Over the past two decades, 11 biologic agents have been approved for use in most countries for the treatment of moderate-to-severe inflammatory bowel disease (IBD). Antitumor necrosis factor α ...(anti-TNF) agents are commonly used as the first biologic in clinical practice, and nearly all pivotal studies of induction therapy enrolled patients with and without prior use of anti-TNF therapy. This narrative review presents a reasonable approach to devising treatment sequences, examining the magnitude of benefit for each drug versus placebo or active comparator and then considering how that benefit changes with prior anti-TNF treatment. Data from ULTRA 2, GEMINI 1, VARSITY, and True North in patients with ulcerative colitis indicate that induction adalimumab, vedolizumab, and ozanimod showed lower clinical remission rates after anti-TNF therapy, while UNIFI, OCTAVE 1&2, and U-ACHIEVE/U-ACCOMPLISH show ustekinumab, tofacitinib, and upadacitinib did not. In patients with Crohn’s disease, endoscopic remission or mucosal healing after induction therapy rather than clinical remission as well as assessment of persistent endoscopic remission are good measures of long-term disease outcomes. Considering the drugs for which data on endoscopic remission rates are available, EXTEND and GEMINI 2&3 show adalimumab and vedolizumab with persistently lower endoscopic remission rates after prior anti-TNF therapy, while IM-UNIFI, SEAVUE, and FORTIFY show ustekinumab and risankizumab did not. Data from the multicenter retrospective EVOLVE study indicate that the effectiveness of anti-TNF therapy does not seem to be significantly impacted by prior vedolizumab therapy, and may further suggest the benefit of using vedolizumab as a first-line biologic. As adverse event rates remain low across all treatments, the magnitude of harm from untreated or poorly treated disease far outweighs harm from any individual therapy. Regardless of the treatment sequence, careful monitoring for early signs of treatment nonresponse and switching to another potentially highly active therapy are critical to effective management of IBD.
Diagnosis and monitoring of inflammatory bowel diseases rely on clinical, endoscopic, and radiologic parameters. Inflammatory biomarkers have been investigated as a surrogate marker for endoscopic ...diagnosis of inflammatory activity. Fecal inflammatory biomarkers such as calprotectin and lactoferrin are direct products of bowel inflammation and provide an accurate and noninvasive diagnostic and monitoring modality for Crohn's disease and ulcerative colitis. This report contains an overview of the currently existing literature pertaining to clinical implications of fecal biomarkers for diagnosis, monitoring, and prediction of outcomes of inflammatory bowel disease.
The efficacy of vedolizumab, an α4β7 integrin antibody, in Crohn's disease is unknown.
In an integrated study with separate induction and maintenance trials, we assessed intravenous vedolizumab ...therapy (300 mg) in adults with active Crohn's disease. In the induction trial, 368 patients were randomly assigned to receive vedolizumab or placebo at weeks 0 and 2 (cohort 1), and 747 patients received open-label vedolizumab at weeks 0 and 2 (cohort 2); disease status was assessed at week 6. In the maintenance trial, 461 patients who had had a response to vedolizumab were randomly assigned to receive placebo or vedolizumab every 8 or 4 weeks until week 52.
At week 6, a total of 14.5% of the patients in cohort 1 who received vedolizumab and 6.8% who received placebo were in clinical remission (i.e., had a score on the Crohn's Disease Activity Index CDAI of ≤150, with scores ranging from 0 to approximately 600 and higher scores indicating greater disease activity) (P=0.02); a total of 31.4% and 25.7% of the patients, respectively, had a CDAI-100 response (≥100-point decrease in the CDAI score) (P=0.23). Among patients in cohorts 1 and 2 who had a response to induction therapy, 39.0% and 36.4% of those assigned to vedolizumab every 8 weeks and every 4 weeks, respectively, were in clinical remission at week 52, as compared with 21.6% assigned to placebo (P<0.001 and P=0.004 for the two vedolizumab groups, respectively, vs. placebo). Antibodies against vedolizumab developed in 4.0% of the patients. Nasopharyngitis occurred more frequently, and headache and abdominal pain less frequently, in patients receiving vedolizumab than in patients receiving placebo. Vedolizumab, as compared with placebo, was associated with a higher rate of serious adverse events (24.4% vs. 15.3%), infections (44.1% vs. 40.2%), and serious infections (5.5% vs. 3.0%).
Vedolizumab-treated patients with active Crohn's disease were more likely than patients receiving placebo to have a remission, but not a CDAI-100 response, at week 6; patients with a response to induction therapy who continued to receive vedolizumab (rather than switching to placebo) were more likely to be in remission at week 52. Adverse events were more common with vedolizumab. (Funded by Millennium Pharmaceuticals; GEMINI 2 ClinicalTrials.gov number, NCT00783692.).
Background. Inflammatory bowel disease (IBD) patients are not routinely screened for depression and anxiety despite knowledge of an increased prevalence in people with chronic disease and negative ...effects on quality of life. Methods. Prevalence of anxiety and depression was assessed in IBD outpatients through retrospective chart review. The presence of anxiety and/or depression was determined using the Patient Health Questionnaire-9 and Generalized Anxiety Disorder-7 self-report questionnaires or by diagnosis through psychiatric interview. Patient demographics, disease characteristics, and medication information were also collected. Multivariable analysis was used to determine associations between patient factors and depression and anxiety. Results. 327 patient charts were reviewed. Rates of depression and anxiety were found to be 25.8% and 21.2%, with 30.3% of patients suffering from depression and/or anxiety. Disease activity was found to be significantly associated with depression and/or anxiety (p=0.01). Females were more likely to have anxiety (p=0.01). Conclusion. A significant proportion of IBD patients suffer from depression and/or anxiety. The rates of these mental illnesses would justify screening and referral for psychiatric treatment in clinics treating this population. Patients with active disease are particularly at risk for anxiety and depression.
Background & Aims The management of inflammatory bowel disease (IBD) poses a particular challenge during pregnancy because the health of both the mother and the fetus must be considered. Methods A ...systematic literature search identified studies on the management of IBD during pregnancy. The quality of evidence and strength of recommendations were rated using the Grading of Recommendation Assessment, Development and Evaluation (GRADE) approach. Results Consensus was reached on 29 of the 30 recommendations considered. Preconception counseling and access to specialist care are paramount in optimizing disease management. In general, women on 5-ASA, thiopurine, or anti–tumor necrosis factor (TNF) monotherapy for maintenance should continue therapy throughout pregnancy. Discontinuation of anti-TNF therapy or switching from combination therapy to monotherapy may be considered in very select low-risk patients. Women who have a mild to moderate disease flare while on optimized 5-ASA or thiopurine therapy should be managed with systemic corticosteroid or anti-TNF therapy, and those with a corticosteroid-resistant flare should start anti-TNF therapy. Endoscopy or urgent surgery should not be delayed during pregnancy if indicated. Decisions regarding cesarean delivery should be based on obstetric considerations and not the diagnosis of IBD alone, with the exception of women with active perianal Crohn’s disease. With the exception of methotrexate, the use of medications for IBD should not influence the decision to breast-feed and vice versa. Live vaccinations are not recommended within the first 6 months of life in the offspring of women who were on anti-TNF therapy during pregnancy. Conclusions Optimal management of IBD before and during pregnancy is essential to achieving favorable maternal and neonatal outcomes.
Summary Background Conventional management of Crohn's disease features incremental use of therapies. However, early combined immunosuppression (ECI), with a TNF antagonist and antimetabolite might be ...a more effective strategy. We compared the efficacy of ECI with that of conventional management for treatment of Crohn's disease. Methods In this open-label cluster randomised controlled trial (Randomised Evaluation of an Algorithm for Crohn's Treatment, REACT), we included community gastroenterology practices from Belgium and Canada that were willing to be assigned to either of the study groups, participate in all aspects of the study, and provide data on up to 60 patients with Crohn's disease. These practices were randomly assigned (1:1) to either ECI or conventional management. The computer-generated randomisation was minimised by country and practice size. Up to 60 consecutive adult patients were assessed within practices. Patients who were aged 18 years or older; documented to have Crohn's disease; able to speak or understand English, French, or Dutch; able to access a telephone; and able to provide written informed consent were followed up for 2 years. The primary outcome was the proportion of patients in corticosteroid-free remission (Harvey-Bradshaw Index score ≤4) at 12 months at the practice level. This trial is registered with ClinicalTrials.gov , number NCT01030809. Findings This study took place between March 15, 2010, and Oct 1, 2013. Of the 60 practices screened, 41 were randomly assigned to either ECI (n=22) or conventional management (n=19). Two practices (one in each group) discontinued because of insufficient resources. 921 (85%) of the 1084 patients at ECI practices and 806 (90%) of 898 patients at conventional management practices completed 12 months follow-up and were included in an intention-to-treat analysis. The 12 month practice-level remission rates were similar at ECI and conventional management practices (66·0% SD 14·0 and 61·9% 16·9; adjusted difference 2·5%, 95% CI −5·2% to 10·2%, p=0·5169). The 24 month patient-level composite rate of major adverse outcomes defined as occurrence of surgery, hospital admission, or serious disease-related complications was lower at ECI practices than at conventional management practices (27·7% and 35·1%, absolute difference AD 7·3%, hazard ratio HR: 0·73, 95% CI 0·62 to 0·86, p=0·0003). There were no differences in serious drug-related adverse events. Interpretation Although ECI was not more effective than conventional management for controlling Crohn's disease symptoms, the risk of major adverse outcomes was lower. The latter finding should be considered hypothesis-generating for future trials. ECI was not associated with an increased risk of serious drug-related adverse events or mortality. Funding AbbVie Pharmaceuticals.
Background & Aims The medical management of ulcerative colitis (UC) has improved through the development of new therapies and novel approaches that optimize existing drugs. Previous Canadian ...consensus guidelines addressed the management of severe UC in the hospitalized patient. We now present consensus guidelines for the treatment of ambulatory patients with mild to severe active UC. Methods A systematic literature search identified studies on the management of UC. The quality of evidence and strength of recommendations were rated according to the Grading of Recommendation Assessment, Development and Evaluation (GRADE) approach. Statements were developed through an iterative online platform and then finalized and voted on by a working group of specialists. Results The participants concluded that the goal of therapy is complete remission, defined as both symptomatic and endoscopic remission without corticosteroid therapy. The consensus includes 34 statements focused on 5 main drug classes: 5-aminosalicylate (5-ASA), corticosteroids, immunosuppressants, anti–tumor necrosis factor (TNF) therapies, and other therapies. Oral and rectal 5-ASA are recommended first-line therapy for mild to moderate UC, with corticosteroid therapy for those who fail to achieve remission. Patients with moderate to severe UC should undergo a course of oral corticosteroid therapy, with transition to 5-ASA, thiopurine, anti-TNF (with or without thiopurine or methotrexate), or vedolizumab maintenance therapy in those who successfully achieve symptomatic remission. For patients with corticosteroid-resistant/dependent UC, anti-TNF or vedolizumab therapy is recommended. Timely assessments of response and remission are critical to ensuring optimal outcomes. Conclusions Optimal management of UC requires careful patient assessment, evidence-based use of existing therapies, and thorough assessment to define treatment success.
Infliximab is an anti-TNF alpha blocker frequently utilized in the management of moderate to severe Crohn's Disease. The immunosuppressive effects of infliximab may increase the risk for ...post-operative complications among Crohn's Disease patients undergoing abdominal surgery. We conducted a systematic review and meta-analysis of studies comparing the rates of post-operative complications among Crohn's disease patients treated with Infliximab therapy versus alternative therapies.
We used the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) and searched 4 electronic databases along with major conference abstract databases from inception of database until November, 2012. English-language articles and abstracts evaluating post-operative complications among Crohn's disease patients were considered eligible. We applied meta-analysis with random effects model to calculate the overall odds ratio for total major complications as well as several secondary outcomes.
Data were extracted from six studies including 1159 patients among whom 413 complications were identified. The most common complications were wound infections, anastomotic leak and sepsis. There was no significant difference in the major complication rate (OR=1.5995% C.I.: 0.89–2.86; p=0.15), minor complication rate (OR=1.80 C.I.: 0.87–3.71; p=0.11), reoperation rate (OR=1.33 C.I.: 0.55–3.20; p=0.52) or 30day mortality rate (OR=3.74 C.I.: 0.56–25.16; p=0.13) between the Infliximab and control groups.
This meta analysis provides some evidence that infliximab may be safe to continue in the pre-operative period without increasing the risk of post-operative complications for Crohn's disease patients undergoing abdominal surgery.
Background & Aims Guidelines for the management of venous thromboembolism (VTE) from the American College of Chest Physicians do not address patients with inflammatory bowel disease (IBD), a group ...with a high risk of both VTE and gastrointestinal bleeding. We present recommendations for the prevention and treatment of VTE in patients with IBD. Methods A systematic literature search was performed to identify studies on VTE in IBD. The quality of evidence and strength of recommendations were rated according to the Grading of Recommendation Assessment, Development, and Evaluation (GRADE) approach. Statements were developed through an iterative online platform, then finalized and voted on by a working group of adult and pediatric gastroenterologists and thrombosis specialists. Results IBD patients have an approximately 3-fold higher risk of VTE compared with individuals without IBD, and disease flares further increase this risk. Anticoagulant thromboprophylaxis is recommended for IBD patients who are hospitalized with IBD flares without active bleeding and is suggested when bleeding is nonsevere. Anticoagulant thromboprophylaxis is suggested during moderate−severe IBD flares in outpatients with a history of VTE provoked by an IBD flare or an unprovoked VTE, but not otherwise. The recommended duration of anticoagulation after a first VTE is based on the presence of provoking factors. Specific suggestions are made for the prevention and treatment of VTE in pediatric and pregnant IBD patients. Conclusions Using the American College of Chest Physicians’ guidelines as a foundation, we have integrated evidence from IBD studies to develop specific recommendations for the management of VTE in this high-risk population.
The aim of this study was to determine if body mass index (BMI) was an independent predictor of response to antiviral treatment in patients with chronic hepatitis C. A retrospective review was ...performed of all patients at a single center with chronic hepatitis C treated with antiviral medication from 1989 to 2000. A sustained response was defined as either negative hepatitis C virus (HCV) RNA by polymerase chain reaction and/or normal alanine aminotransferase (ALT) level (only in those treated before availability of HCV RNA testing) 6 months following completion of therapy. All patients were classified into one of 3 groups according to BMI (normal, <25 kg/m
2; overweight, 25-30 kg/m
2; obese, >30 kg/m
2). A total of 253 patients were treated with either interferon (IFN) monotherapy or IFN in combination with ribavirin. Patients were excluded if predetermined clinical characteristics were unavailable. Using logistic regression, and after adjusting for the examined variables (age, sex, history of alcohol consumption >50 g/d, cirrhosis on pretreatment biopsy, and BMI), likelihood ratio tests showed significant differences in response to treatment according to BMI group (
P = .01), genotype (
P < .01), and cirrhosis (
P < .01). Those with genotypes 2 or 3 had an odds ratio (OR) for success of 11.7 compared with those with genotype 1, cirrhotic patients had an OR of 0.15 compared with noncirrhotic patients, and obese patients had an OR of 0.23 compared with normal and overweight patients. Hepatic steatosis was not an independent risk factor for response to antiviral treatment. In conclusion, obesity, only when defined as a BMI greater than 30 kg/m
2, is an independent (of genotype and cirrhosis) negative predictor of response to hepatitis C treatment. (H
epatology 2003;38:639-644.)
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