When Perfect Is the Enemy of Good: Results of a RAND Appropriateness Panel on Treat to Target in Asymptomatic Inflammatory Bowel Disease.

BACKGROUND: A treat-to-target strategy for inflammatory bowel disease (IBD) recommends iterative treatment adjustments to achieve clinical and endoscopic remission. In asymptomatic patients with ongoing endoscopic activity, the risk/benefit balance of this approach is unclear, particularly with prior exposure to advanced therapies. METHODS: Using the RAND/University of California Los Angeles Appropriateness Method, 9 IBD specialists rated appropriateness of changing therapy in 126 scenarios of asymptomatic patients with ulcerative colitis and Crohn's disease and active endoscopic disease. Disease extent and behavior, prior treatment, prior complications, and recent disease progression were considered, as were factors that might influence decision-making, including age and pregnancy. Ratings were collected through anonymous survey, discussed at an in-person meeting, and finalized in a second anonymous survey. RESULTS: Panelists rated change in therapy as appropriate (i.e., expected benefit sufficiently outweighs potential harms from continuing therapy) in 96/126 scenarios, generally in patients with progressive, complicated, and/or extensive disease, while changing therapy was rated uncertain in 27 scenarios of mild and/or stable disease. Changing therapy was rated inappropriate in ulcerative colitis patients with mild and stable disease previously exposed to ≥3 therapies or with improved endoscopic activity, and in Crohn's disease patients with only scattered aphthous ulcers. The validated threshold for disagreement was not crossed for any scenario. Patient age older than 65 years and a plan for pregnancy in the next year might influence decision-making in some settings. DISCUSSION: Appropriateness ratings can help guide clinical decision-making about changing therapy to achieve endoscopic remission in asymptomatic patients with IBD until data from ongoing randomized studies are available.

Appropriate Therapeutic Drug Monitoring of Biologic Agents for Patients With Inflammatory Bowel Diseases.

BACKGROUND & AIMS: Therapeutic drug monitoring (TDM) is widely available for biologic therapies in patients with inflammatory bowel disease (IBD). We reviewed current data and provided expert opinion regarding the clinical utility of TDM for biologic therapies in IBD. METHODS: We used a modified Delphi method to establish consensus. A comprehensive literature review was performed regarding the use of TDM of biologic therapy in IBD and presented to international IBD specialists. Subsequently, 28 statements on the application of TDM in clinical practice were rated on a scale of 1 to 10 (1 = strongly disagree and 10 = strongly agree) by each of the panellists. Statements were accepted if 80% or more of the participants agreed with a score ≥7. The remaining statements were discussed and revised based on the available evidence followed by a second round of voting. RESULTS: The panel agreed on 24 (86%) statements. For anti-tumor necrosis factor (anti-TNF) therapies, proactive TDM was found to be appropriate after induction and at least once during maintenance therapy, but this was not the case for the other biologics. Reactive TDM was appropriate for all agents both for primary non-response and secondary loss of response. The panellists also agreed on several statements regarding TDM and appropriate drug and anti-drug antibody (ADA) concentration thresholds for biologics in specific clinical scenarios. CONCLUSION: Consensus was achieved towards the utility of TDM of biologics in IBD, particularly anti-TNF therapies. More data are needed especially on non-anti-TNF biologics to further define optimal drug concentration and ADA thresholds as these can vary depending on the therapeutic outcomes assessed.

Appropriateness of Combination Therapy for Patients With Inflammatory Bowel Diseases: One Size Still Does Not Fit All.

Randomized controlled trials (RCTs) have demonstrated that therapies targeting tumor necrosis factor (TNF) and α4ß7 integrin are effective when given as monotherapy in inducing and/or maintaining remission in patients with ulcerative colitis (UC) or Crohn's disease (CD), but data from RCTs are less clear on whether concomitant immunomodulator (IM) therapy confers additional benefit. In CD, RCT data are mixed,1,2 as are results of systematic reviews and meta-analyses, showing no benefit overall,3 minimal benefit with individual agents,4 and comparative benefit over some monotherapies but not others.5 For example, concomitant azathioprine with infliximab is more effective than either drug alone in patients with CD naive to both drugs,2 but whether combination therapy is more effective than monotherapy with infliximab in nonnaive patients, or with other approved biologic drugs in any population, remains unknown. In UC, RCTs have shown that the benefit may be limited to specific populations,6 whereas systematic reviews suggest no benefit at all.7.

Appropriateness of Testing for Anti-Tumor Necrosis Factor Agent and Antibody Concentrations, and Interpretation of Results.

BACKGROUND & AIMS: The availability of tests for blood concentrations of anti-tumor necrosis factor (TNF) agents and antibodies against these drugs could improve dose selection for patients with inflammatory bowel disease (IBD). However, there is little consensus on when to test and how to interpret test results. We used the RAND/UCLA Appropriateness Method to determine when these tests are appropriate and how to clinically interpret their results. METHODS: We conducted a systematic literature search in November 2013 to identify observational or experimental studies of the measurement of anti-TNF drug and antibody concentrations in patients with IBD and interpretation of their results. We developed 35 scenarios that assessed the appropriateness of testing and 143 scenarios that addressed clinical strategies in response to test results, and presented the findings to an expert panel. The appropriateness of each scenario was rated before and after an in-person meeting with the panel. Panelists rated the appropriateness of various clinical management options including changing therapy within class, switching out of class, adjusting drug dose or interval, adding or adjusting concomitant immune modulators, and doing nothing for each of 6 permutations of high versus low drug concentrations and high, low, or undetectable antibody concentrations. Disagreement was assessed using a validated index. RESULTS: Assessment of anti-TNF drug and antibody concentrations was rated appropriate at the end of induction therapy in primary nonresponders, in secondary nonresponders, at least once during the first year of maintenance therapy, and following a drug holiday. Routine assessment in responders at the end of induction was rated uncertain. In nearly all scenarios, escalation of drug dosing was rated appropriate when drug concentration was low in the absence of antibodies, and switching within class was rated appropriate when antibodies were present. Other recommendations depended on the specific clinical scenario for which the test was obtained. CONCLUSIONS: Based on the RAND/UCLA Appropriateness Method of analysis, an expert panel recommends testing for drug and antibody concentrations in many clinical scenarios. The appropriate timing and best way to respond to anti-TNF drug and antibody testing for IBD depends on the specific clinical scenario. These recommendations can help guide clinicians to best optimize anti-TNF therapy.

The appropriateness of concomitant immunomodulators with anti-tumor necrosis factor agents for Crohn's disease: one size does not fit all.

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.

Treatment of inflammatory bowel disease: a review of medical therapy.

Crohn's disease (CD) and ulcerative colitis (UC) are chronic inflammatory diseases of the gastrointestinal tract. While a cure remains elusive, both can be treated with medications that induce and maintain remission. With the recent advent of therapies that inhibit tumor necrosis factor (TNF) alpha the overlap in medical therapies for UC and CD has become greater. Although 5-ASA agents have been a mainstay in the treatment of both CD and UC, the data for their efficacy in patients with CD, particularly as maintenance therapy, are equivocal. Antibiotics may have a limited role in the treatment of colonic CD. Steroids continue to be the first choice to treat active disease not responsive to other more conservative therapy; non-systemic steroids such as oral and rectal budesonide for ileal and right-sided CD and distal UC respectively are also effective in mild-moderate disease. 6-mercaptopurine (6-MP) and its prodrug azathioprine are steroid-sparing immunomodulators effective in the maintenance of remission of both CD and UC, while methotrexate may be used in both induction and maintenance of CD. Infliximab and adalimumab are anti-TNF agents approved in the US and Europe for the treatment of Crohn's disease, and infliximab is also approved for the treatment of UC.

Recommendations for Quality Colonoscopy Reporting for Patients with Inflammatory Bowel Disease: Results from a RAND Appropriateness Panel.

BACKGROUND: Consensus on what constitutes a quality colonoscopy report for patients with inflammatory bowel disease (IBD) is lacking. We developed a template for quality colonoscopy reporting that can be used broadly by endoscopists. METHODS: After a literature review of topics relevant to colonoscopy reporting, members of the Building Research in Inflammatory Bowel Disease Globally (BRIDGe) group and 2 external experts proposed candidate reporting elements. The RAND/University of California, Los Angeles appropriateness method was applied to rate the importance and feasibility of elements for inclusion in colonoscopy reports for patients with IBD. Panelists used the modified Delphi method to anonymously rate the importance and feasibility of candidate elements on a 1-to-9 scale (1-3: not important/feasible, 4-6: moderately important/feasible, 7-9: very important/feasible). Disagreement was assessed using a validated index. The panelists then met in person for discussion followed by a second round of voting. Elements rated a median of 7 or higher on importance after rerating were retained. RESULTS: One hundred two reporting elements were proposed. A total of 48 elements were retained across the four themes of "disease background," "findings and interventions," "Crohn's disease with an ileocolonic anastomosis," and "pouchoscopy." CONCLUSIONS: A comprehensive list of recommended elements for quality IBD colonoscopy reporting stratified by clinical scenario has been described, using a rigorous and evidence-based approach. These elements can be incorporated into endoscopy reporting software platforms. Standardized endoscopy reporting may improve the quality of care in IBD.

Current Controversies in Crohn's Disease: A Roundtable Discussion of the BRIDGe Group.

In March 2008, a roundtable discussion was convened by the inflammatory bowel disease (IBD) specialist panel the BRIDGe (Building Resources and Research in IBD Globally) group, which consists of junior faculty gastroenterologists who have undergone advanced fellowship training at IBD referral centers in the United States, Canada, the United Kingdom, and Australia. An agenda was formulated to discuss three current controversies in Crohn's disease management: the role of 5-aminosalicylates, the use of biologic combination therapy versus monotherapy, and the use of step-up therapy versus top-down therapy for Crohn's disease. The aim of the meeting was three-fold: to review the data pertaining to each topic; to collect opinions from the participants as to their analysis of the literature and their current practice; and, where possible, to formulate recommendations of current best practice given the available evidence. This manuscript summarizes the discussions on these three areas of controversy in the current management of Crohn's disease.

General principles and pharmacology of biologics in inflammatory bowel disease.

The pharmacology of each biologic agent is important regarding the dose required to achieve benefits, duration of therapeutic effect, and the induction of immunogenicity. Comprehension of the individual pharmacology, pharmacodynamics, and pharmacokinetics, in addition to the impact of concomitant immunomodulation on immunogenicity allows optimization of each biologic agent in the appropriate inductive or maintenance setting of IBD.