Summary Crohn's disease is a chronic inflammatory disease of the gastrointestinal tract, with increasing incidence worldwide. Crohn's disease might result from a complex interplay between genetic ...susceptibility, environmental factors, and altered gut microbiota, leading to dysregulated innate and adaptive immune responses. The typical clinical scenario is a young patient presenting with abdominal pain, chronic diarrhoea, weight loss, and fatigue. Assessment of disease extent and of prognostic factors for complications is paramount to guide therapeutic decisions. Current strategies aim for deep and long-lasting remission, with the goal of preventing complications, such as surgery, and blocking disease progression. Central to these strategies is the introduction of early immunosuppression or combination therapy with biologicals in high-risk patients, combined with a tight and frequent control of inflammation, and adjustment of therapy on the basis of that assessment (treat to target strategy). The therapeutic armamentarium for Crohn's disease is expanding, and therefore the need to develop biomarkers that can predict response to therapies will become increasingly important for personalised medicine decisions in the near future. In this Seminar, we provide a physician-oriented overview of Crohn's disease in adults, ranging from epidemiology and cause to clinical diagnosis, natural history, patient stratification and clinical management, and ending with an overview of emerging therapies and future directions for research.
In 2015, the Selecting Therapeutic Targets in Inflammatory Bowel Disease (STRIDE) program proposed shifting the therapeutic focus on ulcerative colitis (UC) toward altering the natural history of the ...disease course by regularly monitoring objective measurements of disease activity and tailoring treatment accordingly. The therapeutic paradigm shift was well received in the research community and is often cited. However, new evidence on optimal UC treatment targets continues to accumulate since the time of the STRIDE guidelines. This systematic review summarizes the evidence accrued since the STRIDE UC recommendations, discusses the barriers for adoption of treat-to-target approaches in clinical practice in UC, and suggests directions for future research.
We systematically reviewed MEDLINE for studies from the time of the STRIDE systematic review up to March 31, 2018, that assessed the potential treatment targets identified by the STRIDE recommendations.
Each potential treatment target literature search returned > 200 articles, which were then reviewed by 2 independent investigators for relevant studies. Selected studies of clinical factors, patient-reported outcomes, endoscopy, histology, imaging, and biomarkers and implications on treatment targets are summarized.
It appears that the relative weight given to different therapeutic targets in the development and improvement of UC treatments could be optimized, with an increased emphasis on endoscopic and histological targets over clinical or symptomatic targets. For this evolution to occur, however, new research has to demonstrate that the treat-to-target approach will deliver on the promise of better long-term outcomes compared with current approaches.
In this 52-week randomized trial, the α
4
β
7
integrin antibody vedolizumab was effective in treating ulcerative colitis. There were not significantly more adverse events with vedolizumab than with ...placebo, but the trial was not large or long enough to fully assess safety.
Ulcerative colitis is a chronic inflammatory bowel disease characterized by symptoms of bloody diarrhea, abdominal cramps, and fatigue.
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Current medical therapy has important limitations. Aminosalicylates
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–
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are only modestly effective; glucocorticoids can cause unacceptable adverse events and do not provide a benefit as maintenance therapy. Tumor necrosis factor (TNF) antagonists, although efficacious,
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,
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predispose patients to serious infection.
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Thus, new treatment strategies are needed.
The migration of leukocytes into inflamed intestinal tissue is highly regulated by specific molecular mechanisms. The α
4
β
7
integrin,
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a cell-surface glycoprotein variably expressed on circulating B and T lymphocytes, interacts with mucosal addressin-cell . . .
Summary
Background
Vedolizumab, a gut‐selective α4β7 integrin antibody, is approved for moderately to severely active ulcerative colitis (UC) and Crohn's disease (CD).
Aim
To report the final results ...from the vedolizumab GEMINI long‐term safety (LTS) study.
Methods
The phase 3, open‐label GEMINI LTS study (initiated May 2009) enrolled patients with UC or CD from four prior clinical trials and vedolizumab‐naïve patients. Vedolizumab LTS was evaluated; efficacy and patient‐reported outcomes were exploratory endpoints.
Results
Enrolled patients (UC, n = 894; CD, n = 1349) received vedolizumab 300 mg IV every 4 weeks; median cumulative exposure was 42.4 months (range: 0.03‐112.2) for UC and 31.5 months (range: 0.03‐100.3) for CD. Over 8 years, adverse events (AEs) occurred in 93% (UC) and 96% (CD) of patients, with UC (36%) and CD (35%) exacerbations most frequent. Serious AEs were reported for 31% (UC) and 41% (CD) of patients. Vedolizumab discontinuation due to AEs occurred in 15% (UC) and 17% (CD) of patients. There were no new trends for infections, malignancies, infusion‐related reactions, or hepatic events, and no cases of progressive multifocal leukoencephalopathy. Of the ten deaths (UC, n = 4; CD, n = 6), two were considered drug‐related by local investigators (West Nile virus infection‐related encephalitis and hepatocellular carcinoma). Continuous vedolizumab maintained clinical response long‐term, with 33% (UC) and 28% (CD) of patients in clinical remission at 400 treatment weeks.
Conclusions
The safety profile of vedolizumab remains favourable with no unexpected or new safety concerns. These results further establish the safety of vedolizumab and support its long‐term use (NCT00790933/EudraCT 2008‐002784‐14).
Background & Aims Patients with inflammatory bowel disease (IBD) who have been exposed to thiopurines might have an increased risk of skin cancer. We assessed this risk among patients in France. ...Methods We performed a prospective observational cohort study of 19,486 patients with IBD, enrolled from May 2004 to June 2005, who were followed up until December 31, 2007. The incidence of nonmelanoma skin cancer (NMSC) in the general population, used for reference, was determined from the French Network of Cancer Registries. Results Before the age of 50 years, the crude incidence rates of NMSC among patients currently receiving or who previously received thiopurines were 0.66/1000 and 0.38/1000 patient-years, respectively; these values were 2.59/1000 and 1.96/1000 patient-years for the age group of 50 to 65 years and 4.04/1000 and 5.70/1000 patient-years for patients older than 65 years. Among patients who had never received thiopurines, the incidence of NMSC was zero before the age of 50 years, 0.60/1000 for the ages of 50 to 65 years, and 0.84/1000 for those older than 65 years. A multivariate Cox regression model stratified by propensity score quintiles showed that ongoing thiopurine treatment (hazard ratio HR, 5.9; 95% confidence interval CI, 2.1–16.4; P = .0006) and past thiopurine exposure (HR, 3.9; 95% CI, 1.3–12.1; P = .02) were risk factors for NMSC. They also identified age per 1-year increase as a risk factor for NMSC (HR, 1.08; 95% CI, 1.05–1.11; P < .0001). Conclusions Ongoing and past exposure to thiopurines significantly increases the risk of NMSC in patients with IBD, even before the age of 50 years. These patients should be protected against UV radiation and receive lifelong dermatologic screening.
Background & Aims Immunomodulator therapy is effective for patients with Crohn’s disease (CD) but has not been shown to affect disease progression, presumably because it is given too late after ...diagnosis. We compared the efficacy of early treatment (within 6 months after diagnosis) with azathioprine versus conventional management of patients at high risk for disabling disease. Methods We performed an open-label trial of adults with a diagnosis of CD for less than 6 months who were at risk for disabling disease. From July 2005 to November 2010, patients at 24 French centers were randomly assigned to treatment with azathioprine (2.5 mg ∙ kg−1 ∙ day−1 , n = 65) or conventional management (azathioprine only in cases of corticosteroid dependency, chronic active disease with frequent flares, poor response to corticosteroids, or development of severe perianal disease) (n = 67). The primary end point was the proportion of trimesters spent in corticosteroid-free and anti–tumor necrosis factor (TNF)—free remission during the first 3 years after inclusion. Results During the 3-year follow-up period, 16 patients in the azathioprine group were switched to mercaptopurine or methotrexate therapy because of intolerance or poor efficacy. Forty-one patients in the conventional management group required immunosuppressant therapy (61%; median time to first prescription, 11 months). In the azathioprine group, a median 67% of trimesters were spent in remission (interquartile range, 11%–85%) compared with 56% in the conventional management group (interquartile range, 29%–73%) ( P = .69). Among secondary outcomes, a higher cumulative proportion of patients in the azathioprine group were free of perianal surgery than in the conventional management group (96% ± 3% and 82% ± 6% at month 36, respectively; P = .036). The cumulative proportion of patients free of intestinal surgery and anti-TNF therapy did not differ between groups. Conclusions Based on results from a clinical trial, administration of azathioprine within 6 months of diagnosis of CD was no more effective than conventional management in increasing time of clinical remission. Clinicaltrials.gov , Number NCT00546546.
In a randomized, active-controlled trial, patients with moderately to severely active ulcerative colitis were assigned to receive vedolizumab or adalimumab. At 52 weeks, vedolizumab was superior to ...adalimumab in terms of clinical remission and endoscopic improvement but not in corticosteroid-free clinical remission.
In the 21st century, urbanization represents a major demographic shift in developed and developing countries. Rapid urbanization in the developing world has been associated with an increasing ...incidence of several autoimmune diseases, including IBD. Patients with IBD exhibit a decrease in the diversity and richness of the gut microbiota, while urbanization attenuates the gut microbial diversity and might have a role in the pathogenesis of IBD. Environmental exposures during urbanization, including Westernization of diet, increased antibiotic use, pollution, improved hygiene status and early-life microbial exposure, have been shown to affect the gut microbiota. The disparate patterns of the gut microbiota composition in rural and urban areas offer an opportunity to understand the contribution of a 'rural microbiome' in potentially protecting against the development of IBD. This Perspective discusses the effect of urbanization and its surrogates on the gut microbiome (bacteriome, virome, mycobiome and helminths) in both human health and IBD and how such changes might be associated with the development of IBD.
SUMMARY
Background
For patients with UC, flexible maintenance dosing therapy may confer advantages for safety, efficacy, costs and patient preference. Tofacitinib is an oral, small molecule JAK ...inhibitor for the treatment of UC.
Aim
To assess the efficacy and safety of tofacitinib dose de‐escalation and escalation in patients with UC.
Methods
We evaluated data (November 2017 data cut‐off) from OCTAVE Open, an ongoing, open‐label, long‐term extension study. The dose de‐escalation group comprised 66 tofacitinib induction responders in remission following 52 weeks' tofacitinib 10 mg b.d. maintenance therapy, subsequently de‐escalated to 5 mg b.d. in OCTAVE Open. The dose escalation group comprised 57 tofacitinib induction responders who experienced treatment failure while receiving 5 mg b.d. maintenance therapy, subsequently escalated to 10 mg b.d. in OCTAVE Open.
Results
After tofacitinib de‐escalation, 92.4% (61/66) and 84.1% (53/63) of patients maintained clinical response and 80.3% (53/66) and 74.6% (47/63) maintained remission, at months 2 and 12, respectively. After dose escalation, 57.9% (33/57) and 64.9% (37/57) of patients recaptured clinical response and 35.1% (20/57) and 49.1% (28/57) were in remission, at months 2 and 12, respectively. The incidence rate of herpes zoster with dose escalation (7.6 patients with events/100 patient‐years) was numerically higher than in the overall tofacitinib UC programme.
Conclusions
Following tofacitinib de‐escalation in patients already in remission on 10 mg b.d., most maintained remission, although 25.4% lost remission, at month 12. For induction responders who dose‐escalated following treatment failure on 5 mg b.d. maintenance therapy, 49.1% achieved remission by month 12. (ClinicalTrials.gov number: NCT01470612).
Abstract
Background and Aims
Management of Crohn’s disease and ulcerative colitis has typically relied upon treatment intensification driven by symptoms alone. However, a ‘treat-to-target’ management ...approach may help to address underlying inflammation, minimise disease activity at early stages of inflammatory bowel disease, limit progression, and improve long-term outcomes.
Methods
A systematic literature review was conducted to identify data relevant to a treat-to-target approach in inflammatory bowel disease, published between January 1, 2007 and May 15, 2017.
Results
Consistent with recommendations of the Selecting Therapeutic Targets in Inflammatory Bowel Disease STRIDE working group, studies have investigated factors influencing the achievement of both endoscopic and histological mucosal healing and patient-level outcomes in inflammatory bowel disease IBD. Histological healing and biomarker levels have also been shown to be modifiable outcomes. Although there is a lack of prospectively derived evidence validating mucosal healing as a treatment target, data are emerging to suggest that targeting mucosal healing or inflammation rather than symptoms may be cost-effective in some settings. The review highlighted several strategies that may support the implementation of a treat-to-target approach in IBD. The prospective randomised CALM study demonstrated how tight control whereby treatment decisions are based on close monitoring of inflammatory biomarkers leads to improvements in endoscopic and clinical outcomes. The review also considered the influence of coordinated care from a multidisciplinary team and patient engagement with improved adherence, as well as the role of therapeutic drug monitoring in inflammatory bowel disease management.
Conclusions
A treat-to-target strategy may impact on disease progression and improve outcomes in inflammatory bowel disease. Prospective studies including long-term data are required to ensure that the most appropriate targets and strategies are identified.
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