Predictors of Perianal Fistula Healing in Children With Newly Diagnosed Crohn Disease.

OBJECTIVES: Perianal fistulas are among the most severe complications of Crohn disease, but limited data regarding their outcomes are available in children. Our objective was to determine predictors of perianal fistula healing among pediatric patients newly diagnosed with Crohn disease. METHODS: This single-center retrospective study followed patients with perianal fistulas at Crohn disease diagnosis until fistula healing. Time to healing was analyzed using Cox proportional hazard regression models considering relevant covariates including patient demographics, disease characteristics, medical therapies [no anti-tumor necrosis factor (TNF)α therapy, anti-TNFα therapy ±therapeutic drug monitoring], and perianal surgical procedures including fistulotomy, fistulectomy, removal of perianal lesions, seton placement, and incision and drainage. RESULTS: Of 485 patients identified, 107 (22%) had a perianal fistula at Crohn disease diagnosis. Multivariate analysis identified that perianal fistulotomy, fistulectomy, and lesion removal [hazard ratio (HR) 0.46; P = 0.028], non-White race (HR 0.30, P < 0.01), and male sex (HR 0.42; P = 0.02) were associated with delayed fistula healing. Faster fistula healing was associated with treatment with anti-TNFα with therapeutic drug monitoring (HR 1.78, P = 0.009). There were no other differences in healing by treatment. CONCLUSIONS: Fistulotomy, fistulectomy, and perianal lesion removal as well as non-White race were associated with delayed fistula healing. Anti-TNFα therapy was associated with faster fistula healing when combined with therapeutic drug monitoring, compared to all other medical treatment groups, including anti-TNFα therapy without therapeutic drug monitoring.

Quantification of Mucosal Activity from Colonoscopy Reports via the Simplified Endoscopic Mucosal Assessment for Crohn's Disease.

BACKGROUND: Endoscopic mucosal healing is the gold standard for evaluating Crohn's disease (CD) treatment efficacy. Standard endoscopic indices are not routinely used in clinical practice, limiting the quality of retrospective research. A method for retrospectively quantifying mucosal activity from documentation is needed. We evaluated the simplified endoscopic mucosal assessment for CD (SEMA-CD) to determine if it can accurately quantify mucosal severity recorded in colonoscopy reports. METHODS: Pediatric patients with CD underwent colonoscopy that was video recorded and evaluated via Simple Endoscopic Score for CD (SES-CD) and SEMA-CD by central readers. Corresponding colonoscopy reports were de-identified. Central readers blinded to clinical history and video scoring were randomly assigned colonoscopy reports with and without images. The SEMA-CD was scored for each report. Correlation with video SES-CD and SEMA-CD were assessed with Spearman rho, inter-rater, and intrarater reliability with kappa statistics. RESULTS: Fifty-seven colonoscopy reports were read a total of 347 times. The simplified endoscopic mucosal assessment for CD without images correlated with both SES-CD and SEMA-CD from videos (rho = 0.82, P < .0001 for each). The addition of images provided similar correlation. Inter-rater and intrarater reliability were 0.93 and 0.92, respectively. CONCLUSIONS: The SEMA-CD applied to retrospective evaluation of colonoscopy reports accurately and reproducibly correlates with SES-CD and SEMA-CD of colonoscopy videos. The SEMA-CD for evaluating colonoscopy reports will enable quantifying mucosal healing in retrospective research. Having objective outcome data will enable higher-quality research to be conducted across multicenter collaboratives and in clinical registries. External validation is needed.

Granulomas in Diagnostic Biopsies Associated With High Risk of Crohn's Complications-But May Be Preventable.

BACKGROUND: Granulomatous intestinal inflammation may be associated with aggressive Crohn's disease (CD) behavior. However, this has not been confirmed, and it is unknown if associated disease complications are preventable. METHODS: This is a retrospective cohort of patients younger than 21 years at CD diagnosis (November 1, 2005 to November 11, 2015). Clinical information was abstracted, including dates of starting medications and the timing of perianal fistula or stricture development, if any. Diagnostic pathology reports were reviewed, and a subset of biopsy slides were evaluated by a blinded pathologist. Patients were excluded if perianal fistula or stricture developed within 30 days after CD diagnosis. Medications were included in analyses only if started >90 days before development of perianal fistula or stricture. RESULTS: In total, 198 patients were included. Half (54%) had granulomas at diagnosis. Granulomas were associated with a greater than 3-fold increased risk of perianal fistula (hazard ration [HR] = 3.24; 95% confidence interval CI], 1.40-7.48). Immunomodulator and anti-tumor necrosis factor-α (anti-TNF) therapy were associated with 90% (HR, = 0.10; 95% CI, 0.03-0.42) and 98% (HR, = 0.02; 95% CI, 0.01-0.10) reduced risk of perianal fistula, respectively. Patients with granulomatous inflammation preferentially responded to anti-TNF therapy with reduced risk of perianal fistula. The presence of granulomas was not associated with risk of stricture. Immunomodulator and anti-TNF therapy were associated with 96% (HR, = 0.04; 95% CI, 0.01-0.22) and 94% (HR, = 0.06; 95% CI, 0.02-0.20) reduced risk of stricture, respectively. CONCLUSIONS: Granulomas are associated with increased risk of perianal fistula but not stricture. Steroid sparing therapies seem to reduce the risk of both perianal fistula and stricture. For those with granulomas, anti-TNF-α therapy greatly reduced the risk of perianal fistula development, whereas immunomodulators did not.

Factors Associated With Development of Perianal Fistulas in Pediatric Patients With Crohn's Disease.

Perianal fistulizing complications (PFCs) develop among 15%-40% of patients with Crohn's disease (CD), are difficult to treat, commonly recur, and increase healthcare costs.1-4 Few reliable predictors of PFCs are known, and no evidence-based preventive strategies exist. Studies often rely on inconsistent methods for identifying PFCs.3-5 Rigorous study design is essential. Occult PFCs may be present at CD diagnosis but may not become apparent until later, leading to PFCs being erroneously misclassified as developing later. We therefore sought to determine the risk factors for developing PFCs among children with CD in whom PFCs were conclusively ruled out with cross-sectional imaging at diagnosis.

Development and Testing of a New Simplified Endoscopic Mucosal Assessment for Crohn's Disease: The SEMA-CD.

OBJECTIVES: Endoscopic mucosal improvement is the gold standard for assessing treatment efficacy in clinical trials of Crohn's disease. Current endoscopic indices are not routinely used in clinical practice. The lack of endoscopic information in large clinical registries limits their use for research. A quick, easy, and accurate method is needed for assessing mucosal improvement for clinicians in real-world practice. We developed and tested a novel simplified endoscopic mucosal assessment for Crohn's disease (SEMA-CD). METHODS: We developed a 5-point scale for ranking endoscopic severity of ileum and colon based on Simple Endoscopic Score for Crohn's disease (SES-CD). Central readers were trained to perform SES-CD and SEMA-CD. Pediatric patients with Crohn's disease undergoing colonoscopy were enrolled. Video recordings of colonoscopies were de-identified and randomly assigned to blinded central readers. The SES-CD and SEMA-CD were scored for each video. The SES-CD was considered the validated standard for comparison. Correlation was assessed with Spearman rho, inter- and intrarater reliability with kappa statistics. RESULTS: Fifty-seven colonoscopies were read a total of 212 times. Correlation between SEMA-CD and SES-CD was strong (rho = 0.98, P < 0.0001). Inter-rater reliability for SEMA-CD was 0.80, and intrarater reliability was 0.83. Central readers rated SEMA-CD as easier than SES-CD. CONCLUSION: The SEMA-CD accurately and reproducibly correlates with the standard SES-CD. Central readers viewed SEMA-CD as easier than SES-CD. Use of SEMA-CD in practice should enable collecting mucosal improvement information in large populations of patients. This will improve the quality of research that can be conducted in clinical registries. External validation is needed.

Fistulizing Crohn's Disease Presenting After Surgery on a Perianal Lesion.

Perianal skin lesions, such as skin tags, can be an early presenting sign of Crohn's disease. Surgical intervention on these lesions may increase the risk of fistula development and lead to worse outcomes. This case series examined 8 patients who underwent surgical intervention on what appeared to be benign perianal skin lesions, only to reveal fistulas leading to the diagnosis of Crohn's disease. This patient population comprised 20% of all pediatric patients with Crohn's disease who had perianal fistula present at diagnosis. The initial type of perianal lesion varied from case to case and included skin tags, hemorrhoids, and perianal abscesses. All of the patients had other presenting features that, in retrospect, may have been attributed to Crohn's disease. None presented solely with a perianal lesion. Four patients had weight loss or growth failure. Most of the remainder had abnormal laboratory test results. These findings should raise the awareness of primary care providers that perianal lesions can be the first presenting sign of possible Crohn's disease in otherwise healthy appearing children. Such children should undergo a thorough evaluation for Crohn's disease before surgical intervention on perianal lesions because surgical procedures may be associated with worse outcomes.

Nitrosative stress and myocardial sarcoplasmic endoreticular calcium adenosine triphosphatase subtype 2a activity after lung resection in swine.

BACKGROUND: Chronic, disease-associated oxidative stress induces myocardial peroxynitrite formation that may lead to nitrosative inhibition of the calcium cycling protein sarcoplasmic endoreticular calcium adenosine triphosphatase subtype 2a (SERCA2a). The current study was designed to test the hypothesis that the acute oxidative stress associated with lung resection also induces myocardial nitrosative stress and alters SERCA2a activity. METHODS: Ventricular myocardium from 16 swine was studied; 11 animals had undergone left upper lobectomy (n = 7) or sham thoracotomy (n = 4) 3 days before harvest, and 5 were nonoperated controls. Tissue peroxynitrite was assessed by measurement of 3-nitrotyrosine incorporation into proteins. SERCA2a activity was determined from indo-1 uptake by isolated sarcoplasmic reticular membranes. Expression of SERCA2a and its regulatory protein phospholamban were determined by Western blotting, as was the phospholamban phosphorylation state (when dephosporylated, phospholamban inhibits SERCA2a). Mechanical significance of changes in SERCA2a activity was assessed from the force-frequency relation of isometric myocardial trabeculae. RESULTS: Relative to both the control and sham groups, lobectomy animals exhibited a greater than twofold higher myocardial 3-nitrotyrosine incorporation and an approximately 50% lower SERCA2a activity, but no difference in SERCA2a or phospholamban expression or phospholamban phosphorylation. Concomitantly, whereas the trabecular force-frequency relation of control animals was positive, that of lobectomy animals was negative, consistent with impaired calcium cycling. CONCLUSIONS: These data indicate that oxidative/nitrosative stress associated with lung resection influences SERCA2a activity independent of any influence on protein expression or phospholamban phosphorylation. The findings link an acute event with a subcellular process primarily described for chronic illness and suggest a biochemical basis for perioperative changes in myocardial mechanical reserve.

Moderate calorie restriction improves cardiac remodeling and diastolic dysfunction in the Dahl-SS rat.

Caloric restriction extends longevity and reduces the onset of chronic disease in many animal models. Recently, caloric restriction was shown in humans to be associated with lower blood pressure, decreased systemic inflammation, and improved cardiac diastolic parameters. However, the causation and mechanisms of caloric restriction were obscured by the varied diet composition of the participants. The Dahl salt-sensitive rat which develops gradual, hypertension-associated diastolic dysfunction was used in this study to assess the impact of caloric restriction upon decompensated pressure-overload hypertrophy. Male Dahl salt-sensitive rats were provided either a low-salt diet or a high-salt diet to initiate heart failure progression. A further subset of high-salt rats underwent 15% calorie restriction, with salt load held constant. Parameters measured included serial systolic blood pressure, body weight, and changes of left ventricular systolic and diastolic parameters and ventricular geometry by echocardiography. After 18 weeks, fasting glucose, blood lipids, heart weight, kidney weight, lung weight, plasma interleukin-6 and TNF-alpha, and cardiac lipid peroxidation were measured. Low-salt rats did not develop heart failure. While high-salt rats displayed features of decompensated pressure-overload hypertrophy, moderate calorie restriction remarkably reduced morbidity. Compared to the high-salt fed group, the high-salt, calorie-restricted group showed reduced blood pressure, delayed onset of cachexia, lower fasting hyperlipidemia, lower cardiac, renal and lung weight, less plasma IL-6 and TNF-alpha, less cardiac oxidative damage, and improved diastolic chamber function and cardiac index. Modest calorie restriction, independent of salt intake, reduced pathogenesis in this well described model of decompensated pressure-overload hypertrophy.