. Melmed

      Affiliations

    • Cedars-Sinai Medical Center, Los Angeles, California
    • David Geffen School of Medicine at University of California Los Angeles, Los Angeles, California
    • Corresponding Author InformationReprint requests Address requests for reprints to: Gil Y. Melmed, MD, MS, Cedars-Sinai Medical Center, 8635 West Third Street, #960-W, Los Angeles, California 90048. fax: (310) 967-0131
    • ,
  • Brennan M. Spiegel

      Affiliations

    • David Geffen School of Medicine at University of California Los Angeles, Los Angeles, California
    • VA Greater Los Angeles Healthcare System, Center for Ulcer Research and Education, Digestive Diseases Research Center, University of California, Los Angeles/Veteran's Administration Center for Outcomes Research and Education, Los Angeles, California
    • ,
  • Brian Bressler

      Affiliations

    • University of British Columbia, Vancouver, British Columbia, Canada
    • ,
  • Adam S. Cheifetz

      Affiliations

    • Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts
    • ,
  • Shane M. Devlin

      Affiliations

    • University of Calgary, Alberta, Canada
    • ,
  • Laura E. Harrell

      Affiliations

    • University of Chicago, Chicago, Illinois
    • ,
  • Peter M. Irving

      Affiliations

    • Guy's and St. Thomas' Hospitals, London, United Kingdom
    • ,
  • Jennifer Jones

      Affiliations

    • University of Saskatchewan, Saskatoon, Saskatchewan, Canada
    • ,
  • Gilaad G. Kaplan

      Affiliations

    • University of Calgary, Alberta, Canada
    • ,
  • Patricia L. Kozuch

      Affiliations

    • Jefferson University, Philadelphia, Pennsylvania
    • ,
  • Fernando S. Velayos

      Affiliations

    • University of California San Francisco, San Francisco, California
    • ,
  • Leonard Baidoo

      Affiliations

    • University of Pittsburgh, Pittsburgh, Pennsylvania
    • ,
  • Miles P. Sparrow

      Affiliations

    • Department of Gastroenterology, The Alfred Hospital, Melbourne, Australia
    • ,
  • Corey A. Siegel

      Affiliations

    • Dartmouth-Hitchcock Medical Center, Lebanon, New Hampshire

published online 07 May 2010.

Article Outline

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.

Keywords: Crohn's Disease, Inflammatory Bowel Disease, Infliximab, Adalimumab, Certolizumab, Anti–Tumor Necrosis α Therapy

Abbreviations used in this paper: BRIDGe, Building Research in Inflammatory Bowel Disease Globally, COMMIT, Combination of Maintenance Methotrexate-Infliximab Trial, IBD, inflammatory bowel disease, SONIC, Study of Biologic and Immunomodulator Naive Patients in Crohn's Disease, TNF, tumor necrosis factor

 

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, 2, 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, 6, 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.

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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 long-term 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 SONIC4 and COMMIT11 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 SONIC4 population); Chapter 2: Steroid-induced, starting an anti-TNF concurrently for maintenance (similar to the COMMIT11 population); Chapter 3: Failing immunomodulators and starting anti-TNF therapy (similar to many subjects enrolled in anti-TNF pivotal trials)12, 13, 14, 15, 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 al17).

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, appropriate10). 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

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Results 

Overall Results 

Overall, the panelists rated concomitant immunomodulator therapy as appropriate in 63 of 134 total scenarios, uncertain in 60 scenarios, and inappropriate for 11 scenarios. There was a high degree of agreement among the panelists, with only 6 of 134 scenarios showing disagreement. Scenarios with common ratings and agreement were collapsed into 58 scenarios divided into 5 chapter headings. Table 1 shows examples of ratings within each chapter; for complete ratings of all 134 scenarios, see Supplementary Table 2 or visit www.BRIDGeIBD.com.

Table 1. Examples of Scenario Ratings for Each of the 5 Chapters
ChapterDisease extent/behaviorPatient characteristicsRecommendation
Chapter 1: Medication-naive (ie, SONIC population)Limited disease/no perianal involvement
Males <26 years, with disease duration >2 years

Male <26 years, with disease duration ≤2 years

Inappropriate
Extensive/complicated diseaseAppropriatea
Chapter 2: Steroid induced (ie, COMMIT population)Limited disease, with or without perianal involvement
Male or female, any age, with no resection

Male or female, any age, with ≥1 resection

Uncertain
Appropriate
Chapter 3: On immunomodulator (ie, those on concomitant immunomodulators in pivotal anti-TNF trials)Limited disease/no perianal involvementMale or female, any age, with no resectionInappropriate
Extensive/complicated diseaseMale or female, any age, extensive resection(s)Appropriate
Chapter 4: Attenuated response while on anti-TNF monotherapy, now switching anti-TNFsLimited disease/no perianal involvement
Male or female, any age, with no resection

Male or female, any age, with ≥1 resection

Uncertain
Appropriate
Chapter 5: Appropriateness of immunomodulator withdrawal in patients in clinical remission on concomitant anti-TNF for 6 monthsLimited disease/no perianal involvementMale or female, any age, ≥1 resectionUncertain
Limited disease/with peri-anal involvementMales <26 years, no resectionAppropriatea

NOTE. Each scenario reflects specific patient characteristics within a defined disease extent/behavior within each chapter, and is rated on a separate row. For complete ratings of all 134 scenarios, please see Supplementary Table 2 or visit www.BRIDGeIBD.com.

aDenotes disagreement, defined by statistically measurable variability in panelist ratings.

Chapter 1: Immunomodulator-Naive 

For patients with Crohn's disease naive to all immunosuppressive medications, concomitant immunomodulators were considered inappropriate for young men with limited disease, no perianal involvement, and a longer (>2 y) duration of disease. All other scenarios were considered uncertain or appropriate. In this chapter there was agreement for all but 2 scenarios, which involved males with a short duration of disease and females with a longer duration of disease.

Chapter 2: Steroid Induction With Anti–Tumor Necrosis Factor Maintenance 

In patients induced with steroids and started on an anti-TNF for maintenance therapy, concomitant immunomodulator use was considered appropriate in all cases in which a patient already had a surgical resection, and in all those with extensive/complicated disease; all other scenarios were rated as uncertain. None of the scenarios in this chapter was rated as inappropriate, and no disagreement was noted.

Chapter 3: Starting Anti–Tumor Necrosis Factor Therapy After Failing Immunomodulators 

For patients starting anti-TNF treatment after failing immunomodulators, continuation of the immunomodulator was considered inappropriate or uncertain in most scenarios, and appropriate in older patients and younger women with extensive/complicated disease who had undergone extensive/multiple surgical resections.

Chapter 4: Switching to a Second Anti–Tumor Necrosis Factor Agent 

For patients failing monotherapy with an anti-TNFα and switching to a second anti-TNF, the addition of an immunomodulator was considered appropriate for most scenarios, and uncertain in the remaining scenarios; no scenarios were rated inappropriate. However, in 3 scenarios that were rated appropriate, disagreement was noted when younger patients were involved.

Chapter 5: Immunomodulator Withdrawal 

Finally, for patients doing well on an anti-TNF and immunomodulator for 6 months, scenarios were rated for the appropriateness of discontinuation of the immunomodulator. In this chapter, panelists rated most scenarios as uncertain but believed that discontinuation was more appropriate in cases of limited disease and no prior resections.

Results of Additional Questions 

Panelists believed that smoking status was somewhat important in their decision to use an immunomodulator, and were more likely to prescribe an immunomodulator in this setting. No panelists believed that sex influenced the use of concomitant immunomodulators in older patients (age, >25 years). However, for patients older than 60 years, most panelists were less likely to start an immunomodulator. Finally, immunomodulators were considered slightly more appropriate for patients receiving infliximab than for those receiving adalimumab or certolizumab (Supplementary Table 3).

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Discussion 

Since the approval of anti-TNF agents for Crohn's disease, the appropriateness of concomitant immunomodulators has been uncertain. The difficulty in establishing appropriateness is in part owing to seemingly conflicting evidence gleaned from heterogeneous study populations across clinical trials, and rare but serious adverse events including infection and lymphoma.

Our study had several important findings. First, the appropriateness of concomitant immunomodulators was influenced significantly by prior medication history, disease phenotype, and patient demographics. Specifically, immunomodulators were considered more appropriate in the presence of more aggressive disease (eg, perianal involvement, more extensive involvement, and in those with prior surgical resections), presumably owing to the need to maximize medical treatment in the setting of disease that likely will require surgery. In most cases, young males were regarded as the group for whom concomitant immunomodulators were considered least appropriate, likely owing to the increased risk of hepatosplenic T-cell lymphoma in this demographic group. Second, appropriateness was not uniform across all scenarios, reinforcing the concept that each patient requires an individualized decision. Finally, although the RAND methodology does not require agreement, there was consensus among panelists for the majority (96%) of scenarios. Although geographic practice variation might be postulated, disagreement did not correlate with geographic origin of the panelists.

Although many scenarios were rated as appropriate, several scenarios were rated as uncertain, which suggests that for those scenarios data are lacking to drive a decision, and therefore both the use or non-use of concomitant immunomodulators is acceptable.

Concomitant therapy with immunomodulators was rated overall least appropriate for chapter 3 (patients failing immunomodulators who are initiating their first anti-TNF). This is arguably the most common clinical scenario for which an anti-TNF currently is prescribed. Only 2 scenarios within this chapter were rated appropriate (young females with extensive resections, and older patients with extensive resections), owing to the lack of data supporting efficacy of combination therapy in this setting.

Most of the anti-TNF pivotal trials and a pooled post hoc analysis of infliximab studies did not show a significant benefit for those on immunomodulators.18 The SONIC trial showed that in naive patients concomitant infliximab and azathioprine allowed for 57% of patients to achieve corticosteroid-free remission at 6 months, as compared with 44% on infliximab alone and 31% on azathioprine alone.4 In contrast, the COMMIT study did not show a difference in treatment success among patients induced with prednisone and infliximab, randomized to receive methotrexate or placebo.11 Importantly, patients enrolled in COMMIT were induced with both corticosteroids and infliximab, whereas SONIC participants were induced with infliximab alone and all were naive to immunomodulators. In addition, the average disease duration among SONIC subjects was 2 years compared with 10 years among COMMIT patients. Finally, there may be differences between azathioprine and methotrexate that account for differences seen between SONIC and COMMIT.

The RAND methodology previously has been applied toward Crohn's disease management,19 including the question of concomitant immunomodulators. However, only 2 variables were considered. For the present study, we incorporated more than 10 variables for this complex decision.

Our study had several limitations. First, the recommendations were subjective because they relied on panelists' interpretations of the best available evidence and their individual clinical experience. Second, not every possible clinical scenario could be rated because of the need to limit panelist burden. For example, some panelists use low-dose immunomodulators (eg, 7.5 mg oral methotrexate, dosed weekly20), which were not included as a variable. Third, panelists were instructed not to consider cost when rating appropriateness, to avoid cost bias. However, in the real world, cost can and does influence therapeutic decisions. Finally, our results were time-bound to the current understanding of the comparative effectiveness of these strategies.

Despite these limitations, our study presents a practical, evidence-based guide for the use of concomitant immunomodulator treatment for patients with Crohn's disease receiving anti-TNF therapies using a modified Delphi panel approach based on expert interpretation of the available literature. Our results can be accessed readily for decision making at the point of care; at www.BRIDGeIBD.com, patient characteristics can be entered to yield a recommendation for any particular scenario. These recommendations should not replace clinical judgment but might clarify factors to consider in making this decision. It thus behooves the practitioner to consider each individual case, rather than maintain a one-size-fits-all approach, in the decision to prescribe concomitant immunomodulators in the setting of anti-TNF therapy.

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Acknowledgments 

The BRIDGe group thanks Drs Steve Hanauer, Marla Dubinsky, and Bruce Sands for review of selected variables, and Jennifer Talley for administrative and technical assistance.

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Supplementary material 

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Supplemental Tables for online only.

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Video Abstract 

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References 

  1. Vermeire S, Noman M, Van Assche G, et al. Effectiveness of concomitant immunosuppressive therapy in suppressing the formation of antibodies to infliximab in Crohn's disease. Gut. 2007;56:1226–1231
  2. Baert F, Noman F, Vermeire S, et al. Influence of immunogenicity on the long-term efficacy of infliximab in Crohn's disease. N Engl J Med. 2003;348:601–608
  3. Hanauer SB, Wagner CL, Bala M, et al. Incidence and importance of antibody responses to infliximab after maintenance or episodic treatment in Crohn's disease. Clin Gastroenterol Hepatol. 2004;2:542–553
  4. Colombel JF, Sandborn WJ, Reinisch W, et al. Infliximab, azathioprine, or combination therapy for Crohn's disease. N Engl J Med. 2010;362:1383–1395
  5. Ljung T, Karlén P, Schmidt D, et al. Infliximab in inflammatory bowel disease: clinical outcome in a population based cohort from Stockholm County. Gut. 2004;53:849–853
  6. Siegel CA, Marden SM, Persing SM, et al. Risk of lymphoma associated with combination anti–tumor necrosis factor and immunomodulator therapy for the treatment of Crohn's disease: a meta-analysis. Clin Gastroenterol Hepatol. 2009;7:874–881
  7. Toruner M, Loftus EV, Harmsen WS, et al. Risk factors for opportunistic infections in patients with inflammatory bowel disease. Gastroenterology. 2008;134:929–936
  8. Rosh JR, Gross T, Mamula P, et al. Hepatosplenic T-cell lymphoma in adolescents and young adults with Crohn's disease: a cautionary tale?. Inflamm Bowel Dis. 2007;13:1024–1030
  9. Mackey AC, Green L, Liang LC, et al. Hepatosplenic T cell lymphoma associated with infliximab use in young patients treated for inflammatory bowel disease. J Pediatr Gastroenterol Nutr. 2007;44:265–267
  10. Brook RH, et al. The RAND/UCLA appropriateness method (Clinical practice guideline development: methodology perspectives). Rockville, MD: Public Health Service, AHCR; 1994;
  11. Feagan BG, McDonald J, Ponich T, et al. A randomized trial of methotrexate in combination with infliximab for treatment of Crohn's disease. Gastroenterology. 2008;135:294
  12. Hanauer SB, Feagan BG, Lichtenstein GR, et al. Maintenance infliximab for Crohn's disease: the ACCENT I randomised trial. Lancet. 2002;359:1541–1549
  13. Colombel JF, Sandborn WJ, Rutgeerts P, et al. Adalimumab for maintenance of clinical response and remission in patients with Crohn's disease: the CHARM trial. Gastroenterology. 2007;132:52–65
  14. Schreiber S, Rutgeerts P, Fedorak RN, et al. A randomized, placebo-controlled trial of certolizumab pegol (CDP870) for treatment of Crohn's disease. Gastroenterology. 2005;129:807–818
  15. Schreiber S, Khaliq-Kareemi M, Lawrance IC, et al. Maintenance therapy with certolizumab pegol for Crohn's disease. N Engl J Med. 2007;357:239–250
  16. Sandborn WJ, Hanauer SB, Rutgeerts P, et al. Adalimumab for maintenance treatment of Crohn's disease: results of the CLASSIC II trial. Gut. 2007;56:1232–1239
  17. Van Assche G, Magdelaine-Beuzelin C, D'Haens G, et al. Withdrawal of immunosuppression in Crohn's disease treated with scheduled infliximab maintenance: a randomized trial. Gastroenterology. 2008;134:1861–1868
  18. Lichtenstein GR, Diamond RH, Wagner CL, et al. Clinical trial: benefits and risks of immunomodulators and maintenance infliximab for IBD-subgroup analyses across four randomized trials. Aliment Pharmacol Ther. 2009;30:210–226
  19. Vader J-P, Froehlich F, Juillerat P, et al. Appropriate treatment for Crohn's disease: methodology and summary results of a multidisciplinary international expert panel approach—EPACT. Digestion. 2006;73:237–248
  20. Maini RN, Breedveld FC, Kalden JR, et al. Therapeutic efficacy of multiple intravenous infusions of anti-tumor necrosis factor alpha monoclonal antibody combined with low-dose weekly methotrexate in rheumatoid arthritis. Arthritis Rheum. 1998;41:1552–1563

 Conflicts of interest These authors disclose the following: Gil Melmed was a consultant and/or received research support from Centocor, Setpoint, Amgen, and Celgene, was on the speaker's bureaus of Abbott, P&G, and Shire, and was on the advisory board of UCB; Corey Siegel was on the advisory boards of Abbott, UCB, and P&G, was a consultant and received research support from Elan and P&G, and performed CME activities for Abbott and UCB; Brennan Spiegel received research funding from AstraZeneca, Amgen, Bristol Meyer Squibb, Salix, Takeda, Rose Pharmaceuticals, and Prometheus, and was on the advisory Boards of Takeda, Prometheus, and Ironwood; Brian Bressler was on the advisory boards of Abbott, Schering-Plough Canada, UCB, Shire, P&G, and Ferring, and was on the speaker's bureaus of Abbott, Schering-Plough Canada, and Shire; Adam Cheifetz was on the speaker's bureau of Centocor, UCB, and Abbott; and the advisory boards of Abbott and UCB; Jennifer Jones was a consultant, on the speaker's bureaus, and received educational funding from Schering-Plough Canada, UCB Pharma, Shire, P&G, and Abbott; Miles Sparrow received research support from Ferring Pharmaceuticals and Abbott Pharmaceuticals, and was on the advisory board of Schering-Plough Pharmaceuticals; Fernando Velayos was on the speaker's bureau of Centocor; Peter Irving was on the advisory board and speaker's bureau of Abbott; Shane Devlin was on the speaker's bureaus for Schering-Plough and Abbott, and on the advisory boards for Abbott, Centocor, and UCB; Gilaad Kaplan was on the advisory boards of Schering-Plough, Abbott, UCB, and Shire; and Laura Harrell was a consultant for Abbott. The remaining authors disclose no conflicts.

 Funding Unrestricted funding for the in-person Dallas RAND Appropriateness Panel meeting generously was provided by Proctor and Gamble Pharmaceuticals. Unrestricted funding for the Building Research in Inflammatory Bowel Disease Globally group is provided by Abbott, Shire, and Proctor and Gamble Pharmaceuticals.Dr Kaplan is a Canadian Institutes of Health Research New Investigator and an Alberta Heritage Foundation for Medical Research Population Health Investigator; Dr Harrell is supported by a Crohn's and Colitis Foundation of America Career Development Award; Dr Siegel is supported by a Crohn's and Colitis Foundation of America Career Development Award and by grant number K23DK078678 from the National Institute of Diabetes and Digestive and Kidney Diseases; Dr Velayos is supported by a Crohn's and Colitis Foundation of America Career Development Award and the National Institutes of Health/NCRR/OD UCSF-CTSI award (KL2 RR024130).The content of this manuscript is solely the responsibility of the authors and does not necessarily represent the official views of the National Institute of Diabetes and Digestive and Kidney Diseases or the National Institutes of Health.

 View this article's video abstract at www.cghjournal.org.

PII: S1542-3565(10)00440-4

doi:10.1016/j.cgh.2010.04.023

Clinical Gastroenterology and Hepatology
Volume 8, Issue 8 , Pages 655-659, August 2010

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