Eduardo Rodrigues-Pinto

Is it Possible to Change Phenotype Progression in Crohn's Disease in the Era of Immunomodulators? Predictive Factors of Phenotype Progression

OBJECTIVES:Crohns disease (CD) induces cumulative structural damage, initially characterized by a non-stenosing non-penetrating behavior (B1) with progression over time to a fibro-stenosing (B2) and/or penetrating phenotype (B3). Our aim was to assess the long-term evolution of disease behavior of CD and determine what factors predict phenotype progression.METHODS:This was a study based on prospectively collected data from a CD database in an inflammatory bowel disease outpatient clinic. B1 corresponds to a non-stenosing non-penetrating disease, B2 to a stenosing behavior, and B3 to a penetrating one.RESULTS:Seven hundred and thirty-six patients with CD (368 female) were followed up for 12.3 years (±8.4), with 87.0% of them exhibiting B1 phenotype at diagnosis. Of these patients, 28.5% progressed to B2 phenotype and 23.5% to B3. Fifty percent of the patients started azathioprine treatment before phenotype change and 13.9% started anti-tumor necrosis factor-α (anti-TNFα) treatment before phenotype change. Monotherapy with azathioprine before phenotype change as well as combination therapy with azathioprine/anti-TNFα before phenotype change delayed disease progression (B1–B2 or B3) in comparison with patients who did not receive treatment (P<0.001). The hazard ratio (HR) for disease progression was lower for both monotherapy with azathioprine (HR: 0.15, P<0.001) or combination therapy with anti-TNFα (HR: 0.33, P<0.001). Upper gastrointestinal tract involvement, male gender, and steroid use were associated with an early progression of phenotype from B1 to B2 or B3 (P<0.001). The HR for disease progression was higher in patients who used steroids without criteria of dependence or resistance (HR: 2.67, P<0.001) and was even higher in patients with criteria of dependence or resistance (HR: 6.44, P<0.001). Longer delays between CD diagnosis and beginning of therapy with azathioprine and/or anti-TNFα were associated with disease progression. The longer the duration of treatment, the less likely the disease progression.CONCLUSIONS:Monotherapy with azathioprine before behavior change as well as combination therapy with azathioprine and anti-TNFα before behavior change delays phenotype progression of CD, whereas upper gastrointestinal tract involvement, male gender, and steroid use with or without criteria of steroid dependence are associated with a higher risk for disease progression.

High C-reactive protein in Crohn's disease patients predicts nonresponse to infliximab treatment.

BACKGROUND Infliximab (IFX) is effective in treating Crohns disease (CD) and C-reactive protein (CRP) is a useful biomarker in assessing inflammatory activity. AIM Correlate CRP levels before beginning of IFX, at week 14 and CRP delta within the first year of IFX treatment. METHODS Retrospective study of CD patients undergoing treatment with IFX. Primary nonresponse (PNR) was defined as no symptomatic improvement and CRP persistently elevated; sustained response (SR) as symptomatic improvement for at least 1 year without therapeutic adjustment; response after therapeutic adjustment (RTA) as analytic and clinical response but requiring IFX dose/frequency adjustment or association with another drug. RESULTS Baseline CRP levels were higher in PNR compared with SR (26.2mg/L vs 9.6 mg/L, p=0.015) and RTA (26.2mg/L vs 7.6 mg/L, p=0.007). CRP levels greater than 15 mg/L at baseline predict PNR with 67% sensitivity and 65% specificity. Lower CRP levels at week 14 were more likely to predict SR relative to RTA (3.1mg/L vs 7.6 mg/L p=0.019) and PNR (3.1mg/L vs 9.1mg/L; p=0.013). CRP levels greater than 4.6 mg/L at week 14 predict PNR with 67% sensitivity and 62% specificity. A higher CRP delta between beginning of treatment and week 14 is more likely to predict SR relative to RTA (5.2mg/L vs 0.6 mg/L p=0.027). CONCLUSION CRP levels at week 14 were associated with SR in patients treated with IFX, independently of baseline CRP serum levels. High inflammatory burden at beginning of IFX treatment was correlated with a worse response.

Tuberculosis in anti-TNF-α treated patients remains a problem in countries with an intermediate incidence: Analysis of 25 patients matched with a control population

BACKGROUND AND AIMS An increased incidence of tuberculosis (TB) in patients under anti-TNF-α therapy has been reported, but outcome compared with TB in the general population are unknown. METHODS Patients who had active tuberculosis while taking anti-TNF-α drugs were studied and compared with a control group of community-acquired TB matched for sex, age and data of TB. RESULTS Twenty-five cases of TB were reported from a cohort of 765 patients under anti-TNF-α from 2001 to 2012. The incidence of TB per 100,000 patient-years was estimated to be 1337, 792 and 405 respectively for those on infliximab, adalimumab and etanercept. Twelve patients had inflammatory bowel disease, ten had rheumatologic diseases and three had psoriasis. From the 17 patients screened for latent TB before anti-TNF-α, three were treated with isoniazid. TB was diagnosed 1-108 months after starting anti-TNF-α, being the median time six, seven and 89 months respectively for those on infliximab, adalimumab and etanercept. Sixty per cent of the cases had extra-pulmonary TB. No deaths occurred in the case groups, while two died in control TB patients. Patients on anti-TNF-α drugs had more frequent extra-pulmonary TB, fever on presentation, higher mean C-reactive protein and lower positive rate of acid-fast bacilli. CONCLUSIONS TB may still occur in those with negative testing, some of them probably representing new infections instead of reactivations. Three out of 25 patients had TB in spite of previously treated LTB, although, the outcome of TB was not worse than in the general population.

Correlation Between Calprotectin and Modified Rutgeerts Score.

Background:Endoscopic recurrence after surgery for Crohns disease (CD) is high, and it has important prognostic value. Crohns disease will recur in the majority of patients after surgery. Fecal calprotectin (FC) and lactoferrin (FL) have attracted interest in the postoperative setting for predicting relapse. We have evaluated the accuracy of FC and FL in diagnosing endoscopic recurrence (ER) using the modified Rutgeerts score (MRS) compared with the Rutgeerts score (RS). Methods:A series of consecutive patients who underwent ileocolonic resection for Crohns disease were evaluated. Biomarkers, clinical indexes, and fecal markers were recorded on the day of ileocolonoscopy. ER was defined as a MRS ≥ i2b or a RS ≥ i2. Results:Ninety-nine patients were included in this prospective cohort. The median time between surgery and colonoscopy was 87.5 months (IQR, 31–137). FC and FL levels were higher in patients with ER than in those in remission (Median FC, 196.5 &mgr;g/g [IQR, 96–634 &mgr;g/g] versus 42.1 &mgr;g/g [IQR 19–91.60 &mgr;g/g; P < 0.001]; Median FL, 23.27 &mgr;g/g [IQR 8.9–47.8 &mgr;g/g] versus 2 &mgr;g/g [IQR 0.9–7.26 &mgr;g/g; P < 0.001]). Using the MRS, 34% of patients presented with ER compared with 76% if the RS was used. The RS performed worse than the MRS with a decrease in sensitivity (74% versus 48% for FC and 85% versus 55% for FL) and in NPV (91% versus 33% for FC, and 90% versus 37% for FL). Furthermore, the accuracy of the MRS was higher than that of the RS (75% versus 55%). Conclusions:Both FC and FL proved to correlate well with endoscopic findings in the evaluation of Crohns disease after surgery. Both markers predicted recurrence with greater accuracy when the MRS was used. Fecal markers can be used to monitor disease recurrence after intestinal resection, with patients being selected to undergo further endoscopic evaluation.

Crohn's disease outcome in patients under azathioprine: A tertiary referral center experience

BACKGROUND AND AIMS Azathioprine is of major importance in the treatment of Crohns disease; its efficacy has been showed in several works, but real-life data regarding its use is scarce. Our aim was to address the outcome of patients with Crohns disease under azathioprine in the real-life setting. METHODS Crohns disease patients followed at an Inflammatory Bowel Disease Outpatient Clinic under azathioprine were consecutively enrolled, being allocated in one of four groups. Two groups included patients on treatment with this drug, regarding its two major indications - prevention of post-operative recurrence and steroid-dependent disease; a third group included patients who needed infliximab in addition to azathioprine and a fourth group comprised patients who did not tolerate azathioprine. RESULTS A total of 221 patients were enrolled, 180 on azathioprine due to steroid-dependency (64 needing additional treatment with infliximab) and 41 for prevention of post-operative recurrence. Steroid-free remission was obtained in 48%. Immunosuppression decreased the number of hospitalized patients (64% vs 36%; p<0.001), but not the surgery rates per person per year. Azathioprine as a post-operative drug was effective in decreasing hospitalizations. The addition of infliximab decreased the number of patients hospitalized (p=0.009) and hospitalization rates per person per year (p<0.001), but had no effect in the surgery rates per person per year. Sixty patients (23%) experienced adverse effects with AZA, 39 requiring discontinuation of the drug. CONCLUSIONS In this real-life study, azathioprine had a long-term steroid sparing effect and reduced hospitalizations. Combination with infliximab reduced hospitalizations but did not decrease the surgery rate.

Risk factors associated with refractoriness to esophageal dilatation for benign dysphagia.

Background Benign esophageal strictures need repeated dilatations to relieve dysphagia. Literature is scarce on the risk factors for refractoriness of these strictures. Aim This study aimed to assess the risk factors associated with refractory strictures. Materials and methods This is a retrospective study of patients with benign esophageal strictures who were referred for esophageal dilatation over a period of 3 years. Results A total of 327 esophageal dilatations were performed in 103 patients; 53% of the patients reported dysphagia for liquids. Clinical success was achieved in 77% of the patients. There was a need for further dilatations in 54% of patients, being more frequent in patients with dysphagia for liquids [78 vs. 64%, P=0.008, odds ratio (OR) 1.930], in those with caustic strictures (89 vs. 70%, P=0.007, OR 3.487), and in those with complex strictures (83 vs. 70%, P=0.047, OR 2.132). Caustic strictures, peptic strictures, and complex strictures showed statistical significance in the multivariate analysis. Time until subsequent dilatations was less in patients with dysphagia for liquids (49 vs. 182 days, P<0.001), in those with peptic strictures (49 vs. 98 days, P=0.004), in those with caustic strictures (49 vs. 78 days, P=0.005), and in patients with complex strictures (47 vs. 80 days P=0.009). In multivariate analysis, further dilatations occurred earlier in patients with dysphagia for liquids [hazard ratio (HR) 1.506, P=0.004], in those with peptic strictures (HR 1.644, P=0.002), in those with caustic strictures (HR 1.581, P=0.016), and in patients with complex strictures (HR 1.408, P=0.046). Conclusion Caustic, peptic, and complex strictures were associated with a greater need for subsequent dilatations. Time until subsequent dilatations was less in patients with dysphagia for liquids and in those with caustic, peptic, and complex strictures.

CA 19-9 as a Marker of Survival and a Predictor of Metastization in Cholangiocarcinoma

Background: Cholangiocarcinoma is the second most frequent primitive liver malignancy and is responsible for 3% of the malignant gastrointestinal neoplasms. The aims of this study were to determine the association of serum levels of CA 19-9 at diagnosis with other clinical data and serum liver function tests and to identify possible factors that influence the survival rates during follow-up. Methods: Retrospective observational study of 89 patients with a diagnosis of cholangiocarcinoma followed at the Department of Gastroenterology during 5 years. Statistical analyses were performed using SPSS version 20.0. Results: Patients were followed up for a median time of 127 days (IQR: 48-564), and the median age at diagnosis was 71.0 years (IQR: 62.0-77.5). The median survival rate was 14.0 months (IQR: 4.3-23.7), and the mortality rate was 79%. Patients with CA 19-9 levels ≥103 U/L had lower albumin levels and higher levels of alanine aminotransferase and γ-glutamyltransferase. CA 19-9 levels ≥103 U/L were associated with a higher probability of metastization (p = 0.001) and lower rates of treatment with curative intent (p = 0.024). In a multivariate analysis, CA 19-9 levels <103 U/L and surgery were independent predictors of survival. Conclusion: Predictive factors for overall survival were identified, namely presence of metastasis, surgery, and chemotherapy. CA 19-9 levels ≥103 U/L were predictive factors for survival and metastization.

Evaluation of the AXIOS stent for the treatment of pancreatic fluid collections

ABSTRACT Introduction: Endoscopic ultrasound guided translumenal drainage of pancreatic fluid collections (PFCs) has been widely practiced for over a decade, using conventional plastic and self-expandable metal stents. The use of such stents for transmural drainage is off-label and limited by the lack of lumen-to-lumen anchorage, which can lead to leakage, migration and tissue trauma. Areas covered: Novel stent designs dedicated to applications of translumenal drainage have recently emerged and promise to make transmural drainage quicker, safer, and more effective. Achieving faster resolution of the fluid collection, decreasing adverse events, decreasing recurrence rates, and lowering costs are critical to advancing the endoscopic management of PFCs. Expert commentary: Our paper suggests that the AXIOS stent is an innovative therapeutic approach for PFC drainage with excellent efficacy, safety, and relatively few adverse outcomes. Preliminary reports appear promising and large multicenter prospective studies are needed in the future to further determine its safety and efficacy.

Earlier need of infliximab intensification in Ulcerative Colitis than in Crohn's disease

To the editors: The response to infliximab (IFX) in Crohns disease (CD) and Ulcerative Colitis (UC) is initially good, although over time, a loss of response frequently occurs. Fifty percent of CD patients require IFX escalation,1 with regained responsiveness in majority of patients, at least in the short-term.2 Reports are scarcer regarding UC, however, early reports suggest a similar need for escalation in up to 60% of patients.3 Whether these patients have different long-term outcomes in clinical practice is unknown. We performed a retrospective observational study of …

Diagnostic Accuracy of Controlled Attenuation Parameter for Detecting Hepatic Steatosis in Patients with Chronic Liver Disease

Introduction: Controlled attenuation parameter (CAP), measured by transient elastography, has been suggested as a noninvasive method for the detection and quantification of steatosis. We aimed to assess the accuracy of CAP to detect steatosis in patients with chronic liver disease (CLD) compared with liver histology and to evaluate factors that correlate with the CAP value. Methods: Patients with CLD who underwent liver biopsy and simultaneous CAP determination were consecutively enrolled. CAP was measured using the M probe of FibroScan® (Echosens, Paris, France). Histologically, steatosis was categorized as absent (S0: <5%), mild (S1: 5-33%), moderate (S2: 34-66%) and severe (S3: >66% of all hepatocytes). Results: We analyzed 159 patients with CLD (61% men, mean age 47.9 ± 12.9 years). We found a positive correlation between CAP and steatosis in histology (rs = 0.869, p < 0.001), arterial hypertension (rs = 0.222, p = 0.005), type 2 diabetes mellitus (rs = 0.279, p < 0.001), body mass index (BMI; rs = 0.533, p < 0.001), total cholesterol (rs = 0.442, p < 0.001), triglycerides (rs = 0.272, p = 0.001), and non-alcoholic fatty liver disease (NAFLD; rs = 0.588, p < 0.001). In the multivariate analysis, BMI >25 (odds ratio [OR] 48.4, 95% confidence interval [CI] 23.78-72.95, p < 0.001), serum total cholesterol (OR 3.803, 95% CI 2.203-13.889, p = 0.008), and NAFLD etiology (OR 40.8, 95% CI 15.01-66.66, p = 0.002) were independently associated with higher CAP values. We did not find any significant correlation between CAP and the grade of necroinflammatory activity (rs = 0.063, p = 0.808) or fibrosis (rs = 0.071, p = 0.713) in histology and with alanine aminotransferase (rs = 0.190, p = 0.356) or aspartate aminotransferase (rs = 0.117, p = 0.142). Optimal CAP cutoff values for detecting steatosis ≥S1, ≥S2, and ≥S3 were 206.5, 232.5, and 282.5 dB/m, respectively. CAP performance was 0.822, 0.956, and 0.976 for diagnosing steatosis ≥S1, ≥S2, and ≥S3, respectively. Conclusions: CAP had an excellent diagnostic accuracy for the detection of steatosis in diverse CLD patients. A CAP value cutoff of <282.5 dB/m excludes severe steatosis ≥S3 with an accuracy of 98%.