Highly connected individuals disseminate information effectively within their social network. To apply this concept to inflammatory bowel disease (IBD) care and lay the foundation for network ...interventions to disseminate high-quality treatment, we assessed the need for improving the IBD practices of highly connected clinicians. We aimed to examine whether highly connected clinicians who treat IBD patients were more likely to provide high-quality treatment than less connected clinicians.
We used network analysis to examine connections among clinicians who shared patients with IBD in the Veterans Health Administration between 2015-2018. We created a network comprised of clinicians connected by shared patients. We quantified clinician connections using degree centrality (number of clinicians with whom a clinician shares patients), closeness centrality (reach via shared contacts to other clinicians), and betweenness centrality (degree to which a clinician connects clinicians not otherwise connected). Using weighted linear regression, we examined associations between each measure of connection and two IBD quality indicators: low prolonged steroids use, and high steroid-sparing therapy use.
We identified 62,971 patients with IBD and linked them to 1,655 gastroenterologists and 7,852 primary care providers. Clinicians with more connections (degree) were more likely to exhibit high-quality treatment (less prolonged steroids beta -0.0268, 95%CI -0.0427, -0.0110, more steroid-sparing therapy beta 0.0967, 95%CI 0.0128, 0.1805). Clinicians who connect otherwise unconnected clinicians (betweenness) displayed more prolonged steroids use (beta 0.0003, 95%CI 0.0001, 0.0006). The presence of variation is more relevant than its magnitude.
Clinicians with a high number of connections provided more high-quality IBD treatments than less connected clinicians, and may be well-positioned for interventions to disseminate high-quality IBD care. However, clinicians who connect clinicians who are otherwise unconnected are more likely to display low-quality IBD treatment. Efforts to improve their quality are needed prior to leveraging their position to disseminate high-quality care.
This ECCO topical review of the European Crohn’s and Colitis Organisation ECCO focused on prediction, diagnosis, and management of fibrostenosing Crohn’s disease CD. The objective was to achieve ...evidence-supported, expert consensus that provides guidance for clinical practice.
Statins and the risk of colorectal cancer Poynter, Jenny N; Gruber, Stephen B; Higgins, Peter D R ...
The New England journal of medicine,
05/2005, Letnik:
352, Številka:
21
Journal Article
Recenzirano
Odprti dostop
Statins are inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A reductase and effective lipid-lowering agents. Statins inhibit the growth of colon-cancer cell lines, and secondary analyses of some, ...but not all, clinical trials suggest that they reduce the risk of colorectal cancer.
The Molecular Epidemiology of Colorectal Cancer study is a population-based case-control study of patients who received a diagnosis of colorectal cancer in northern Israel between 1998 and 2004 and controls matched according to age, sex, clinic, and ethnic group. We used a structured interview to determine the use of statins in the two groups and verified self-reported statin use by examining prescription records in a subgroup of patients for whom prescription records were available.
In analyses including 1953 patients with colorectal cancer and 2015 controls, the use of statins for at least five years (vs. the nonuse of statins) was associated with a significantly reduced relative risk of colorectal cancer (odds ratio, 0.50; 95 percent confidence interval, 0.40 to 0.63). This association remained significant after adjustment for the use or nonuse of aspirin or other nonsteroidal antiinflammatory drugs; the presence or absence of physical activity, hypercholesterolemia, and a family history of colorectal cancer; ethnic group; and level of vegetable consumption (odds ratio, 0.53; 95 percent confidence interval, 0.38 to 0.74). The use of fibric-acid derivatives was not associated with a significantly reduced risk of colorectal cancer (odds ratio, 1.08; 95 percent confidence interval, 0.59 to 2.01). Self-reported statin use was confirmed for 276 of the 286 participants (96.5 percent) who reported using statins and whose records were available.
The use of statins was associated with a 47 percent relative reduction in the risk of colorectal cancer after adjustment for other known risk factors. Because the absolute risk reduction is likely low, further investigation of the overall benefits of statins in preventing colorectal cancer is warranted.
Management of Crohn Disease-Reply Cushing, Kelly; Higgins, Peter D R
JAMA : the journal of the American Medical Association,
05/2021, Letnik:
325, Številka:
17
Journal Article
Mirikizumab is a humanized monoclonal antibody targeting interleukin 23p19 with demonstrated efficacy in psoriasis and ulcerative colitis. We investigated the safety and efficacy of mirikizumab in ...patients with moderate-to-severe Crohn’s disease (CD).
Patients (N = 191) were randomized (2:1:1:2) to receive placebo (PBO), 200, 600, or 1000 mg mirikizumab, administered intravenously (IV) every 4 weeks. Patients who received mirikizumab and achieved ≥1 point improvement in Simple Endoscopic Score-CD at Week 12 (rerandomized maintenance cohort) were rerandomized to continue their induction IV treatment (combined IV groups IV-C) or receive 300 mg mirikizumab subcutaneously (SC) every 4 weeks. Nonrandomized maintenance cohort included endoscopic nonimprovers (1000 mg) and PBO patients (PBO/1000 mg) who received 1000 mg mirikizumab IV from Week 12. The primary objective was to evaluate superiority of mirikizumab to PBO in inducing endoscopic response (50% reduction from baseline in Simple Endoscopic Score-CD) at Week 12.
At Week 12, endoscopic response was significantly higher by the predefined 2-sided significance level of 0.1 for all mirikizumab groups compared with PBO (200 mg: 25.8%, 8/31, 95% confidence interval CI, 10.4–41.2, P = .079; 600 mg: 37.5%, 12/32, 95% CI, 20.7–54.3, P = .003; 1000 mg: 43.8%, 28/64, 95% CI, 31.6–55.9, P < .001; PBO: 10.9 %, 7/64, 95% CI, 3.3–18.6). Endoscopic response at Week 52 was 58.5% (24/41) and 58.7% (27/46) in the IV-C and SC groups, respectively. Frequencies of adverse events (AE) in the mirikizumab groups were similar to PBO. Through Week 52, frequencies of treatment-emergent AEs were similar across all groups. Frequencies of serious AE and discontinuations due to AE were higher in the nonrandomized maintenance cohort.
Mirikizumab effectively induced endoscopic response after 12 weeks in patients with moderate-to-severe CD and demonstrated durable efficacy to Week 52. A detailed summary can be found in the Video Abstract. ClinicalTrials.gov, Number: NCT02891226
In this phase 2 study in patients with moderately-to-severely active Crohn’s disease, mirikizumab demonstrated endoscopic and clinical efficacy compared with placebo after 12 weeks and maintained efficacy through 52 weeks of treatment.
Abstract
Background
Evaluating structural damage using imaging is essential for the evaluation of small intestinal Crohn’s disease (CD), but it is limited by potential interobserver variation. We ...compared the agreement of enterography-based bowel damage measurements collected by experienced radiologists and a semi-automated image analysis system.
Methods
Patients with small bowel CD undergoing a CT-enterography (CTE) between 2011 and 2017 in a tertiary care setting were retrospectively reviewed. CT-enterography studies were reviewed by 2 experienced radiologists and separately underwent automated computer image analysis using bowel measurement software. Measurements included maximum bowel wall thickness (BWT-max), maximum bowel dilation (DIL-max), minimum lumen diameter (LUM-min), and the presence of a stricture. Measurement correlation coefficients and paired t tests were used to compare individual operator measurements. Multivariate regression was used to model identification of strictures using semi-automated measures.
Results
In 138 studies, the correlation between radiologists and semi-automated measures were similar for BWT-max (r = 0.724, 0.702), DIL-max (r = 0.812, 0.748), and LUM-min (r = 0.428, 0.381), respectively. Mean absolute measurement difference between semi-automated and radiologist measures were no different from the mean difference between paired radiologists for BWT-max (1.26 mm vs 1.12 mm, P = 0.857), DIL-max (2.78 mm vs 2.67 mm, P = 0.557), and LUM-min (0.54 mm vs 0.41 mm, P = 0.596). Finally, models of radiologist-defined intestinal strictures using automatically acquired measurements had an accuracy of 87.6%.
Conclusion
Structural bowel damage measurements collected by semi-automated approaches are comparable to those of experienced radiologists. Radiomic measures of CD will become an important new data source powering clinical decision-making, patient-phenotyping, and assisting radiologists in reporting objective measures of disease status.
Measurements of bowel damage using automated computer imaging analysis have similar agreement compared with experienced abdominal radiologists. Automated imaging analysis systems can also identify qualitative features with very good accuracy, providing quantitative descriptions of phenotype, damage, and activity in patients with Crohn’s disease.
Myofibroblasts are crucial to the pathogenesis of tissue fibrosis. Their formation of stress fibers results in the release of myocardin-related transcription factor (MRTF), a transcriptional ...coactivator of serum response factor (SRF). MRTF-A ( Mkl1 )-deficient mice are protected from lung fibrosis. We hypothesized that the SRF/MRTF pathway inhibitor CCG-203971 would modulate myofibroblast function in vitro and limit lung fibrosis in vivo . Normal and idiopathic pulmonary fibrosis lung fibroblasts were treated with/without CCG-203971 (N-4-chlorophenyl-1-3-(2-furanyl)benzoyl-3-piperidine carboxamide) and/or Fas-activating antibody in the presence/absence of transforming growth factor (TGF)-β1, and apoptosis was assessed. In vivo studies examined the effect of therapeutically administered CCG-203971 on lung fibrosis in two distinct murine models of fibrosis induced by bleomycin or targeted type II alveolar epithelial injury. In vitro , CCG-203971 prevented nuclear localization of MRTF-A; increased the apoptotic susceptibility of normal and idiopathic pulmonary fibrosis fibroblasts; blocked TGF-β1–induced myofibroblast differentiation; and inhibited TGF-β1–induced expression of fibronectin, X-linked inhibitor of apoptosis, and plasminogen activator inhibitor-1. TGF-β1 did not protect fibroblasts or myofibroblasts from apoptosis in the presence of CCG-203971. In vivo , CCG-203971 significantly reduced lung collagen content in both murine models while decreasing alveolar plasminogen activator inhibitor-1 and promoting myofibroblast apoptosis. These data support a central role of the SRF/MRTF pathway in the pathobiology of lung fibrosis and suggest that its inhibition can help resolve lung fibrosis by promoting fibroblast apoptosis.
Assessing endoscopic disease severity in ulcerative colitis (UC) is a key element in determining therapeutic response, but its use in clinical practice is limited by the requirement for experienced ...human reviewers.
To determine whether deep learning models can grade the endoscopic severity of UC as well as experienced human reviewers.
In this diagnostic study, retrospective grading of endoscopic images using the 4-level Mayo subscore was performed by 2 independent reviewers with score discrepancies adjudicated by a third reviewer. Using 16 514 images from 3082 patients with UC who underwent colonoscopy at a single tertiary care referral center in the United States between January 1, 2007, and December 31, 2017, a 159-layer convolutional neural network (CNN) was constructed as a deep learning model to train and categorize images into 2 clinically relevant groups: remission (Mayo subscore 0 or 1) and moderate to severe disease (Mayo subscore, 2 or 3). Ninety percent of the cohort was used to build the model and 10% was used to test it; the process was repeated 10 times. A set of 30 full-motion colonoscopy videos, unseen by the model, was then used for external validation to mimic real-world application.
Model performance was assessed using area under the receiver operating curve (AUROC), sensitivity and specificity, positive predictive value (PPV), and negative predictive value (NPV). Kappa statistics (κ) were used to measure agreement of the CNN relative to adjudicated human reference cores.
The authors included 16 514 images from 3082 unique patients (median IQR age, 41.3 26.1-61.8 years, 1678 54.4% female), with 3980 images (24.1%) classified as moderate-to-severe disease by the adjudicated reference score. The CNN was excellent for distinguishing endoscopic remission from moderate-to-severe disease with an AUROC of 0.966 (95% CI, 0.967-0.972); a PPV of 0.87 (95% CI, 0.85-0.88) with a sensitivity of 83.0% (95% CI, 80.8%-85.4%) and specificty of 96.0% (95% CI, 95.1%-97.1%); and NPV of 0.94 (95% CI, 0.93-0.95). Weighted κ agreement between the CNN and the adjudicated reference score was also good for identifying exact Mayo subscores (κ = 0.84; 95% CI, 0.83-0.86) and was similar to the agreement between experienced reviewers (κ = 0.86; 95% CI, 0.85-0.87). Applying the CNN to entire colonoscopy videos had similar accuracy for identifying moderate to severe disease (AUROC, 0.97; 95% CI, 0.963-0.969).
This study found that deep learning model performance was similar to experienced human reviewers in grading endoscopic severity of UC. Given its scalability, this approach could improve the use of colonoscopy for UC in both research and routine practice.
Background
Patients with inflammatory bowel disease (IBD) are at increased risk for many co-morbid diseases. However, little is known about durability of IBD medications in patients with co-morbid ...diseases.
Aims
Determine medication durability in IBD patients with and without psoriasis, rheumatoid arthritis, and/or enteropathic arthropathy.
Methods
All patients with at least three ICD-9 or 10 diagnoses for IBD were included in the cohort. The risk factors of interest were a co-morbid diagnosis of psoriasis (IBD-Ps), rheumatoid arthritis (IBD-RA), and/or enteropathic arthritis (IBD-EA). Medication durability was defined as days of medication use, calculated using order start and stop dates from the electronic medical record. Significant differences were tested using the Wilcoxon rank sum test for continuous variables and Fisher’s exact test or Pearson’s Chi-squared test, as appropriate, for categorical variables. Boxplots were constructed for graphical interpretation of results.
Results
In the psoriasis group, there were 481 patients with 831 medication exposures 131 IBS-Ps (16%), 700 IBD only (84%). The median days of medication use were numerically higher in the IBD-Ps group for all therapies anti-TNF: 1109 vs 861 (
p
= 0.17); anti-IL-12/23: 984 vs 834 (
p
= 0.33); JAKi: 682 vs 230 (
p
= 0.13), anti-TNF/IM: 370 vs 202 (
p
= 0.57), except anti-integrin therapy 214 vs 470 (
p
= 0.08). When restricting to UC only, patients with co-morbid again Ps had a significantly shorter duration on anti-integrin therapy (84 vs 456 days,
p
= 0.02). While not reaching statistical significance, there was a distinctly longer medication duration on JAKi therapy (910 vs 317,
p
= 0.10). When restricting to patients with CD only, no results reached statistical significance though there was a trend towards longer anti-TNF durability in CD-Ps (1340 vs 1000 days,
p
= 0.098). There were no differences in medication durability in IBD-RA or IBD-EA patients.
Discussion
Larger studies investigating medication durability of JAKi and anti-integrin therapy in IBD patients with psoriasis would be beneficial given noteworthy trends towards increased and decreased durability, respectively.
There is a great unmet need for advanced therapies that provide rapid, robust, and sustained disease control for patients with ulcerative colitis. We assessed the efficacy and safety of upadacitinib, ...an oral selective Janus kinase 1 inhibitor, as induction and maintenance therapy in patients with moderately to severely active ulcerative colitis.
This phase 3, multicentre, randomised, double-blind, placebo-controlled clinical programme consisted of two replicate induction studies (U-ACHIEVE induction UC1 and U-ACCOMPLISH UC2) and a single maintenance study (U-ACHIEVE maintenance UC3). The studies were conducted across Europe, North and South America, Australasia, Africa, and the Asia-Pacific region at 199 clinical centres in 39 countries (UC1), 204 clinical centres in 40 countries (UC2), and 195 clinical centres in 35 countries (UC3). Patients aged 16–75 years with moderately to severely active ulcerative colitis (Adapted Mayo score 5–9; endoscopic subscore 2 or 3) for at least 90 days were randomly assigned (2:1) to oral upadacitinib 45 mg once daily or placebo for 8 weeks (induction studies). Patients who achieved clinical response following 8-week upadacitinib induction were re-randomly assigned (1:1:1) to upadacitinib 15 mg, upadacitinib 30 mg, or placebo for 52 weeks (maintenance study). All patients were randomly assigned using web-based interactive response technology. The primary endpoints were clinical remission per Adapted Mayo score at week 8 (induction) and week 52 (maintenance). The efficacy analyses in the two induction studies were based on the intent-to-treat population, which included all randomised patients who received at least one dose of treatment. In the maintenance study, the primary efficacy analyses reported in this manuscript were based on the first 450 (planned) clinical responders to 8-week induction therapy with upadacitinib 45 mg once daily. The safety analysis population in the induction studies consisted of all randomised patients who received at least one dose of treatment; in the maintenance study, this population included all patients who received at least one dose of treatment as part of the primary analysis population. These studies are registered at ClinicalTrials.gov, NCT02819635 (U-ACHIEVE) and NCT03653026 (U-ACCOMPLISH).
Between Oct 23, 2018, and Sept 7, 2020, 474 patients were randomly assigned to upadacitinib 45 mg once daily (n=319) or placebo (n=155) in UC1. Between Dec 6, 2018, and Jan 14, 2021, 522 patients were randomly assigned to upadacitinib 45 mg once daily (n=345) or placebo (n=177) in UC2. In UC3, a total of 451 patients (21 from the phase 2b study, 278 from UC1, and 152 from UC2) who achieved a clinical response after 8 weeks of upadacitinib induction treatment were randomly assigned again to upadacitinib 15 mg (n=148), upadacitinib 30 mg (n=154), and placebo (n=149) in the primary analysis population. Statistically significantly more patients achieved clinical remission with upadacitinib 45 mg (83 26% of 319 patients in UC1 and 114 34% of 341 patients in UC2) than in the placebo group (seven 5% of 154 patients in UC1 and seven 4% of 174 patients; p<0·0001; adjusted treatment difference 21·6% 95% CI 15·8–27·4 for UC1 and 29·0% 23·2–34·7 for UC2). In the maintenance study, clinical remission was achieved by statistically significantly more patients receiving upadacitinib (15 mg 63 42% of 148; 30 mg 80 52% of 154) than those receiving placebo (18 12% of 149; p<0·0001; adjusted treatment difference 30·7% 21·7–39·8 for upadacitinib 15 mg vs placebo and 39·0% 29·7–48·2 for upadacitinib 30 mg vs placebo). The most commonly reported adverse events in UC1 were nasopharyngitis (15 5% of 319 in the upadacitinib 45 mg group vs six 4% of 155 in the placebo group), creatine phosphokinase elevation (15 4% vs three 2%), and acne (15 5% vs one 1%). In UC2, the most frequently reported adverse event was acne (24 7% of 344 in the upadacitinib 45 mg group vs three 2% of 177 in the placebo group). In both induction studies, serious adverse events and adverse events leading to discontinuation of treatment were less frequent in the upadacitinib 45 mg group than in the placebo group (serious adverse events eight 3% vs nine (6%) in UC1 and 11 3% vs eight 5% in UC2; adverse events leading to discontinuation six 2% vs 14 9% in UC1 and six 2% vs nine 5% in UC2). In UC3, the most frequently reported adverse events (≥5%) were worsening of ulcerative colitis (19 13% of 148 in the upadacitinib 15 mg group vs 11 7% of 154 in the upadacitinib 30 mg group vs 45 30% of 149 in the placebo group), nasopharyngitis (18 12% vs 22 14% vs 15 10%), creatine phosphokinase elevation (nine 6% vs 13 8% vs three 2%), arthralgia (nine 6% vs five 3% vs 15 10%), and upper respiratory tract infection (seven 5% vs nine 6% vs six 4%). The proportion of serious adverse events (ten 7% vs nine 6% vs 19 13%) and adverse events leading to discontinuation (six 4% vs ten 6% vs 17 11%) was lower in both upadacitinib groups than in the placebo group. Events of cancer, adjudicated major adverse cardiac events, or venous thromboembolism were reported infrequently. There were no treatment-related deaths.
Upadacitinib demonstrated a positive efficacy and safety profile and could be an effective treatment option for patients with moderately to severely active ulcerative colitis.
AbbVie.
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