The degree of bowel remission predicts phenotype progression in Crohn's disease.

BACKGROUND: Patients with Crohn's disease (CD) are at risk of progressing from inflammatory to stricturing and penetrating phenotypes. The influence of the depth of remission on the risk of progression has not been adequately evaluated. METHODS: A retrospective cohort study including surgically naïve CD patients with inflammatory phenotype evaluated concomitantly by magnetic resonance enterography and colonoscopy. The degree of remission was correlated with the risk of progressing to stricturing and penetrating phenotypes. RESULTS: Three hundred nineteen CD patients were included: 27.0% with transmural remission, 16.0% with isolated endoscopic remission, 14.4% with isolated radiologic remission, and 42.6% without remission. Patients with transmural remission presented the lowest rates of phenotype progression (1.2%), with a significant difference compared to isolated radiologic remission (10.9%, p = 0.019), to isolated endoscopic remission (19.6%, p ≤ 0.001), and to no remission (46.3%, p ≤ 0.001). In multivariate regression analysis, transmural remission (OR 0.017 95% CI 0.002-0.135, p < 0.001), isolated radiologic remission (OR 0.139 95% CI 0.049-0.396, p < 0.001), and isolated endoscopic remission (OR 0.301 95% CI 0.123-0.736, p = 0.008) resulted in lower rates of phenotype progression compared to no remission. No patient with transmural or isolated radiologic remission progressed to penetrating phenotypes. CONCLUSION: The degree of bowel remission correlates with the risk of phenotype progression. Patients with transmural remission are at the lowest risk of progressing to stricturing and penetrating phenotypes.

Tight control using fecal calprotectin and early disease intervention increase the rates of transmural remission in Crohn's disease.

BACKGROUND: Increasing evidence supports the use of transmural remission as a treatment target in Crohn's disease (CD), but it is seldom achieved in clinical practice. Tight monitoring of inflammation using fecal calprotectin with reactive treatment escalation may potentially improve these results. AIMS: To evaluate if treatment escalation based on fecal calprotectin can improve the rates of transmural remission in CD. The influence of the timing of intervention on this strategy was also evaluated. METHODS: Retrospective cohort study including 256 CD patients with 2 consecutive assessments by MRI-enterography and colonoscopy and with regular monitoring using fecal calprotectin. For each occurrence of an elevated fecal calprotectin (≥250 µg/g), we evaluated whether a reactive adjustment of medical treatment was performed. The ratio of treatment escalation/elevated fecal calprotectin was correlated with the chances of reaching transmural remission. Early disease was defined as disease duration <18 months without previous exposure to immunomodulators and biologics. RESULTS: After a median follow-up of 2 years (IQR 1-4), 61 patients (23.8%) reached transmural remission. Ratios of escalation ≥50% resulted in higher rates of transmural remission (34.2% vs. 15.1%, p < 0.001). The effect was more pronounced in patients with early disease (50.0% vs. 12.0%, p = 0.003). In multivariate analysis, a treatment escalation ratio ≥50% (OR 3.46, 95% CI 1.67-7.17, p = 0.001) and early disease intervention (OR 3.24, 95% CI 1.12-9.34, p = 0.030) were independent predictors of achieving transmural remission. CONCLUSION: Tight-monitoring and reactive treatment escalation increase the rates of transmural remission in CD. Intervention in early disease further improves these results.

Proactive Infliximab Monitoring Improves the Rates of Transmural Remission in Crohn's Disease: A Propensity Score-Matched Analysis.

BACKGROUND: Few patients can reach transmural remission in Crohn's disease (CD) with currently available therapies. Proactive optimization of infliximab (IFX) based on trough levels may potentially improve these results. METHODS: Retrospective cohort study including consecutive CD patients starting treatment with IFX. Rates of transmural remission were compared between patients with and without therapeutic drug monitoring (target level: 5-7 µg/mL). A propensity score-matched analysis was performed to adjust for potential confounders. RESULTS: A total of 195 CD patients were included, 57.9% receiving proactive therapeutic drug monitoring. The rates of transmural remission were higher in patients under proactive therapeutic drug monitoring (37.2% vs 18.3%; P = .004) with similar results in the propensity score-matched analysis (34.2% vs 17.1%; P = .025). In multivariate analysis, proactive therapeutic drug monitoring was independently associated with transmural remission (odds ratio, 2.95; 95% confidence interval, 1.44-6.06; P = .003). CONCLUSIONS: Proactive optimization of IFX based on trough levels increases the rates of transmural remission in CD.

In the following study, we demonstrate that proactive optimization of infliximab using a trough level protocol (aim 5-7 µg/mL) results in higher rates of transmural remission compared with conventional infliximab treatment. These results remained significant in a propensity score­matched analysis.

Proactive infliximab is more effective than vedolizumab in inducing fecal calprotectin remission in inflammatory bowel disease.

BACKGROUND: Current evidence suggests vedolizumab (VDZ) may be as effective as Infliximab (IFX) in inflammatory bowel disease. It is unknown if proactive therapeutic drug monitoring (PTDM) of IFX may improve these results. METHODS: Case-control study including consecutive patients with primary response to conventional IFX (n = 70), proactive IFX (n = 148), and VDZ (n = 95). PTDM was performed at week 14 and every other infusion, aiming at a trough level between 5 and 10 µg/ml. The primary outcome was fecal calprotectin (Fc) remission (<250 µg/g) at 1 year of treatment. Secondary outcomes included Fc remission at week 14 (proactive IFX/VDZ), clinical remission, treatment discontinuation, hospitalization, and surgery at 1-year of follow-up. RESULTS: Proactive IFX was superior to conventional IFX and VDZ in inducing Fc remission at 1-year (69.4% vs 47.1% vs 37.9%, p = .003 and p < .001). Results remained significant in biologic naïve patients (70.8% vs 44.4% vs 51.4%, p = .001 and p = .043) but comparisons between conventional IFX and VDZ were not significant (p = .265 and p = .664). In multivariate analysis correcting for prior biologic exposure, proactive IFX was more effective than conventional IFX (OR 2.480 95%CI [1.367-4.499], p = .003) and VDZ (OR 3.467 95%CI [1.578-7.617], p = .002) in inducing Fc remission. Amongst secondary outcomes, only clinical remission was significant between proactive IFX and VDZ in the overall cohort (80.4% vs 55.8%, p < .001) and in biologic naïve patients (80.2% vs 62.9%, p = .043). Fc remission at 1-year was associated with better results in most secondary outcomes. CONCLUSION: Proactive IFX was superior to VDZ in inducing Fc remission at 1-year, which was associated with improved clinical outcomes.SUMMARYCurrent evidence suggests that vedolizumab may be as effective as Infliximab in the treatment of patients with inflammatory bowel disease.There have been no studies comparing vedolizumab with proactively optimized Infliximab based on trough levels.We confirm that conventional IFX is as effective as vedolizumab but proactive IFX appears superior to vedolizumab in inducing fecal calprotectin remission.Fecal calprotectin remission associates with better clinical outcomes.

Proactive Infliximab Drug Monitoring Is Superior to Conventional Management in Inflammatory Bowel Disease.

BACKGROUND: Increasing evidence supports the use of reactive therapeutic drug monitoring (TDM) in Crohn's disease (CD) and ulcerative colitis (UC) following secondary loss of response. It is still unknown if proactive TDM can improve clinical outcomes. METHODS: Consecutive patients completing infliximab (IFX) induction therapy were prospectively allocated into a proactive TDM protocol (pTDM). Before the fourth infusion and every 2 infusions, IFX trough levels and antidrug antibodies were measured using a drug-sensitive assay (Theradiag, Lisa Tracker). Treatment was proactively escalated aiming at an IFX trough level between 3 and 7 ug/mL (CD) and 5 and 10 ug/mL (UC). A retrospective cohort treated with IFX but without TDM served as the reference group. End points included the need for surgery, hospitalization, treatment discontinuation, and mucosal healing at 2 years of follow-up. RESULTS: Two hundred five patients were included, 56 in the proactive regimen. Treatment escalation was more common in pTDM patients (76.8% vs 25.5%; P < 0.001), who also required less surgery (8.9% vs 20.8%; P = 0.032) and presented higher rates of mucosal healing (73.2% vs 38.9%; P < 0.0001). Proactive TDM significantly decreased the odds of reaching any unfavorable outcome (odds ratio, 0.358; 95% confidence interval, 0.188-0.683; P = 0.002). CONCLUSIONS: Proactive TDM is associated with fewer surgeries and higher rates of mucosal healing than conventional non-TDM-based management.

The risk of disabling, surgery and reoperation in Crohn's disease - A decision tree-based approach to prognosis.

INTRODUCTION: Crohn's disease (CD) is a chronic inflammatory bowel disease known to carry a high risk of disabling and many times requiring surgical interventions. This article describes a decision-tree based approach that defines the CD patients' risk or undergoing disabling events, surgical interventions and reoperations, based on clinical and demographic variables. MATERIALS AND METHODS: This multicentric study involved 1547 CD patients retrospectively enrolled and divided into two cohorts: a derivation one (80%) and a validation one (20%). Decision trees were built upon applying the CHAIRT algorithm for the selection of variables. RESULTS: Three-level decision trees were built for the risk of disabling and reoperation, whereas the risk of surgery was described in a two-level one. A receiver operating characteristic (ROC) analysis was performed, and the area under the curves (AUC) Was higher than 70% for all outcomes. The defined risk cut-off values show usefulness for the assessed outcomes: risk levels above 75% for disabling had an odds test positivity of 4.06 [3.50-4.71], whereas risk levels below 34% and 19% excluded surgery and reoperation with an odds test negativity of 0.15 [0.09-0.25] and 0.50 [0.24-1.01], respectively. Overall, patients with B2 or B3 phenotype had a higher proportion of disabling disease and surgery, while patients with later introduction of pharmacological therapeutic (1 months after initial surgery) had a higher proportion of reoperation. CONCLUSIONS: The decision-tree based approach used in this study, with demographic and clinical variables, has shown to be a valid and useful approach to depict such risks of disabling, surgery and reoperation.

The use of a segmental endoscopic score may improve the prediction of clinical outcomes in acute severe ulcerative colitis.

BACKGROUND: Acute severe colitis (ASC) remains a challenging complication of ulcerative colitis. The early identification of patients who will not respond to optimal therapy is warranted. Increasing evidence suggests that endoscopy may play a role in predicting important outcomes in acute severe colitis. METHODS: The endoscopic activity of consecutive patients with acute severe colitis was evaluated using the Mayo endoscopic sub-score (Mayo) and the ulcerative colitis endoscopic index of severity (UCEIS). Two segmental indexes were also produced by summing the scores of the rectum and sigmoid (seg-Mayo and seg-UCEIS, respectively). Endpoints included the need for salvage therapy with infliximab or cyclosporine, refractoriness to corticosteroids, and colectomy. RESULTS: Of one hundred and eight patients enrolled in the study, 60 (55.6%) were male; with a median age of 34.5 years (range 15-80). All patients received intravenous steroids. Fifty-nine patients (55.6%) showed an incomplete or absent response to steroids, 35 patients (34.3%) received salvage therapy with infliximab or cyclosporine and 38 patients (33.3%) were colectomized during the index hospitalization or within the first year of follow-up. All scores were able to predict the need for surgery, but only the seg-UCEIS significantly predicted refractoriness to steroids. CONCLUSIONS: There was a strong correlation between endoscopic severity and unfavorable outcomes. The UCEIS outperformed the Mayo endoscopic sub-score in all important outcomes. Segmental scoring further improved the performance of the UCEIS.

Primary liposarcoma of the sigmoid presenting as colonic intussusception - A case report.

Liposarcomas are malignant soft tissue neoplasms usually located in the retroperitoneum, head, neck and extremities. Although secondary invasion of the gastrointestinal tract by retroperitoneal sarcomas is frequent, primary involvement is uncommon. We report a young patient with Crohn's disease in remission presenting with intussusception of the colon due to a primary liposarcoma of the sigmoid. Emergency resection confirmed the diagnosis. The patient remains in remission after five years. This represents the youngest diagnosis of liposarcoma to date and the first occurring in the sigmoid. We also highlight the concomitant diagnosis of Crohn´s disease.

Clinical and genetic factors predicting response to therapy in patients with Crohn's disease.

AIM: To identify clinical and/or genetic predictors of response to several therapies in Crohn's disease (CD) patients. METHODS: We included 242 patients with CD (133 females) aged (mean ± standard deviation) 39 ± 12 years and a disease duration of 12 ± 8 years. The single-nucleotide polymorphisms (SNPs) studied were ABCB1 C3435T and G2677T/A, IL23R G1142A, C2370A, and G9T, CASP9 C93T, Fas G670A and LgC844T, and ATG16L1 A898G. Genotyping was performed with real-time PCR with Taqman probes. RESULTS: Older patients responded better to 5-aminosalicylic acid (5-ASA) and to azathioprine (OR 1.07, p = 0.003 and OR 1.03, p = 0.01, respectively) while younger ones responded better to biologicals (OR 0.95, p = 0.06). Previous surgery negatively influenced response to 5-ASA compounds (OR 0.25, p = 0.05), but favoured response to azathioprine (OR 2.1, p = 0.04). In respect to genetic predictors, we observed that heterozygotes for ATGL16L1 SNP had a significantly higher chance of responding to corticosteroids (OR 2.51, p = 0.04), while homozygotes for Casp9 C93T SNP had a lower chance of responding both to corticosteroids and to azathioprine (OR 0.23, p = 0.03 and OR 0.08, p = 0.02,). TT carriers of ABCB1 C3435T SNP had a higher chance of responding to azathioprine (OR 2.38, p = 0.01), while carriers of ABCB1 G2677T/A SNP, as well as responding better to azathioprine (OR 1.89, p = 0.07), had a lower chance of responding to biologicals (OR 0.31, p = 0.07), which became significant after adjusting for gender (OR 0.75, p = 0.005). CONCLUSIONS: In the present study, we were able to identify a number of clinical and genetic predictors of response to several therapies which may become of potential utility in clinical practice. These are preliminary results that need to be replicated in future pharmacogenomic studies.

IL23R polymorphisms influence phenotype and response to therapy in patients with ulcerative colitis.

OBJECTIVE: We aimed to identify the clinical and genetic [IL23 receptor (IL23R) single nucleotide polymorphisms (SNPs)] predictors of response to therapy in patients with ulcerative colitis. PATIENTS AND METHODS: A total of 174 patients with ulcerative colitis, 99 women and 75 men, were included. The mean age of the patients was 47±15 years and the mean disease duration was 11±9 years. The number of patients classified as responders (R) or nonresponders (NR) to several therapies was as follows: 110 R and 53 NR to mesalazine (5-ASA), 28 R and 20 NR to azathioprine (AZT), 18 R and 7 NR to infliximab. Clinical and demographic variables were recorded. A total of four SNPs were studied: IL23R G1142A, C2370A, G43045A, and G9T. Genotyping was performed by real-time PCR using Taqman probes. RESULTS: Older patients were more prone to respond to 5-ASA (P=0.004), whereas those with pancolitis were less likely to respond to such therapies (P=0.002). Patients with extraintestinal manifestations (EIMs) were less likely to respond to 5-ASA (P=0.001), AZT (P=0.03), and corticosteroids (P=0.06). Carriers of the mutant allele for IL23R SNPs had a significantly higher probability of developing EIMs (P<0.05), a higher probability of being refractory to 5-ASA (P<0.03), but a higher likelihood of responding to AZT (P=0.05). A significant synergism was observed between IL23R C2370A and EIMs with respect to nonresponse to 5-ASA (P=0.03). CONCLUSION: Besides extent of disease and age at disease onset, the presence of EIMs may be a marker of refractoriness to 5-ASA, corticosteroids, and AZT. IL23R SNPs are associated both with EIMs and with nonresponse to 5-ASA and corticosteroids.

A comprehensive approach to evaluate nutritional status in Crohn's patients in the era of biologic therapy: a case-control study.

OBJECTIVES: Evaluate the nutritional status of patients with inactive or mildly active Crohn's disease (CD), and identify possible causes for potential deficiencies. METHODS: A total of 78 CD patients and 80 healthy controls were evaluated in respect of nutritional status, dietary intake, and life styles factors. RESULTS: These 73/78 CD patients were on immunomodulating therapies. Mean body mass index (BMI) was lower in patients as compared to controls (P= 0.006) but 32% of CD patients and 33.8% of controls had a BMI > 25, whereas 8% and 23.8% in each group, respectively, were obese (BMI > 30Kg/m(2)). Fat free mass was significantly decreased in both genders (P < 0.05) whereas fat mass was decreased only in males (P= 0.01). Energy intake was significantly lower in CD patients (P < 0.0001) and we observed significantly lower adjusted mean daily intakes of carbohydrates, monounsaturated fat, fiber, calcium, and vitamins C, D, E, and K (P < 0.05). 29% of patients had excluded grains from their usual diet, 28% milk, 18% vegetables, and 11% fruits. Milk exclusion resulted in a significantly lower consumption of calcium and vitamin K (P < 0.001) and the exclusion of vegetables was associated to a lower consumption of vitamins C and E (P < 0.05). Physical activity was significantly lower in CD patients (P= 0.01) and this lack of physical activity was inversely correlated with increased fat mass percentage (r=-0.315, P= 0.001). CONCLUSIONS: Results showed that the most prevalent form of malnutrition in CD patients was an excess of body weight, which was concomitant with an inadequate dietary intake, namely micronutrients, clearly related to dietary exclusion of certain foods.