Iron therapy supplementation in inflammatory bowel disease patients with iron deficiency anemia: findings from a real-world analysis in Italy.

BACKGROUND: This real-world analysis evaluated iron therapy supplementation in inflammatory bowel disease patients with iron-deficiency anemia, considering disease progression and healthcare resource consumption. METHODS: A retrospective observational study was conducted using administrative databases of a pool of Italian healthcare entities, covering about 9.3 million beneficiaries. Between January 2010 and September 2017, adult patients were enrolled in the presence of either hospitalization or active exemption code for ulcerative colitis/Crohn's disease, or one vedolizumab prescription. Iron-deficiency anemia was identified by at least one prescription for iron and/or hospitalization for iron-deficiency anemia and/or blood transfusion (proxy of diagnosis). Patients were divided in untreated and iron-treated during 12-month follow-up and analyzed before and after propensity score matching. Disease progression, was evaluated through inflammatory bowel disease-related hospitalizations and surgeries, and healthcare resource utilization was assessed. RESULTS: Overall, 1753 patients were included, 1077 (61.4%) treated with iron therapy and 676 (38.6%) untreated. After propensity score matching, 655 patients were included in each group. In unbalanced cohorts, disease progression was significantly reduced in patients receiving iron therapy compared to the untreated (11.0% vs. 15.7%, P  < 0.01), and this trend was maintained also after applying propensity score matching. The overall mean cost/patient was significantly lower in iron-treated than untreated (4643€ vs. 6391€, P  < 0.01). CONCLUSION: The findings of this real-world analysis suggest that iron therapy was associated with significant benefits in inflammatory bowel disease patients with iron-deficiency anemia, in terms of both disease progression and healthcare resource utilization.

Unravelling the Oral-Gut Axis: Interconnection Between Periodontitis and Inflammatory Bowel Disease, Current Challenges, and Future Perspective.

As the opposite ends of the orodigestive tract, the oral cavity and the intestine share anatomical, microbial, and immunological ties that have bidirectional health implications. A growing body of evidence suggests an interconnection between oral pathologies and inflammatory bowel disease [IBD], implying a shift from the traditional concept of independent diseases to a complex, reciprocal cycle. This review outlines the evidence supporting an 'oral-gut' axis, marked by a higher prevalence of periodontitis and other oral conditions in IBD patients and vice versa. We present an in-depth examination of the interconnection between oral pathologies and IBD, highlighting the shared microbiological and immunological pathways, and proposing a 'multi-hit' hypothesis in the pathogenesis of periodontitis-mediated intestinal inflammation. Furthermore, the review underscores the critical need for a collaborative approach between dentists and gastroenterologists to provide holistic oral-systemic healthcare.

Mild Crohn's Disease: Definition and Management.

PURPOSE OF REVIEW: Crohn's Disease (CD) is a chronic inflammatory disease that can lead to progressive damage to the gastrointestinal tract and significant disability. Early, "top-down" biologic therapy is recommended in moderate-to-severe CD to induce remission and to prevent hospitalization and complications. However, an estimated 20-30% of patients with CD have a mild disease course and may not garner sufficient benefit from expensive, immunosuppressing agents to justify their risks. Herein, we review characteristics of patients with mild CD, the available options for disease treatment and monitoring, and future directions of research. RECENT FINDINGS: For ambulatory outpatients with low-risk, mild, ileal or ileocolonic CD, induction of remission with budesonide is recommended. For colonic CD, sulfasalazine is a reasonable choice, although other aminosalicylates have no role in the treatment of CD. No large, randomized trial has supported the use of antibiotics or antimycobacterials in the treatment of CD. Partial Enteral Nutrition and Crohn's Disease Exclusion Diets may be appropriate for inducing remission in some adult patients, with trials ongoing. Select patients with mild-to-moderate CD may benefit from maintenance therapy with azathioprines or gut specific biologics, such as vedolizumab. The role of complementary and alternative medicine is not well defined. The identification, risk stratification, and monitoring of patients with mild CD can be a challenging clinical scenario. Some patients with low risk of disease progression may be appropriate for initial induction of remission with budesonide or sulfasalazine, followed by close clinical monitoring. Future research should focus on pre-clinical biomarkers to stratify disease, novel therapies with minimal systemic immune suppression, and validation of rigorous clinical monitoring algorithms.

Early Reduction in MM-SES-CD Score After Initiation of Biologic Therapy is Highly Specific for 1-year Endoscopic Remission in Moderate to Severe Crohn's Disease.

BACKGROUND AND AIMS: This study evaluated the minimal clinically important short-term improvement in the Modified Multiplier Simple Endoscopic Score for crohn's Disease [MM-SES-CD], a novel modified scoring system of the SES-CD, which reliably predicted 1-year endoscopic remission [ER]. METHODS: This post-hoc analysis of two CD clinical trial programmes pooled data of 198 participants with baseline ulcers and SES-CD ≥3, who had baseline, post-induction [8-12 weeks], and 1-year endoscopic assessments. Different cut-off values for endoscopic response were evaluated using receiver operating characteristic [ROC] curves, positive likelihood ratios [PLR], and negative likelihood ratios [NLR]. ER [SES-CD <3] was the binary classifier in all cases. A distribution of cut-offs minimising NLR and maximising PLR was created with 10 000 bootstrapped resamples. An optimal cut-point for low and high probability of 1-year ER was determined based on the maximum Youden Index. RESULTS: MM-SES-CD ≥40% reduction from baseline was selected as the cut-off maximising PLR and minimising NLR. Among 7.6% [15/198] participants achieving this cut-off post-induction, 1-year ER was 46.7%. One-year ER was 16.9% among those not achieving this cut-off. This threshold predicted 1-year ER with 95.0% (95% confidence interval [CI] 90.4%-97.8%) specificity and a PLR of 3.7 [95% CI 1.4-9.5], which was higher than traditional endoscopic response criteria of SES-CD ≥50% reduction [specificity 62.5%, 95% CI 54.5%-70.0%; PLR 1.9, 95% CI 1.4-2.5]. Lower thresholds of MM-SES-CD reduction also were highly specific for 1-year ER [e.g., MM-SES-CD ≥20% reduction was achieved in 19.7% of patients with 83.1% specificity]. CONCLUSIONS: In CD patients, post-induction endoscopic response defined by MM-SES-CD ≥40% reduction from baseline identified patients most likely to achieve 1-year ER.

Integrative Analysis of the Inflammatory Bowel Disease Serum Metabolome Improves Our Understanding of Genetic Etiology and Points to Novel Putative Therapeutic Targets.

BACKGROUND & AIMS: Polygenic and environmental factors are underlying causes of inflammatory bowel disease (IBD). We hypothesized that integration of the genetic loci controlling a metabolite's abundance, with known IBD genetic susceptibility loci, may help resolve metabolic drivers of IBD. METHODS: We measured the levels of 1300 metabolites in the serum of 484 patients with ulcerative colitis (UC) and 464 patients with Crohn's disease (CD) and 365 controls. Differential metabolite abundance was determined for disease status, subtype, clinical and endoscopic disease activity, as well as IBD phenotype including disease behavior, location, and extent. To inform on the genetic basis underlying metabolic diversity, we integrated metabolite and genomic data. Genetic colocalization and Mendelian randomization analyses were performed using known IBD risk loci to explore whether any metabolite was causally associated with IBD. RESULTS: We found 173 genetically controlled metabolites (metabolite quantitative trait loci, 9 novel) within 63 non-overlapping loci (7 novel). Furthermore, several metabolites significantly associated with IBD disease status and activity as defined using clinical and endoscopic indexes. This constitutes a resource for biomarker discovery and IBD biology insights. Using this resource, we show that a novel metabolite quantitative trait locus for serum butyrate levels containing ACADS was not supported as causal for IBD; replicate the association of serum omega-6 containing lipids with the fatty acid desaturase 1/2 locus and identify these metabolites as causal for CD through Mendelian randomization; and validate a novel association of serum plasmalogen and TMEM229B, which was predicted as causal for CD. CONCLUSIONS: An exploratory analysis combining genetics and unbiased serum metabolome surveys can reveal novel biomarkers of disease activity and potential mediators of pathology in IBD.

Approach to the Management of Recently Diagnosed Inflammatory Bowel Disease Patients: A User's Guide for Adult and Pediatric Gastroenterologists.

Inflammatory bowel diseases (IBDs), including Crohn's disease and ulcerative colitis, are chronic, progressive, immune-mediated diseases of adults and children that have no cure. IBD can cause significant morbidity and lead to complications such as strictures, fistulas, infections, and cancer. In children, IBD can also result in growth impairment and pubertal delays. IBD is highly heterogenous, with severity ranging from mild to severe and symptoms ranging from mild to debilitating. Delay in IBD diagnosis, especially in Crohn's disease, is common and associated with adverse outcomes. Early diagnosis and prompt institution of treatment are the cornerstones for improving outcomes and maximizing health. Early diagnosis requires a low threshold of suspicion and red flags to guide early specialist referral at the primary provider level. Although the armamentarium of IBD medications is growing, many patients will not respond to treatment, and the selection of first-line therapy is critical. Risk stratification of disease severity, based on clinical, demographic, and serologic markers, can help guide selection of first-line therapy. Clinical decision support tools, genomics, and other biomarkers of response to therapy and risk of adverse events are the future of personalized medicine. After starting appropriate therapy, it is important to confirm remission using objective end points (treat to target) with continued control of inflammation with adjustment of therapy using surrogate biomarkers (tight control). Lastly, IBD therapy extends far beyond medications, and other aspects of the overall health and wellbeing of the patient are critical. These include preventive health, nutrition, and psychobehavioral support addressing patients' concerns around complementary therapy and medication adherence, prevention of disability, and ensuring open communication.

A User's Guide to De-escalating Immunomodulator and Biologic Therapy in Inflammatory Bowel Disease.

De-escalation of immunomodulators and biologic agents in inflammatory bowel disease is frequently discussed with patients and must weigh the risk of continued medical therapy with the risk of disease recurrence. Risk factors for disease flare after withdrawal of inflammatory bowel disease medications such as disease activity at de-escalation, disease prognostic features, and prior course of disease have been identified predominately in retrospective studies, allowing for risk stratification of patients. This review evaluates the published literature regarding therapeutic de-escalation and provides a framework for physicians to apply this to clinical practice. Prospective trials are underway and planned, which should provide further insight into this treatment paradigm and better inform patient selection for this strategy.

De-escalation of immunomodulator and biological therapy in inflammatory bowel disease.

Treatment strategies for inflammatory bowel disease (IBD) focus on the induction and long-term maintenance of deep remission to avoid complications of active disease and improve long-term outcomes. Medical therapies for IBD, notably the increasingly widespread use of biological therapy, are often effective at controlling disease, but these drugs are associated with substantial adverse events, which together with other factors-including increasing treatment costs and patient preferences-leads to concerns regarding indefinite use of medical therapy. Consequently, the need to consider the safety and feasibility of drug de-escalation once IBD remission has been achieved is clear. Here, we review the current evidence surrounding de-escalation of immunomodulator and biological therapy in Crohn's disease and ulcerative colitis. We discuss strategies for de-escalation, including the selection of patients who are appropriate for treatment de-escalation and the use of proactive drug monitoring, and review the evidence on subsequent optimal follow-up. We conclude by proposing an algorithm to guide de-escalation decisions, and highlight future perspectives, including the potential effect of emerging medication and personalised medicine for these diseases.

Stopping Mesalamine Therapy in Patients With Crohn's Disease Starting Biologic Therapy Does Not Increase Risk of Adverse Outcomes.

BACKGROUND & AIMS: Little is known about the effects of discontinuing mesalamine therapy for patients with Crohn's disease (CD) who initiate therapy with an anti-tumor necrosis factor (anti-TNF) agent. We analyzed data from 2 national population cohorts to compare outcomes of patients with CD already on mesalamine therapy who started treatment with an anti-TNF agent and then either stopped or continued mesalamine. METHODS: The primary outcome was any adverse clinical event, defined as a composite of new corticosteroid use or CD-related hospitalization or surgery. We collected data from the Truven MarketScan (IBM, Armonk, NY) health claims database in the United States and the Danish health registers. Our analysis included patients with CD who started anti-TNF therapy after at least 90 days of oral mesalamine therapy. Patients were classified as stopping mesalamine if therapy was discontinued within 90 days of starting anti-TNF. We performed multivariable Cox regression models controlling for demographics, clinical factors, and health care utilization. Adjusted hazard ratios with 95% CIs were calculated, comparing stopping mesalamine with continuing mesalamine. RESULTS: A total of 3178 patients with CD were included in our final analysis (2960 in the United States and 218 in Denmark). Stopping mesalamine after initiating anti-TNF therapy was not associated with an increased risk of adverse clinical events in the US cohort (adjusted hazard ratio, 0.89; 95% CI, 0.77-1.03; P = .13) or in the Danish cohort (adjusted hazard ratio, 1.13; 95% CI, 0.68-1.87; P = .63). Similar results were obtained from sensitivity analyses of concomitant immunomodulator use and duration of mesalamine treatment before initiation of anti-TNF therapy. CONCLUSIONS: In a retrospective analysis of 2 national databases, we found that stopping mesalamine therapy for patients with CD who were starting anti-TNF therapy did not increase their risk of adverse clinical events. These results should be validated in a prospective study.

The Role of Early Biologic Therapy in Inflammatory Bowel Disease.

The goals for treatment of inflammatory bowel diseases (IBDs) are changing from elimination of symptoms toward complete disease control-a process that demands both clinical and endoscopic remission. This new IBD treatment paradigm has been shifting from a conventional "step-up" approach toward a more "top-down" early intervention treatment strategy. Recent studies suggest that the use of biologic agents, specifically those targeting tumor necrosis factor alpha, earlier in the treatment course improves patient outcomes and can prevent progression to irreversible bowel damage. Although the strategy of early intervention has accumulating evidence in Crohn's disease, there is less evidence supporting its impact in ulcerative colitis.

Novel Targets For Therapeutic Intervention in Inflammatory Bowel Disease. What is the Best Way to Assess the Safety Profile of a Drug?

The emergence of biologic therapies has revolutionized the management of inflammatory bowel disease (IBD) by halting disease progression, increasing remission rates and improving long-term clinical outcomes. Despite these well-described benefits, many patients are reluctant to commence therapy due to drug safety concerns. Adverse events can be detected at each stage of drug development and during the post-marketing period. In this article, we review how to best assess the safety parameters of new IBD medications, from the earliest stage of development to population-based registries, with a focus on the special populations often excluded from the evaluation process.

Stopping 5-aminosalicylates in patients with ulcerative colitis starting biologic therapy does not increase the risk of adverse clinical outcomes: analysis of two nationwide population-based cohorts.

OBJECTIVE: The benefit of continuing 5-aminosalicylate (5-ASA) in patients with ulcerative colitis (UC) who initiate anti-tumour necrosis factor-alpha (anti-TNF) biologics is unknown. We aimed to compare clinical outcomes in patients with UC already on 5-ASA who started anti-TNF and then either stopped or continued 5-ASA. DESIGN: Our primary outcome was any adverse clinical event defined as a composite of new corticosteroid use, UC-related hospitalisation or surgery. We used two national databases: the United States (US) Truven MarketScan health claims database and the Danish health registers. Patients with UC who started anti-TNF after having been on oral 5-ASA for at least 90 days were included. Patients were classified as stopping 5-ASA if therapy was discontinued within 90 days of starting anti-TNF. We performed multivariable Cox regression models controlling for demographics, clinical factors and healthcare utilisation. Adjusted HRs (aHR) with 95% CI are reported comparing stopping 5-ASA with continuing 5-ASA. RESULTS: A total of 3589 patients with UC were included (2890 US and 699 Denmark). Stopping 5-ASA after initiating anti-TNF was not associated with an increased risk of adverse clinical events in the U.S. cohort (aHR 1.04; 95% CI 0.90 to 1.21, p=0.57) nor in the Danish cohort (aHR 1.09; 95% CI 0.80 to 1.49, p=0.60). Results were similar in sensitivity analyses investigating concomitant immunomodulator use and duration of 5-ASA treatment before initiating anti-TNF. CONCLUSION: In two national databases, stopping 5-ASA in patients with UC starting anti-TNF therapy did not increase the risk of adverse clinical events. These results should be validated in a prospective clinical trial.

AGA Clinical Practice Update on Functional Gastrointestinal Symptoms in Patients With Inflammatory Bowel Disease: Expert Review.

DESCRIPTION: The purpose of this clinical practice update review is to describe key principles in the diagnosis and management of functional gastrointestinal (GI) symptoms in patients with inflammatory bowel disease (IBD). METHODS: The evidence and best practices summarized in this manuscript are based on relevant scientific publications, systematic reviews, and expert opinion where applicable. Best practice advice 1: A stepwise approach to rule-out ongoing inflammatory activity should be followed in IBD patients with persistent GI symptoms (measurement of fecal calprotectin, endoscopy with biopsy, cross-sectional imaging). Best practice advice 2: In those patients with indeterminate fecal calprotectin levels and mild symptoms, clinicians may consider serial calprotectin monitoring to facilitate anticipatory management. Best practice advice 3: Anatomic abnormalities or structural complications should be considered in patients with obstructive symptoms including abdominal distention, pain, nausea and vomiting, obstipation or constipation. Best practice advice 4: Alternative pathophysiologic mechanisms should be considered and evaluated (small intestinal bacterial overgrowth, bile acid diarrhea, carbohydrate intolerance, chronic pancreatitis) based on predominant symptom patterns. Best practice advice 5: A low FODMAP diet may be offered for management of functional GI symptoms in IBD with careful attention to nutritional adequacy. Best practice advice 6: Psychological therapies (cognitive behavioural therapy, hypnotherapy, mindfulness therapy) should be considered in IBD patients with functional symptoms. Best practice advice 7: Osmotic and stimulant laxative should be offered to IBD patients with chronic constipation. Best practice advice 8: Hypomotility agents or bile-acid sequestrants may be used for chronic diarrhea in quiescent IBD. Best practice advice 9: Antispasmodics, neuropathic-directed agents, and anti-depressants should be used for functional pain in IBD while use of opiates should be avoided. Best practice advice 10: Probiotics may be considered for treatment of functional symptoms in IBD. Best practice advice 11: Pelvic floor therapy should be offered to IBD patients with evidence of an underlying defecatory disorder. Best practice advice 12: Until further evidence is available, fecal microbiota transplant should not be offered for treatment of functional GI symptoms in IBD. Best practice advice 13: Physical exercise should be encourage in IBD patients with functional GI symptoms. Best practice advice 14: Until further evidence is available, complementary and alternative therapies should not be routinely offered for functional symptoms in IBD. This Clinical Practice Update was produced by the AGA Institute.

Integrated Care for Crohn's Disease: A Plea for the Development of Clinical Decision Support Systems.

Evolution in the management of Crohn's disease [CD] has been characterized by recent paradigm changes. First, new biological therapies induce intestinal healing and full disease control in a substantial number of patients, particularly when introduced early in the disease course. However, they are expensive and associated with potentially severe side effects, raising the question of optimal treatment duration. Secondly, progress in biomarkers and medical imaging performance has enabled better refinement of the definition and prediction of remission or relapse of the disease through monitoring [tight control]. This progress may help to improve tailoring treatment in relation to target ['treat-to target' approach], applying patient-centred and collaborative perspectives, consistent with other chronic disease management. Such an approach requires the integration of a potentially large number of parameters coming from different stakeholders. This integration would be difficult based solely on implementation of classical guidelines and the clinician's intuition. To this end, clinical decision support systems should be developed that integrate a combination of various outcomes to facilitate the treatment decision and to share information between patients, primary care specialists, and health insurance companies or health authorities. This should ease complex therapeutic decisions and serve as a basis for continued research into effectiveness of CD management.

The current state of the art for biological therapies and new small molecules in inflammatory bowel disease.

The emergence of biologic therapies is arguably the greatest therapeutic advance in the care of inflammatory bowel disease (IBD) to date, allowing directed treatments targeted at highly specific molecules shown to play critical roles in disease pathogenesis, with advantages in potency and selectivity. Furthermore, a large number of new biologic and small-molecule therapies in IBD targeting a variety of pathways are at various stages of development that should soon lead to a dramatic expansion in our therapeutic armamentarium. Additionally, since the initial introduction of biologics, there have been substantial advances in our understanding as to how biologics work, the practical realities of their administration, and how to enhance their efficacy and safety in the clinical setting. In this review, we will summarize the current state of the art for biological therapies in IBD, both in terms of agents available and their optimal use, as well as preview future advances in biologics and highly targeted small molecules in the IBD field.

Interactions Between Diet and the Intestinal Microbiota Alter Intestinal Permeability and Colitis Severity in Mice.

BACKGROUND & AIMS: It is not clear how the complex interactions between diet and the intestinal microbiota affect development of mucosal inflammation or inflammatory bowel disease. We investigated interactions between dietary ingredients, nutrients, and the microbiota in specific pathogen-free (SPF) and germ-free (GF) mice given more than 40 unique diets; we quantified individual and synergistic effects of dietary macronutrients and the microbiota on intestinal health and development of colitis. METHODS: C56BL/6J SPF and GF mice were placed on custom diets containing different concentrations and sources of protein, fat, digestible carbohydrates, and indigestible carbohydrates (fiber). After 1 week, SPF and GF mice were given dextran sulfate sodium (DSS) to induce colitis. Disease severity was determined based on the percent weight change from baseline, and modeled as a function of the concentration of each macronutrient in the diet. In unchallenged mice, we measured intestinal permeability by feeding mice labeled dextran and measuring levels in blood. Feces were collected and microbiota were analyzed by 16S rDNA sequencing. We collected colons from mice and performed transcriptome analyses. RESULTS: Fecal microbiota varied with diet; the concentration of protein and fiber had the strongest effect on colitis development. Among 9 fiber sources tested, psyllium, pectin, and cellulose fiber reduced the severity of colitis in SPF mice, whereas methylcellulose increased severity. Increasing dietary protein increased the density of the fecal microbiota and the severity of colitis in SPF mice, but not in GF mice or mice given antibiotics. Psyllium fiber reduced the severity of colitis through microbiota-dependent and microbiota-independent mechanisms. Combinatorial perturbations to dietary casein protein and psyllium fiber in parallel accounted for most variation in gut microbial density and intestinal permeability in unchallenged mice, as well as the severity of DSS-induced colitis; changes in 1 ingredient could be offset by changes in another. CONCLUSIONS: In an analysis of the effects of different dietary components and the gut microbiota on mice with and without DSS-induced colitis, we found complex mixtures of nutrients affect intestinal permeability, gut microbial density, and development of intestinal inflammation.

Treatment With Biologic Agents Has Not Reduced Surgeries Among Patients With Crohn's Disease With Short Bowel Syndrome.

BACKGROUND & AIMS: Little is known about the effects of biologic agents used to treat Crohn's disease (CD) on its long-term complications, such as short bowel syndrome and intestinal failure (SBS-IF). We evaluated trends in small bowel resections and health care utilization among patients with CD with and without SBS-IF. METHODS: We collected data on the National Inpatient Sample on 2,989,185 patients hospitalized with CD in the United States before the time period in which CD was treated with biologic agents (1993-1997) and after biologic therapy became widespread (1998-2014). We used Poisson and linear regression analyses to evaluate trends for small bowel resections and health care utilization among patients with CD with and without SBS-IF. Multivariable models were adjusted for age, sex, Charlson-Deyo comorbidity index, payer source, hospital size, region, and teaching status. RESULTS: The proportions of patients who underwent resection did not significantly change during the period before biologic therapy (121.8 per 1000 hospitalizations in 1993 to 110.1 per 1000 hospitalizations in 1997; P trend =.14) but decreased significantly during the period after biologic therapy began (99.0 per 1000 hospitalizations in 1998 to 64.6 per 1000 hospitalizations in 2014; P trend < .01). However, among patients with SBS-IF, similar proportions of patients underwent resection during the period before biologic therapy (0.7 per 1000 hospitalizations in 1993 to 0.7 per 1000 hospitalizations in 1997; P trend = .92) and during the period after biologic therapy (0.6 per 1000 hospitalizations in 1998 to 0.7 per 1000 hospitalizations in 2014; P trend = .06). Rates of hospitalization for patients with SBS-IF increased from 16.5 per 1000 hospitalizations in 1998 to 19.5 per 1000 hospitalizations in 2014 (P trend < .01). SBS-IF hospitalizations were associated with longer lengths of stay (P < .01) and greater total charges (P < .01). CONCLUSIONS: In a study of the United States population, we found that the use of biologic agents to treat CD reduced the proportion of patients undergoing resection, but not among patients with SBS-IF. These findings indicate that biologic agents reduce some but not all features of CD. Studies are needed to identify patients at risk for SBS-IF, prevent and treat this complication, and identify new treatments.

Interpreting Registrational Clinical Trials of Biological Therapies in Adults with Inflammatory Bowel Diseases.

BACKGROUND: The use of biologics to treat inflammatory bowel disease is supported by robust randomized controlled trials in both ulcerative colitis and Crohn's disease. Nonetheless, an understanding of the principles of clinical trial design is necessary to extrapolate study findings to clinical practice. METHODS: We conducted a review of inflammatory bowel disease registrational clinical trials of biologics to determine how differences in trial design potentially influence results and interpretation. RESULTS: Registrational trials of biological agents have used diverse patient populations, outcome measures, and designs, which makes comparisons of results among studies difficult. Key differences among trials include patient populations, choice of symptom-based measures or objective outcomes as endpoints, and overall trial design. Additional factors, including analytical methods, can also influence the interpretation of outcomes. CONCLUSIONS: The most robust evidence is derived from comparative effectiveness trials. In the absence of these, clinicians should be aware of the various methodological issues which could impact interpretation of efficacy and safety outcomes, including differences in patient population, study design, and analytic methodology.

Converging goals of treatment of inflammatory bowel disease from clinical trials and practice.

It is important to have clear goals for treating inflammatory bowel disease in clinical practice and in research. Conventional end points for trials in ulcerative colitis and Crohn's disease have been based on composite indices, such as the Mayo Clinic Score and the Crohn's Disease Activity Index; these indices incorporate symptoms, signs, and findings from laboratory tests and sometimes endoscopic assessments. Although definitions of clinical response and remission have been based on these indices for regulatory purposes, they are difficult to apply to practice because they are complex and not intuitive to clinicians. This has caused a disconnect between clinical trials and practice. Recently, the use of composite indices in trials has been reevaluated in Food and Drug Administration-sponsored Gastroenterology Regulatory Endpoints and the Advancement of Therapeutics workshops due to concerns about the validity of the indices. Alternative measures of outcome and definitions of response are being developed. Patient-reported outcomes are psychometric instruments created and defined by patients to quantify symptoms. A combination of end points, comprising patient-reported outcomes and objective evaluation of inflammation by endoscopy, offers a clinically meaningful and scientifically valid alternative to existing composite indices. Unlike composite indices, response definitions based on endoscopy and patient-reported outcomes can be readily applied in practice. This convergence of outcome assessment in clinical trials and practice could expedite implementation of "treat-to-target" algorithms, in which therapy is progressively intensified until a specific treatment goal is reached. This approach could improve patient care by reducing rates of disease-related complications, surgery, and hospitalization.

Treat to target: a proposed new paradigm for the management of Crohn's disease.

The traditional management of Crohn's disease, which is based on progressive, step-wise treatment intensification with re-evaluation of response according to symptoms, does not improve long-term outcomes of Crohn's disease and places patients at risk for bowel damage. The introduction of novel therapies and the development of new approaches to treatment in rheumatoid arthritis led to better outcomes for patients. Prominent among these is a "treat to target" strategy that is based on regular assessment of disease activity by using objective clinical and biological outcome measures and the subsequent adjustment of treatments. This approach is complementary to the concept of early intervention in high-risk patients. This review evaluates current literature on this topic and proposes a definition for the concept of treating to targets for Crohn's disease.