Crohn's Disease In Clinical Remission Research Articles

Intestinal ultrasound accurately predicts future therapy failure in Crohn's disease patients in a biologics-induced remission.

Intestinal ultrasound (IUS) is used to assess disease activity, complications, and treatment follow-up in Crohn's disease (CD). Less is known about the association of disease activity on IUS with the risk of future disease relapse during biologically sustained clinical remission in CD. The study aimed to investigate the association between IUS activity parameters and subsequent therapy failure in asymptomatic biologically treated patients with CD. A retrospective cohort study examined the association between IUS parameters and forthcoming therapy failure (drug discontinuation, dose escalation, corticosteroid use, hospitalization, or surgery) in CD patients on biological therapy in remission. A total of 57 patients with ileal (65%) or ileocolonic (35%) CD on biological therapy were included in the study. Therapy failure occurred in 50.8% [defined as need for dose escalation (31%), drug discontinuation (51.7%), steroid use (10.5%), and hospitalization (6.8%)] during a median follow-up of 5 (SD + 9.5) months after IUS. On univariate analysis, a bowel wall thickness (BWT) of 2.5 vs. 4 mm ( P = 0.005), the existence of an enlarged lymph node ( P = 0.02), and the loss of bowel wall stratification ( P = 0.01) were correlated with therapy failure. On multivariable analysis, only BWT ≥ 4 mm was associated with the risk of future treatment failure (hazard ratio, 3.7; 95% confidence interval, 0.6-15; P = 0.02). Our findings suggest that BWT ≥4 mm during clinical remission is associated with subsequent treatment failure in patients with CD treated with biologics. Our results support the use of IUS for monitoring CD during remission and may point to a novel threshold for predicting disease reactivation.

COVID-19 impact in Crohn’s disease patients submitted to autologous hematopoietic stem cell transplantation

BACKGROUND Severe acute respiratory syndrome coronavirus 2 is the virus responsible for coronavirus disease 2019 (COVID-19), a disease that has been blamed for inducing or exacerbating symptoms in patients with autoimmune diseases. Crohn's disease (CD) is an inflammatory bowel disease that affects genetically susceptible patients who develop an abnormal mucosal immune response to the intestinal microbiota. Patients who underwent hematopoietic stem cell transplantation (HSCT) are considered at risk for COVID-19. AIM To describe for the first time the impact of COVID-19 in CD patients who had undergone autologous, non-myeloablative HSCT. METHODS In this descriptive study a series of 19 patients were diagnosed with positive COVID-19. For two patients there were reports of the occurrence of two infectious episodes. Parameters related to HSCT, such as time elapsed since the procedure, vaccination status, CD status before and after infection, and clinical manifestations resulting from COVID-19, were evaluated. RESULTS Among the patients with COVID-19, three, who underwent Auto HSCT less than six months ago, relapsed and one, in addition to the CD symptoms, started to present thyroid impairment with positive anti-TPO. Only one of the patients required hospitalization for five days to treat COVID-19 and remained in CD clinical remission. Nine patients reported late symptoms that may be related to COVID-19. There were no deaths, and a statistical evaluation of the series of COVID-19 patients compared to those who did not present any infectious episode did not identify significant differences regarding the analyzed parameters. CONCLUSION Despite the change in CD status in three patients and the presence of nine patients with late symptoms, we can conclude that there was no significant adverse impact concerning COVID-19 in the evaluated patients who underwent HSCT to treat CD.

Serum levels of infliximab and adalimumab are associated with deep remission in inflammatory bowel disease

ObjectiveDeep remission defined by clinical-biomarker remission and mucosal healing has emerged as a new therapeutic target in inflammatory bowel disease. The aim of this study was to define an optimal cut-off concentration for infliximab and adalimumab during maintenance therapy associated with deep remission. The secondary objective, was to evaluate the influence of variables on anti tumor necrosis factor-alpha concentrations and deep remission. MethodRetrospective study including 120 and 122 patients inflammatory bowel disease diagnosed who received maintenance therapy with infliximab and adalimumab. Biomarker remission was considered by C-reactive protein < 5 mg/L and fecal calprotectin < 100 µg/g. Crohn's disease clinical remission was defined by a Harvey Bradshaw score < 5 and mucosal healing by a simple endoscopic score for Crohn's disease< 3. In ulcerative colitis, it was defined as a Mayo total score < 3 and Mayo endoscopic subscore < 2. Receiver operating characteristic test was performed to determine drug concentration thresholds associated with deep remission. Anti tumor necrosis factor-alpha concentrations were classified into quartiles. X2 and Kruskal-Wallis test were used to compare discrete and continuous variables between quartile groups. Multivariate logistic regression was performed to identify patient characteristics and serological facto C-reactive protein rs associated with deep remission. ResultsAnti tumor necrosis factor-alpha concentrations were higher in patients with deep remission, in infliximab (4.4, interquartile range: 3.3-6.5 vs 2.3, interquartile range: 1.1-4.2 µg/mL, P < 0.005) and adalimumab (6.3, interquartile range: 4.2-8.2 vs 3.9, interquartile range: 2.4-5.5 µg/mL, P < 0.005). A Receiver operating characteristic test identified a concentration threshold of 3.1 µg/mL in infliximab (area under the Receiver operating characteristic test curve, 0.72) and 6.3 µg/mL in adalimumab (area under receiver operating characteristic test curve, 0.75) associated with deep remission. Factors associated with the highest quartiles of serum infliximab concentration were: elevated body mass index, absence of previous inflammatory bowel disease-surgery, C-reactive protein < 5 mg/L, and fecal calprotectin < 100 µg/g. In adalimumab, higher quartiles were related to concomitant immunosuppressants, low body mass index, absence of previous inflammatory bowel disease-surgery, and C-reactive protein < 5 mg/L and fecal calprotectin < 100 µg/g. Multivariate regression identified fecal calprotectin < 100 µg/g, C-reactive protein < 5 mg/L, infliximab > 3.1 µg/mL and adalimumab concentrations > 6.3 µg/mL as factors significantly associated with deep remission. ConclusionsTrough infliximab and adalimumab concentrations, C-reactive protein < 5 mg/L and fecal calprotectin < 100 µg/g are associated with deep remission during maintenance therapy. Cutoff point of 3.1 and 6.3 g/mL for infliximab and adalimumab respectively, were identified as deep remission predictors.

Serum leucine-rich alpha-2 glycoprotein levels for predicting active ultrasonographic findings in intestinal lesions of patients with Crohn's disease in clinical remission.

This study aimed to investigate the cutoff value of leucine-rich alpha-2 glycoprotein (LRG) in predicting active intestinal ultrasonography (IUS) findings in patients with Crohn's disease (CD) in clinical remission. Data were retrospectively collected from patients with CD evaluated using LRG and undergoing IUS from September 2020 to August 2022. Patients with a Harvey-Bradshaw Index of ≤4 were included and those who underwent intestinal resection were excluded. Bowel wall thickness and stratification and blood flow signal using superb microvascular imaging (SMI) were used to assess ultrasonography findings. SMI signals were categorized into 4 grades following the Limberg score. Receiver operating characteristic curves were constructed and the area under the curve was calculated to determine the LRG cutoff values for predicting active IUS findings and were compared with those of C-reactive protein. This study included 213 patients. The LRG cutoff values to predict active bowel wall thickness, loss of bowel wall stratification, and SMI of ≥1, ≥2, and 3 were 14.6 μg/mL, 14.6 μg/mL, 14.6 μg/mL, 14.6 μg/mL, and 16.9 μg/mL, respectively, with significantly higher areas under the curve in SMI of ≥1 and 3 than in C-reactive protein. The best LRG cutoff value for predicting active IUS findings was 14.6 μg/mL in patients with CD in clinical remission, suggesting that LRG is better than C-reactive protein for detecting active IUS findings in CD.

Fecal transplantation for treatment of inflammatory bowel disease.

Fecal transplantation for treatment of inflammatory bowel disease.

Toward transmural healing: Sonographic healing is associated with improved long-term outcomes in patients with Crohn's disease.

Background and AimsTransmural healing has emerged as a treatment target in Crohn’s disease (CD). We investigated whether transmural healing assessed with intestinal ultrasound (IUS) is associated with improved clinical outcomes in patients with CD in clinical remission.MethodsPatients with CD in clinical remission at baseline (HBI <4) having IUS between August 2017 and June 2020 with at least 6‐months’ follow‐up were retrospectively studied. Time to medication escalation, corticosteroid use and CD‐related hospitalisation or surgery were compared by the presence or absence of sonographic healing, defined as bowel wall thickness ≤3 mm without hyperemia on color Doppler, inflammatory fat, or disrupted bowel wall stratification. Factors associated with survival were analyzed by Kaplan–Meier analysis using Cox proportional‐hazard model.ResultsOf 202 consecutive patients (50% male), sonographic inflammation was present in 61%. During median follow‐up of 19 (IQR 13–27) months, medication escalation occurred in 52%, corticosteroid use in 23%, hospitalisation in 21%, and CD‐related surgery in 13%. Sonographic healing was significantly associated with a reduced risk of medication escalation (p = 0.0018), corticosteroid use (p = 0.0247), hospitalisation (p = 0.0102), and surgery (p = 0.083). On multivariable analysis, sonographic healing was significantly associated with an increased odds of medication escalation‐free survival (hazard ratio [HR]:1.94; 95% CI 1.23–3.06; p = 0.004) and corticosteroid‐free survival (HR:2.41; 95% CI 1.24–4.67; p = 0.009), but not with hospitalisation or surgery.ConclusionIn patients with CD in clinical remission, sonographic healing is associated with improved clinical outcomes. Further studies are needed to determine whether sonographic healing should be a treatment target.

Fecal Calprotectin Assay at an Early Stage of Treatment Can Be Used as a Surrogate Marker to Predict Clinical Remission and Mucosal Healing in Pediatric Crohn's Disease.

PurposeThis study evaluated the predictive role of fecal calprotectin (FC) measured at an early stage of treatment for monitoring clinical remission (CR) after six months and endoscopic remission (ER) after one year of treatment in pediatric Crohn’s disease (CD).MethodsThis retrospective study included 45 patients who simultaneously underwent ileocolonoscopy and FC testing during follow-up. FC levels were measured before and after six weeks of treatment. CR was assessed after six months of treatment using Pediatric Crohn’ s Disease Activity Index and acute-phase reactants. ER was assessed after one year using the Simple Endoscopic Score for Crohn’s Disease.ResultsTwenty-nine (64.4%) patients used oral prednisolone for remission induction and 16 (35.6%) patients used anti-tumor necrosis factor-alpha. Thirty (66.7%) patients achieved CR, while 24 (53.3%) achieved ER. The FC level measured after six weeks of treatment could predict CR (χ2=9.15, p=0.0025) and ER (χ2=12.31, p=0.0004). The δFC could predict CR (χ2=7.91, p=0.0049), but not ER (χ2=1.85, p=0.1738). With a threshold of ≤950.4 µg/g, FC at week six could predict CR with 76.7% sensitivity and 73.3% specificity. The area under the curve (AUC) was 0.769 (standard error 0.0773, p=0.0005). The same threshold predicted ER with 87.5% sensitivity and 71.4% specificity. The AUC was 0.774 (standard error 0.074, p=0.0002).ConclusionFC assay at an early stage of treatment can be used as a surrogate marker to predict CR and mucosal healing in pediatric CD.

Usefulness of the capsule endoscopy Crohn's disease activity index in assessing the necessity of early additional treatment in patients with Crohn's disease in clinical remission.

The Capsule Endoscopy Crohn's Disease Activity Index (CECDAI) was recently reported as a new scoring system to evaluate the mucosal lesions of patients with Crohn's disease (CD). We investigated whether CECDAI is useful for assessing the necessity of early additional treatment in patients with CD in clinical remission.Twenty-one patients with small intestinal CD in clinical remission underwent capsule endoscopy (CE). The CECDAI and Lewis score (LS) were used to evaluate the intestinal lesions. We analyzed the correlations between several biomarkers and CECDAI or LS and examined the changes in therapeutic regimens based on the CECDAI.CE identified intestinal abnormalities in most CD patients in clinical remission: 81.0% and 85.7%, as assessed using CECDAI and LS, respectively. A significant positive correlation was observed between the CDAI and LS (P = .025), as well as between CDAI and CECDAI (P = .014) in these cases. Compared to LS, CECDAI scores were more evenly distributed. No significant correlations were observed between endoscopic scores and serum markers, including CRP, hemoglobin, and albumin levels. Additional treatment was performed significantly more often in patients with moderate-severe disease activity (CECDAI ≥5.8) (P = .012) than in those with normal (CECDAI <3.5) and mild (3.5≤CECDAI<5.8) disease activity. Resection of the small intestine did not affect the small bowel transit time or CE score.CECDAI is useful in evaluating mucosal lesions in small bowel CD patients in clinical remission and helps in assessing the requirement for additional treatment for these patients, including those who undergo intestinal resection.

Значение мониторинга уровня инфликсимаба и антител к нему в сыворотке крови для оптимизации терапии воспалительных заболеваний кишечника у детей

Objective. To evaluate the prognostic value of serum levels of infliximab (IFX) and anti-IFX antibodies for predicting treatment efficacy in children with inflammatory bowel disease (IBD). Patients and methods. This study included 123 children with IBD (65 patients with ulcerative colitis (UC) and 58 patients with Crohn's disease (CD)) aged between 3 and 18 years. Children were examined upon the completion of an induction course of therapy and then after 1 year of therapy and between 1 and 3 years of treatment. The induction course was administered according to the scheme of 0–2–6 weeks; maintenance therapy was administered with 6-week and 8-week intervals. The residual level of IFX and the level of anti-IFX antibodies in serum were measured using enzyme-linked immunosorbent assay. Results. We observed a significant increase in the IFX level during clinical remission of CD (remission – 5.21 [3.32; 7.43] μg/mL; exacerbation – 2.42 [0.42; 4.51] μg/mL, p = 0.001) and UC (remission – 4.57 [3.4; 6.74] μg/mL; exacerbation – 0.63 [0.4; 3.27] μg/mL, p = 0.000). ROC analysis demonstrated high accuracy of our model based on measuring residual IFX level for distinguishing between exacerbation and remission in both CD patients (AUC = 0.812) and UC patients (AUC = 0.851). The optimal minimum level of IFX for maintaining clinical remission was 3.7 μg/mL in children with CD and 3.4 μg/mL in children with UC. Anti-IFX antibodies were detected in 18% of patients; children with exacerbation were 4.7 times more likely to have detectable level of anti-IFX antibodies than those in clinical remission. Conclusion. Monitoring of serum levels of IFX and anti-IFX antibodies is a promising method for predicting treatment efficacy and its optimization in children with IBD. Key words: inflammatory bowel disease, tumor necrosis factor-α, infliximab, residual level of infliximab, anti-infliximab antibodies

Changes in the Crohn's Disease Activity Index and Safety of Administering Saccharomyces Boulardii in Patients with Crohn's Disease in Clinical Remission: A Single Hospital-based Retrospective Cohort Study.

Crohn's disease (CD) is characterized by uncontrolled inflammation of the intestine. Saccharomyces boulardii (S. boulardii), a probiotic, stabilizes the intestinal wall. This study examined the changes in the CD activity index (CDAI) after taking S. boulardii in patients with CD in clinical remission. In this single hospital-based retrospective cohort study, the medical records of CD patients in clinical remission, who had received S. boulardii for more than 6 months, were reviewed. The CDAI, BMI, and serum levels of hemoglobin (Hb), ferritin, iron, vitamin B12, folate, total protein, albumin, total cholesterol, CRP, and fecal calprotectin (FC) between the initiation and the 6th month were compared. The timing and reasons for the discontinuation were also investigated. One hundred and fifty-four patients were included, and 92 patients, who received for more than 6 months, were analyzed. The changes in CDAI, BMI, Hb, and total cholesterol were significant as follows: CDAI from 38.52 to 30.53 (p<0.01), BMI (kg/m2 ) from 23.38 to 23.97 (p<0.01), Hb (g/dL) from 13.73 to 14.03 (p<0.01), and total cholesterol (mg/dL) from 154.9 to 161.5 (p<0.01). On the other hand, the changes in FC, CRP, ferritin, vitamin B12, folate, total protein, and albumin were not statistically significant. Only one patient stopped due to a flare-up, but this was not believed to be related to the drug. In patients with CD in remission, S. boulardii appears to improve the CDAI, BMI, serum Hb, and total cholesterol level without safety issues. Further randomized controlled studies will be needed.

Combination of Biological Agents in Moderate to Severe Pediatric Inflammatory Bowel Disease: A Case Series and Review of the Literature.

BackgroundTreatment with biological agents such as anti-tumor necrosis factors (TNFs) has become standard of care in moderate to severe pediatric inflammatory bowel disease (IBD). However, a significant proportion of patients experience loss of response to anti-TNFs, need treatment escalation, or develop side effects. There is no data in the literature regarding combination of biological agents in pediatric IBD.MethodsAt our hospital, which is a tertiary referral center, we have combined the anti-TNF infliximab with either vedolizumab or ustekinumab in patients with severe pediatric IBD. The indications for dual biological therapy were insufficient efficacy of infliximab or vedolizumab monotherapy, or side effects such as psoriasis due to anti-TNFs.ResultsEight patients (four boys) aged 14–17.5 years received a combination of infliximab and vedolizumab due to only a partial response to infliximab, four with Crohn’s disease (CD) and four with ulcerative colitis (UC). Clinical remission was achieved in four patients (3 UC) and four had a colectomy (3 CD, 1 UC). Five CD patients (3 girls) aged 11–17 years, on maintenance therapy with infliximab, developed psoriasis resistant to topical treatment. A combination of infliximab and ustekinumab resulted in clinical remission of CD without skin symptoms. No serious adverse events occurred in any of the patients on combination therapy. Thirteen publications report on combining biologicals, all in adult IBD.ConclusionIn pediatric IBD, combining biological agents seems to be safe and beneficial in selected patients. The safety should be addressed in long-term follow-up studies.

Efficacy and safety of methotrexate in the management of inflammatory bowel disease: A systematic review and meta-analysis of randomized, controlled trials

BackgroundThe therapeutic role of methotrexate (MTX) for management of inflammatory bowel disease (IBD) remains unclear. MethodsWe systematically reviewed randomized, controlled trials (RCTs) of MTX for induction and maintenance of remission in IBD until January 2020 in accordance with PROSPERO protocol (#CRD42018115047). Relative risk (RR) of maintenance of remission, induction of remission, endoscopic disease activity, and adverse events were combined in a meta-analysis. FindingsMTX monotherapy was not superior to placebo for induction of clinical remission in Crohn's disease (CD). However, MTX was superior to placebo in maintaining clinical remission of CD. Concomitant therapy with MTX and the TNF inhibitor infliximab (IFX) was not superior to IFX monotherapy in CD. In ulcerative colitis (UC), MTX monotherapy was not superior to placebo neither for induction of clinical remission, nor for maintenance of clinical remission. MTX did not result in superior endoscopic outcomes during induction or maintenance therapy compared with placebo. Regarding adverse events (AEs), our meta-analysis on CD studies showed a significantly higher risk of AEs when comparing MTX versus placebo in studies investigating induction of remission, but not in maintenance of remission. In UC, no such differences in AEs between MTX or placebo were observed. InterpretationCurrent data support the efficacy of parenteral MTX monotherapy for maintenance of clinical remission in CD. MTX is not confirmed to be effective for treatment of UC or for induction of remission in CD. No evidence supports concomitant MTX to improve efficacy of IFX (no other biologics investigated).

Histologic Healing Is More Strongly Associated with Clinical Outcomes in Ileal Crohn’s Disease than Endoscopic Healing

Deep remission, based on clinical remission and evidence of healing during endoscopic evaluation, are goals of medical treatments for Crohn's disease (CD). We investigated whether histologic healing is associated with outcomes of patients with CD ileitis. We performed a retrospective study of 101 patients with CD (52% male) isolated to the terminal ileum who had a colonoscopy between September 2005 and June 2015. Our analysis included patients in clinical remission at colonoscopy who had biopsies collected from colon and ileum. The ileum was evaluated for endoscopic healing (no ulceration) and histologic evidence of healing (no active inflammation, erosions, ulceration, or neutrophil infiltration). We compared times of clinical relapse-free survival, medication escalation, corticosteroid use, or hospitalization secondary to disease activity between patients with and without histological and endoscopic healing, followed for a median 21 months. We identified factors associated with survival using Kaplan Meier analysis and Cox proportional hazard model. At ileo-colonoscopy, 63% of patients had endoscopic healing and 55% had histologic evidence of healing. The level of agreement between endoscopic and histologic activity was fair (62%, K = 0.2250, P = .0064). Forty-two patients had clinical relapse, 45 had medication escalation, 30 required corticosteroids, and 17 were hospitalized (3 required surgery). On multivariate analysis, only histologic healing was associated with decreased risk of clinical relapse (hazard ratio [HR], 2.05; 95% CI, 1.07-3.94; P = .031), medication escalation (HR, 2.17; 95% CI, 1.2-3.96; P = .011), and corticosteroid use (HR, 2.44; 95% CI, 1.17-5.09; P = .018). No factors were associated with hospitalization. In patients with ileal CD in clinical remission, histologic healing but not endoscopic healing is associated with decreased risk of clinical relapse, medication escalation, or corticosteroid use.

Efficacy and Safety of Oral Janus Kinase Inhibitors for Inflammatory Bowel Disease: A Systematic Review and Meta-Analysis

Background: Janus kinase (JAK) inhibitors are novel agents for treatment of inflammatory bowel disease. We aimed to determine the efficacy and safety of Janus kinase (JAK) inhibitors for the treatment of Crohn's disease (CD) and ulcerative colitis (UC). Methods: A systematic review and meta-analysis were conducted. PubMed, Embase, and CENTRAL were searched to November 1, 2018 for randomized placebo-controlled trials (RCTs) of JAK inhibitors in adult patients with CD or UC. Clinical, endoscopic, and safety outcomes were extracted and rates relative to placebo were pooled using a random-effects model. Findings: A total of 12 RCTs (5 CD, 7 UC) were included. Patients were randomized to placebo (n=844), tofacitinib (n=1,882), filgotinib (n=130), peficitinib (n=176), upadacitinib (n=387), or TD-1473 (n=31). JAK inhibitor treatment was associated with induction of clinical remission in CD (relative risk RR 1∙38 [95% confidence interval CI 1∙04-1∙83], p=0 ∙025, I2=14%) and UC (RR 3∙07 [95% CI: 2∙03-4∙63], p<0∙001, I2=0%). In UC, JAK inhibitor treatment was associated with induction of endoscopic remission (endoscopic Mayo subscore MCSe=0/1) (RR 2∙43 [95% CI: 1∙64- 3∙59], p<0∙001, I2=27%) and mucosal healing (MCSe=0) (RR 5∙50 [95% CI: 2∙46-12∙32], p<0∙001, I2=0%). JAK inhibitor treatment increased the risk of infection compared to placebo (RR 1∙40 [95% CI: 1∙18-1∙67], p<0∙001, I2=0%), particularly for herpes zoster. All studies were rated as low or unclear risk of bias. Interpretation: JAK inhibitors are effective for induction of clinical and endoscopic remission in CD and UC, although are associated with an increased risk of infectious complications. Funding Statement: There was no funding source for this study. Christopher Ma is supported by a Clinician Fellowship from the Canadian Institutes of Health Research and the Canadian Association of Gastroenterology. Niels Vande Casteele is supported by a Research Scholar Award from the American Gastroenterological Association. Declaration of Interests: Christopher Ma, Jeffrey Lee, Anish Mitra, Anouar Teriaky, and Daksh Choudhary have no conflicts of interest to disclose. Tran Nguyen is an employee of Robarts Clinical Trials, Inc. Niels Vande Casteele has received research support from R-Biopharm and Takeda and consulting fees from Janssen, Pfizer, Progenity, Prometheus, Takeda, and UCB. Reena Khanna has received consulting/speaker fees from AbbVie, Encycle, Janssen, Merck, Pendopharm, Pfizer, Roche, Robarts Clinical Trials, Shire, and Takeda Canada. Remo Panaccione has received scientific advisory board fees from Abbott/AbbVie, Amgen, Janssen, Merck, Pfizer, Prometheus Laboratories, Salix Pharma, Shire, Takeda, and Warner Chilcott, consulting fees from Abbott/AbbVie, Amgen, Aptalis, Astra Zeneca, Baxter, BMS, Centocor, Elan/Biogen, Eisai, Ferring, GSK, Janssen, Merck, Millennium, Pfizer, Proctor & Gamble, Prometheus Therapeutics and Diagnostics, Schering-Plough, Shire, Takeda, UCB Pharma, and Warner Chilcott, research grants from Abbott/AbbVie, Amgen, Aptalis, Astra Zeneca, Baxter, BMS, Centocor, Eisai, Elan/Biogen, Ferring, GSK, Janssen, Merck, Millennium, Pfizer, Proctor & Gamble, Prometheus, Shire, Schering-Plough, Takeda, UCB Pharma, and Warner Chilcott, and speaker’s bureau fees from Abbott/AbbVie, Amgen, Aptalis, Astra Zeneca, Baxter, BMS, Centocor, Eisai, Elan/Biogen, Ferring, GSK, Janssen, Merck, Millennium, Pfizer, Proctor & Gamble, Prometheus, Schering-Plough, Shire, Takeda, UCB Pharma, and Warner Chilcott. Brian Feagan has received grant/research support from Millennium Pharmaceuticals, Merck, Tillotts Pharma AG, AbbVie, Novartis Pharmaceuticals, Centocor Inc., Elan/Biogen, UCB Pharma, Bristol-Myers Squibb, Genentech, ActoGenix, and Wyeth Pharmaceuticals Inc.; consulting fees from Millennium Pharmaceuticals, Merck, Centocor Inc., Elan/Biogen, Janssen440 Ortho, Teva Pharmaceuticals, Bristol-Myers Squibb, Celgene, UCB Pharma, AbbVie, Astra Zeneca, Serono, Genentech, Tillotts Pharma AG, Unity Pharmaceuticals, Albireo Pharma, Given Imaging Inc., Salix Pharmaceuticals, Novonordisk, GSK, Actogenix, Prometheus Therapeutics and Diagnostics, Athersys, Axcan, Gilead, Pfizer, Shire, Wyeth, Zealand Pharma, Zyngenia, GiCare Pharma Inc., and Sigmoid Pharma; and speaker’s fees from UCB, AbbVie, and J&J/Janssen. Vipul Jairath has received consulting fees from AbbVie, Eli Lilly, GlaxoSmithKline, Arena pharmaceuticals, Genetech, Pendopharm, Sandoz, Merck, Takeda, Janssen, Robarts Clinical Trials, Topivert, Celltrion; speaker’s fees from Takeda, Janssen, Shire, Ferring, Abbvie, Pfizer Ethics Approval Statement: PRISMA guidelines referenced.

P038 Persistent inflammatory markers and deregulated immune response in clinical remission Crohn's disease patients treated with infliximab

BACKGROUND: The development of Inflammatory Bowel Diseases (IBD) comprises an imbalance among gut microbiota, genetic susceptibility and exacerbated immune responses, which predispose to chronic inflammation in affected patients, who are usually treated with biological agents such as anti-tumor necrosis factor-α (TNF-α). Despite that, even during clinical remission periods, Crohn’s disease (CD) patients may still present endoscopic disease activity and possibly a residual systemic inflammatory response. Therefore, in this study we aimed to evaluate the responsiveness and immune profile of peripheral blood mononuclear cells (PBMC) of infliximab-treated patients, as well as the relationship between the altered responses and the clinical disease presentation. METHODS: We enrolled 20 healthy controls (HC) and 39 CD patients, which were classified according to the Harvey-Bradshaw Index (HBI) and Simple Endoscopic Score for Crohn’s Disease (SES-CD). All were using anti-TNF-α therapy (infliximab), including 61.5% in combination with Azathioprine. RESULTS: Although 94% of the patients were in clinical remission, 51.3% presented disease mucosal activity. Considering the Montreal classification, 12.8% had colonic disease, while 33.4% had ileal and 53.8% ileocolonic disease. Most the patients developed complications, being 20.5% stenosis and 35.9% structuring disease, while 59% had perianal disease. The immunophenotyping identification of PBMC by flow cytometry showed increased CD14+ and CD14++CD16+ monocytes in CD, indicating a tendency towards an inflammatory response because of the increased CD16 expression, along with augmented NKT and decreased NK cells and B lymphocytes. Considering the population of regulatory lymphocytes, CD patients had increased CD4+CD25+CTLA-4+ and CD4+CD25+FOXP3+ cells, together with augmented expression of CTLA-4 and FOXP3 in CD4+CD25- and CD4+CD25+ lymphocytes, indicating the raising of an important systemic counter regulatory response. Nevertheless, there was an increase in the inflammatory cytokine IL-6 in plasma and when PBMC was restimulated in vitro with bacterial-derived lipopolysaccharide (LPS), CD patients produced more TNF than healthy controls. Indeed, plasma dosage of LPS pointed to increased detection in CD samples, suggesting that these patients still present bacteria translocation to circulation. CONCLUSION(S): Even in clinical remission, CD patients had a relevant systemic inflammatory response together with increased regulatory population, probably elicited in an attempt to achieve immune-regulation after biological therapy. Financial support: Fapesp # 2017/08651-1.

Systematic review with meta-analysis: efficacy and safety of oral Janus kinase inhibitors for inflammatory bowel disease.

Janus kinase (JAK) inhibitors represent a novel therapeutic class for treatment of inflammatory bowel disease. To determine the efficacy and safety of JAK inhibitors compared to placebo for the treatment of Crohn's disease (CD) and ulcerative colitis (UC). PubMed, Embase and CENTRAL were systematically searched to November 1, 2018. Randomised placebo-controlled trials (RCTs) of JAK inhibitors in adult patients with CD or UC were eligible. Open-label extension studies without a placebo comparator arm were excluded. Clinical, endoscopic, and safety outcomes were extracted and rates relative to placebo were pooled using a random-effects model. A total of 12 RCTs (5 CD, 7 UC) were included. Patients were randomised to placebo (n=844), tofacitinib (n=1882), filgotinib (n=130), peficitinib (n=176), upadacitinib (n=387) or TD-1473 (n=31). JAK inhibitor treatment was associated with induction of clinical remission in CD (RR, relative risk 1.38 [95% confidence interval CI 1.04-1.83], P=0.025, I2 =14%) and UC (RR 3.07 [95% CI 2.03-4.63], P<0.001, I2 =0%). In UC, JAK inhibitor treatment was associated with induction of endoscopic remission (endoscopic Mayo subscore MCSe=0/1) (RR 2.43 [95% CI 1.64-3.59], P<0.001, I2 =27%) and mucosal healing (MCSe=0) (RR 5.50 [95% CI 2.46-12.32], P<0.001, I2 =0%). JAK inhibitor treatment increased the risk of infection compared to placebo (RR 1.40 [95% CI 1.18-1.67], P<0.001, I2 =0%), particularly for herpes zoster. JAK inhibitors are effective for inducing clinical remission in CD and induction of clinical and endoscopic remission in UC, although are associated with an increased risk of infectious complications.

Crohn's Disease in Clinical Remission Is Marked by Systemic Oxidative Stress.

Introduction: Crohn’s disease (CD) is characterized by chronic and relapsing inflammation of the gastro-intestinal tract. It is assumed that oxidative stress contributes to CD pathogenesis, but systemic biomarkers for oxidative stress in CD are not yet identified. A reduction in free thiol groups in plasma proteins (“plasma free thiols”) reflects systemic oxidative stress since they are prime substrates for reactive oxygen species. Here, we determined the concentrations of plasma free thiols in CD patients and healthy controls and studied the putative correlation with disease parameters.Methods: Free thiols were quantified in plasma of patients with CD in clinical remission [according to the Harvey Bradshaw Index (HBI)] and healthy controls and adjusted for plasma albumin. Albumin-adjusted free thiol concentrations were analyzed for associations with clinical and biochemical disease markers.Results: Mean plasma free thiol concentrations were significantly lower in patients with CD (n = 51) compared to healthy controls (n = 27) (14.7 ± 2.4 vs. 17.9 ± 1.8 μmol/g albumin; P < 0.001). Patients with CD with above-average free thiols had significantly lower CRP levels (median 1.4 [interquartile range] [0.4; 2.6] vs. 3.6 [0.6; 7.0] mg/L; P < 0.05) and BMI (23.6 ± 4.8 vs. 27.1 ± 5.2 kg/m2; P < 0.05). Patients with CD having solely colonic disease demonstrated markedly reduced plasma free thiol concentrations compared to patients with ileocolonic involvement (13.2 ± 1.8 vs. 15.2 ± 2.2 μmol/g; P < 0.05). Finally, plasma free thiol concentrations negatively correlated with biomarkers of inflammation, including hsCRP, SAA, IL-17A (all P < 0.05), and VEGF.Conclusion: Plasma free thiols are reduced in patients with CD in clinical remission compared to healthy controls. Thus, subclinical CD disease activity is reflected by systemic oxidative stress and plasma free thiols may be a relevant therapeutic target and biomarker to monitor disease activity in CD.

Consecutive fecal calprotectin measurements for predicting relapse in pediatric Crohn's disease patients.

BACKGROUNDAsymptomatic children with Crohn’s disease (CD) require ongoing monitoring to ensure early recognition of a disease exacerbation.AIMIn a cohort of pediatric CD patients, we aimed to assess the utility of serial fecal calprotectin measurements to detect intestinal inflammatory activity and predict disease relapse.METHODSIn this prospective longitudinal cohort study, children with CD on infliximab therapy in clinical remission were included. Fecal calprotectin levels were assessed at baseline and at subsequent 2-5 visits. Clinical and biochemical disease activity were assessed using the Pediatric Crohn’s Disease Activity Index, C-reactive protein and erythrocyte sedimentation rate at baseline and at visits over the following 18 mo.RESULTS53 children were included and eighteen patients (34%) had a clinical disease relapse during the study. Baseline fecal calprotectin levels were higher in patients that developed symptomatic relapse [median (interquartile range), relapse 723 μg/g (283-1758) vs 244 μg/g (61-627), P = 0.02]. Fecal calprotectin levels > 250 μg/g demonstrated good predictive accuracy of a clinical flare within 3 mo (area under the receiver operator curve was 0.86, 95% confidence limits 0.781 to 0.937).CONCLUSIONRoutine fecal calprotectin testing in children with CD in clinical remission is useful to predict relapse. Levels > 250 μg/g are a good predictor of relapse in the following 3 mo. This information is important to guide monitoring standards used in this population.

Vitamin D administration leads to a shift of the intestinal bacterial composition in Crohn's disease patients, but not in healthy controls

Dysbiosis is a common feature in the pathogenesis of inflammatory bowel diseases (IBD). Environmental factors, such as vitamin D deficiency, seem to play a role in the intestinal inflammation of IBD. The aim of this study was to investigate whether vitamin D administration has an impact on the bacterial composition in Crohn's disease (CD) compared to healthy controls (HC). A prospective, longitudinal, controlled interventional analysis was conducted in seven patients with CD in clinical remission and 10 HC to investigate the effect of orally administrated vitamin D on the intestinal bacterial composition using 16S ribosomal RNA gene amplicon sequencing. Clinical parameters were assessed. In contrast to HC, microbial communities of CD patients changed significantly during early vitamin D administration. However, a further increase in vitamin D level was associated with a reversal of this effect and additionally with a decrease in the bacterial richness in the CD microbiome. Specific species with a high abundancy were found during vitamin D administration in CD, but not in HC; the abundancy of Alistipes, Barnesiella, unclassified Porphyromonadaceae (both Actinobacteria), Roseburia, Anaerotruncus, Subdoligranulum and an unclassified Ruminococaceae (all Firmicutes) increased significantly after 1-week vitamin D administration in CD. Vitamin D has a specific influence on the bacterial communities in CD, but not in HC. Administration of vitamin D may have a positive effect in CD by modulating the intestinal bacterial composition and also by increasing the abundance of potential beneficial bacterial strains.

NOD2- and disease-specific gene expression profiles of peripheral blood mononuclear cells from Crohn's disease patients.

AIMTo investigate disease-specific gene expression profiles of peripheral blood mononuclear cells (PBMCs) from Crohn’s disease (CD) patients in clinical remission.METHODSPatients with CD in clinical remission or with very low disease activity according to the Crohn’s disease activity index were genotyped regarding nucleotide-binding oligomerization domain 2 (NOD2), and PBMCs from wild-type (WT)-NOD2 patients, patients with homozygous or heterozygous NOD2 mutations and healthy donors were isolated for further analysis. The cells were cultured with vitamin D, peptidoglycan (PGN) and lipopolysaccharide (LPS) for defined periods of time before RNA was isolated and subjected to microarray analysis using Clariom S assays and quantitative real-time PCR. NOD2- and disease-specific gene expression profiles were evaluated with repeated measure ANOVA by a general linear model.RESULTSEmploying microarray assays, a total of 267 genes were identified that were significantly up- or downregulated in PBMCs of WT-NOD2 patients, compared to healthy donors after challenge with vitamin D and/or a combination of LPS and PGN (P < 0.05; threshold: ≥ 2-fold change). For further analysis by real-time PCR, genes with known impact on inflammation and immunity were selected that fulfilled predefined expression criteria. In a larger cohort of patients and controls, a disease-associated expression pattern, with higher transcript levels in vitamin D-treated PBMCs from patients, was observed for three of these genes, CLEC5A (P < 0.030), lysozyme (LYZ; P < 0.047) and TREM1 (P < 0.023). Six genes were found to be expressed in a NOD2-dependent manner (CD101, P < 0.002; CLEC5A, P < 0.020; CXCL5, P < 0.009; IL-24, P < 0.044; ITGB2, P < 0.041; LYZ, P < 0.042). Interestingly, the highest transcript levels were observed in patients with heterozygous NOD2 mutations.CONCLUSIONOur data identify CLEC5A and LYZ as CD- and NOD2-associated genes of PBMCs and encourage further studies on their pathomechanistic roles.