Crohn's disease Baumgart, Daniel C, Prof; Sandborn, William J, Prof
The Lancet (British edition),
11/2012, Letnik:
380, Številka:
9853
Journal Article
Recenzirano
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Summary Crohn's disease is a relapsing systemic inflammatory disease, mainly affecting the gastrointestinal tract with extraintestinal manifestations and associated immune disorders. Genome wide ...association studies identified susceptibility loci that—triggered by environmental factors—result in a disturbed innate (ie, disturbed intestinal barrier, Paneth cell dysfunction, endoplasmic reticulum stress, defective unfolded protein response and autophagy, impaired recognition of microbes by pattern recognition receptors, such as nucleotide binding domain and Toll like receptors on dendritic cells and macrophages) and adaptive (ie, imbalance of effector and regulatory T cells and cytokines, migration and retention of leukocytes) immune response towards a diminished diversity of commensal microbiota. We discuss the epidemiology, immunobiology, amd natural history of Crohn's disease; describe new treatment goals and risk stratification of patients; and provide an evidence based rational approach to diagnosis (ie, work-up algorithm, new imaging methods ie, enhanced endoscopy, ultrasound, MRI and CT and biomarkers), management, evolving therapeutic targets (ie, integrins, chemokine receptors, cell-based and stem-cell-based therapies), prevention, and surveillance.
The efficacy of ustekinumab, an antagonist of the p40 subunit of interleukin-12 and interleukin-23, as induction and maintenance therapy in patients with ulcerative colitis is unknown.
We evaluated ...ustekinumab as 8-week induction therapy and 44-week maintenance therapy in patients with moderate-to-severe ulcerative colitis. A total of 961 patients were randomly assigned to receive an intravenous induction dose of ustekinumab (either 130 mg 320 patients or a weight-range-based dose that approximated 6 mg per kilogram of body weight 322) or placebo (319). Patients who had a response to induction therapy 8 weeks after administration of intravenous ustekinumab were randomly assigned again to receive subcutaneous maintenance injections of 90 mg of ustekinumab (either every 12 weeks 172 patients or every 8 weeks 176) or placebo (175). The primary end point in the induction trial (week 8) and the maintenance trial (week 44) was clinical remission (defined as a total score of ≤2 on the Mayo scale range, 0 to 12, with higher scores indicating more severe disease and no subscore >1 range, 0 to 3 on any of the four Mayo scale components).
The percentage of patients who had clinical remission at week 8 among patients who received intravenous ustekinumab at a dose of 130 mg (15.6%) or 6 mg per kilogram (15.5%) was significantly higher than that among patients who received placebo (5.3%) (P<0.001 for both comparisons). Among patients who had a response to induction therapy with ustekinumab and underwent a second randomization, the percentage of patients who had clinical remission at week 44 was significantly higher among patients assigned to 90 mg of subcutaneous ustekinumab every 12 weeks (38.4%) or every 8 weeks (43.8%) than among those assigned to placebo (24.0%) (P = 0.002 and P<0.001, respectively). The incidence of serious adverse events with ustekinumab was similar to that with placebo. Through 52 weeks of exposure, there were two deaths (one each from acute respiratory distress syndrome and hemorrhage from esophageal varices) and seven cases of cancer (one each of prostate, colon, renal papillary, and rectal cancer and three nonmelanoma skin cancers) among 825 patients who received ustekinumab and no deaths and one case of cancer (testicular cancer) among 319 patients who received placebo.
Ustekinumab was more effective than placebo for inducing and maintaining remission in patients with moderate-to-severe ulcerative colitis. (Funded by Janssen Research and Development; UNIFI ClinicalTrials.gov number, NCT02407236.).
Summary Crohn's disease and ulcerative colitis are two idiopathic inflammatory bowel disorders. In this paper we discuss the current diagnostic approach, their pathology, natural course, and common ...complications, the assessment of disease activity, extraintestinal manifestations, and medical and surgical management, and provide diagnostic and therapeutic algorithms. We critically review the evidence for established (5-aminosalicylic acid compounds, corticosteroids, immunomodulators, calcineurin inhibitors) and emerging novel therapies—including biological therapies—directed at cytokines (eg, infliximab, adalimumab, certolizumab pegol) and receptors (eg, visilizumab, abatacept) involved in T-cell activation, selective adhesion molecule blockers (eg, natalizumab, MLN-02, alicaforsen), anti-inflammatory cytokines (eg, interleukin 10), modulation of the intestinal flora (eg, antibiotics, prebiotics, probiotics), leucocyte apheresis and many more monoclonal antibodies, small molecules, recombinant growth factors, and MAP kinase inhibitors targeting various inflammatory cells and pathways. Finally, we summarise the practical aspects of standard therapies including dosing, precautions, and side-effects.
The Selecting Therapeutic Targets in Inflammatory Bowel Disease (STRIDE) initiative of the International Organization for the Study of Inflammatory Bowel Diseases (IOIBD) has proposed treatment ...targets in 2015 for adult patients with inflammatory bowel disease (IBD). We aimed to update the original STRIDE statements for incorporating treatment targets in both adult and pediatric IBD.
Based on a systematic review of the literature and iterative surveys of 89 IOIBD members, recommendations were drafted and modified in 2 surveys and 2 voting rounds. Consensus was reached if ≥75% of participants scored the recommendation as 7 to 10 on a 10-point rating scale.
In the systematic review, 11,278 manuscripts were screened, of which 435 were included. The first IOIBD survey identified the following targets as most important: clinical response and remission, endoscopic healing, and normalization of C-reactive protein/erythrocyte sedimentation rate and calprotectin. Fifteen recommendations were identified, of which 13 were endorsed. STRIDE-II confirmed STRIDE-I long-term targets of clinical remission and endoscopic healing and added absence of disability, restoration of quality of life, and normal growth in children. Symptomatic relief and normalization of serum and fecal markers have been determined as short-term targets. Transmural healing in Crohn’s disease and histological healing in ulcerative colitis are not formal targets but should be assessed as measures of the remission depth.
STRIDE-II encompasses evidence- and consensus-based recommendations for treat-to-target strategies in adults and children with IBD. This frameworkshould be adapted to individual patients and local resources to improve outcomes.
Integrins are activatable molecules that are involved in adhesion and signalling. Of the 24 known human integrins, 3 are currently targeted therapeutically by monoclonal antibodies, peptides or small ...molecules: drugs targeting the platelet αIIbβ3 integrin are used to prevent thrombotic complications after percutaneous coronary interventions, and compounds targeting the lymphocyte α4β1 and α4β7 integrins have indications in multiple sclerosis and inflammatory bowel disease. New antibodies and small molecules targeting β7 integrins (α4β7 and αEβ7 integrins) and their ligands are in clinical development for the treatment of inflammatory bowel diseases. Integrin-based therapeutics have shown clinically significant benefits in many patients, leading to continued medical interest in the further development of novel integrin inhibitors. Of note, almost all integrin antagonists in use or in late-stage clinical trials target either the ligand-binding site or the ligand itself.
Summary Ulcerative colitis is an idiopathic, chronic inflammatory disorder of the colonic mucosa, which starts in the rectum and generally extends proximally in a continuous manner through part of, ...or the entire, colon; however, some patients with proctitis or left-sided colitis might have a caecal patch of inflammation. Bloody diarrhoea is the characteristic symptom of the disease. The clinical course is unpredictable, marked by alternating periods of exacerbation and remission. In this Seminar we discuss the epidemiology, pathophysiology, diagnostic approach, natural history, medical and surgical management, and main disease-related complications of ulcerative colitis, and briefly outline novel treatment options. Enhanced understanding of how the interaction between environmental factors, genetics, and the immune system results in mucosal inflammation has increased knowledge of disease pathophysiology. We provide practical therapeutic algorithms that are easily applicable in daily clinical practice, emphasising present controversies in treatment management and novel therapies.
We sought to evaluate the association between obesity and response to anti-tumor necrosis factor-α (TNF) agents, through a systematic review and meta-analysis.
Through a systematic search through ...January 24, 2017, we identified randomized controlled trials (RCTs) or observational studies in adults with select immune-mediated inflammatory diseases-inflammatory bowel diseases (IBD), rheumatoid arthritis (RA), spondyloarthropathies (SpA), psoriasis and psoriatic arthritis (PsA)-treated with anti-TNF agents, and reporting outcomes, stratified by body mass index (BMI) categories or weight. Primary outcome was failure to achieve clinical remission or response or treatment modification. We performed random effects meta-analysis and estimated odds ratios (OR) and 95% confidence interval (CI).
Based on 54 cohorts including 19,372 patients (23% obese), patients with obesity had 60% higher odds of failing therapy (OR,1.60; 95% CI,1.39-1.83;I2 = 71%). Dose-response relationship was observed (obese vs. normal BMI: OR,1.87 1.39-2.52; overweight vs. normal BMI: OR,1.38 1.11-1.74,p = 0.11); a 1kg/m2 increase in BMI was associated with 6.5% higher odds of failure (OR,1.065 1.043-1.087). These effects were observed across patients with rheumatic diseases, but not observed in patients with IBD. Effect was consistent based on dosing regimen/route, study design, exposure definition, and outcome measures. Less than 10% eligible RCTs reported outcomes stratified by BMI.
Obesity is an under-reported predictor of inferior response to anti-TNF agents in patients with select immune-mediated inflammatory diseases. A thorough evaluation of obesity as an effect modifier in clinical trials is warranted, and intentional weight loss may serve as adjunctive treatment in patients with obesity failing anti-TNF therapy.
A comprehensive knowledge of the natural history of ulcerative colitis (UC) helps understand disease evolution, identify poor prognostic markers and impact of treatment strategies, and facilitates ...shared decision-making. We systematically reviewed the natural history of UC in adult population-based cohort studies with long-term follow-up.
Through a systematic literature review of MEDLINE through March 31, 2016, we identified 60 studies performed in 17 population-based inception cohorts reporting the long-term course and outcomes of adult-onset UC (n = 15,316 UC patients).
Left-sided colitis is the most frequent location, and disease extension is observed in 10%-30% of patients. Majority of patients have a mild-moderate course, which is most active at diagnosis and then in varying periods of remission or mild activity; about 10%-15% of patients experience an aggressive course, and the cumulative risk of relapse is 70%-80% at 10 years. Almost 50% of patients require UC-related hospitalization, and 5-year risk of re-hospitalization is ∼50%. The 5-year and 10-year cumulative risk of colectomy is 10%-15%; achieving mucosal healing is associated with lower risk of colectomy. About 50% of patients receive corticosteroids, although this proportion has decreased over time, with a corresponding increase in the use of immunomodulators (20%) and anti-tumor necrosis factor (5%-10%). Although UC is not associated with an increased risk of mortality, it is associated with high morbidity and work disability, comparable to Crohn's disease.
UC is a disabling condition over time. Prospective cohorts are needed to evaluate the impact of recent strategies of early use of disease-modifying therapies and treat-to-target approach with immunomodulators and biologics. Long-term studies from low-incidence areas are also needed.
Since 2010, substantial progress has been made in artificial intelligence (AI) and its application to medicine. AI is explored in gastroenterology for endoscopic analysis of lesions, in detection of ...cancer, and to facilitate the analysis of inflammatory lesions or gastrointestinal bleeding during wireless capsule endoscopy. AI is also tested to assess liver fibrosis and to differentiate patients with pancreatic cancer from those with pancreatitis. AI might also be used to establish prognoses of patients or predict their response to treatments, based on multiple factors. We review the ways in which AI may help physicians make a diagnosis or establish a prognosis and discuss its limitations, knowing that further randomized controlled studies will be required before the approval of AI techniques by the health authorities.
The objective of this study was to review loss of response and need for adalimumab dose intensification in adult and pediatric patients with Crohn's disease. Studies were identified through the ...electronic databases of MEDLINE and the annual meetings of Digestive Disease Week, of the United European Gastroenterology Week, and of the American College of Gastroenterology and the European Crohn's and Colitis Organization meetings. Studies evaluating loss of efficacy and/or need for dose intensification were included. Thirty-nine studies were included. The mean percentage of loss of response to adalimumab among primary responders was 18.2% and the annual risk was 20.3% per patient-year. The mean percentage of patients who required dose intensification among primary responders to adalimumab was 37% and the annual risk was 24.8% per patient-year. When considering initial responders and patients with primary non-response, the mean percentage of patients who needed an adalimumab dose escalation was 21.4% and the annual risk was 24.4% per patient-year. Pooled analysis showed that dose escalation permitted response to be regained in 71.4% and remission in 39.9% of patients. Predictors for loss of response or dose escalation were male gender, current/former smoker status, family history of inflammatory bowel disease, isolated colonic disease, extra-intestinal manifestations, 80/40 mg induction therapy, longer disease duration, greater baseline Crohn's Disease Activity Index, concomitant corticosteroid use, no deep remission at week 12, low serum trough concentrations of adalimumab, previous infliximab non-response and being previously treated with an anti-tumor necrosis factor agent. Overall, around one fifth of adult patients require dose intensification and experience a loss of response after initiation of adalimumab therapy. Adalimumab dose escalation permits response to be regained in the majority of patients.
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