Is Ustekinumab Effective in Refractory Crohn's Disease of the Pouch and Chronic Pouchitis? A Systematic Review.

Crohn's disease (CD) of the pouch and chronic pouchitis represent the most common long-term complications of total proctocolectomy and ileal pouch anal anastomosis (IPAA) for refractory ulcerative colitis (UC). These conditions are treated with multiple agents, including antibiotics, immunomodulators, and biologics. Among the latter, ustekinumab is approved for both CD and UC. We performed a systematic review to evaluate the efficacy of this anti-IL12/23 in CD of the pouch and chronic refractory pouchitis. Pubmed, Embase, Ovid, and the Cochrane Controlled Trials Register were searched to identify studies published until August 2020 investigating the use of ustekinumab for these conditions. Eighty-six eligible patients with IPAA-51 with CD of the pouch, 35 with chronic pouchitis-were identified from 2 retrospective studies and 5 case reports. Reported clinical response to ustekinumab was 63 and 85% in chronic pouchitis and CD of the pouch after 4-12 and 4-16 weeks, respectively. Clinical remission was reported in 10% of patients with chronic pouchitis and 27% of patients with CD of the pouch after 8-52 and 4-52 weeks of treatment, respectively. Endoscopic response was reported in 60% and 67% of patients with chronic pouchitis and CD of the pouch after 24-32 and 8-24 weeks of treatment respectively. Small sample sizes and large heterogeneity of therapy protocols/outcome definitions were significant studies limitations. In conclusion, there is a limited and inconclusive body of evidence suggesting that ustekinumab may be a therapeutic option for patients with chronic pouchitis and CD of the pouch refractory to other therapies.

Fecal Lactoferrin Predicts Primary Nonresponse to Biologic Agents in Inflammatory Bowel Disease.

INTRODUCTION: Fecal lactoferrin (FL) is a timely and accurate marker of inflammation in ulcerative colitis (UC) and Crohn's disease (CD). The aim of this study was to verify whether FL can predict primary nonresponse (PNR) to biologic agents during induction. METHODS: Retrospective outcome review in 27 patients (13 with CD and 14 with UC) tested for baseline FL and retested within a week after the first and second induction doses. Clinical/biochemical outcomes were evaluated at end of induction and at follow-up (3-24 months). RESULTS: Compared to baseline, changes of the Harvey-Bradshaw (CD) and Partial Mayo Scoring (UC) indices at end of induction separated responders (18/27 or 67%) from nonresponders (9/17 or 33%). In all patients, the initial FL value at induction decreased compared to baseline, continuing to decrease after the following dose in clinical responders while bouncing back in the others. Models targeting the 2 consecutively decreased FL values or the second FL value compared to baseline or the second FL value compared to the first were able to accurately predict response at end of induction. Follow-up assessment confirmed clinical remission in initial responders (with FL values reduced on the average by 94 ± 10% compared to baseline). CONCLUSIONS: In CD and UC patients during induction with biologic agents, early FL measurements accurately separate clinical responders from those experiencing PNR. The method described here offers several potential advantages over other strategies to assess and manage these patients.

Diagnostic Modality of Clostridioides difficile Infection Predicts Treatment Response and Outcomes in Inflammatory Bowel Disease.

BACKGROUND: Inflammatory bowel disease (IBD) patients are at increased risk of developing Clostridioides difficile infection (CDI). Common methods to diagnose CDI involve a combination of tests including the toxin A/B enzyme immunoassay (Toxin) and toxin gene polymerase chain reaction assay (PCR). Disease outcomes in Toxin+ versus Toxin-PCR+ IBD patients remain unclear. AIMS: This study aimed to examine the response to antibiotics and risk of IBD therapy escalation in Toxin+ versus Toxin-PCR+ patients. METHODS: IBD patients at an academic center with CDI diagnosis based on Toxin+ or Toxin-PCR+ from 2012 to 2017 were identified. Comparisons of response to antibiotics within 30 days and escalation of IBD therapy within 90 days of CDI diagnosis between these two groups were analyzed by Chi-square analysis. Multivariable regression analysis examined factors associated with antibiotic response. RESULTS: Among 92 patients included, 61% had Crohn's disease and 39% had ulcerative colitis. 70% tested Toxin-PCR+. 60% received vancomycin or fidaxomicin to treat CDI. 82% of Toxin+ patients responded to antibiotics compared to 25% of Toxin-PCR+ patients (p < 0.001). 21% of Toxin+ patients required IBD therapy escalation compared to 63% of Toxin-PCR+ patients (p < 0.001). When adjusted for the types of antibiotics used, IBD subtypes, and immunosuppression status, positivity to Toxin (OR 14.85, CI 4.62-47.72) was the most significant predictor of response to antibiotics. CONCLUSIONS: Toxin+ compared to Toxin-PCR+ IBD patients had a significantly higher rate of response to antibiotics and lower chances of requiring IBD therapy escalation. Future outcome studies involving CDI in IBD patients should be stratified by modality of diagnosis.

Probiotic-Induced Tolerogenic Dendritic Cells: A Novel Therapy for Inflammatory Bowel Disease?

Inflammatory bowel diseases (IBDs) are immune-mediated, chronic relapsing diseases with a rising prevalence worldwide in both adult and pediatric populations. Treatment options for immune-mediated diseases, including IBDs, are traditional steroids, immunomodulators, and biologics, none of which are capable of inducing long-lasting remission in all patients. Dendritic cells (DCs) play a fundamental role in inducing tolerance and regulating T cells and their tolerogenic functions. Hence, modulation of intestinal mucosal immunity by DCs could provide a novel, additional tool for the treatment of IBD. Recent evidence indicates that probiotic bacteria might impact immunomodulation both in vitro and in vivo by regulating DCs' maturation and producing tolerogenic DCs (tolDCs) which, in turn, might dampen inflammation. In this review, we will discuss this evidence and the mechanisms of action of probiotics and their metabolites in inducing tolDCs in IBDs and some conditions associated with them.

Immunomodulation and Generation of Tolerogenic Dendritic Cells by Probiotic Bacteria in Patients with Inflammatory Bowel Disease.

In inflammatory bowel diseases (IBD), the therapeutic benefit and mucosal healing from specific probiotics may relate to the modulation of dendritic cells (DCs). Herein, we assessed the immunomodulatory effects of four probiotic strains including Lactobacillus salivarius, Bifidobacterium bifidum, Bacillus coagulans and Bacillus subtilis natto on the expression of co-stimulatory molecules, cytokine production and gene expression of signal-transducing receptors in DCs from IBD patients. Human monocyte-derived DCs from IBD patients and healthy controls were exposed to four probiotic strains. The expression of co-stimulatory molecules was assessed and supernatants were analyzed for anti-inflammatory cytokines. The gene expression of toll-like receptors (TLRs), IL-12p40 and integrin αvß8 were also analyzed. CD80 and CD86 were induced by most probiotic strains in ulcerative colitis (UC) patients whereas only B. bifidum induced CD80 and CD86 expression in Crohn's disease (CD) patients. IL-10 and TGF-ß production was increased in a dose-independent manner while TLR expression was decreased by all probiotic bacteria except B. bifidum in DCs from UC patients. TLR-4 and TLR-9 expression was significantly downregulated while integrin ß8 was significantly increased in the DCs from CD patients. IL-12p40 expression was only significantly downregulated in DCs from CD patients. Our findings point to the general beneficial effects of probiotics in DC immunomodulation and indicate that probiotic bacteria favorably modulate the expression of co-stimulatory molecules, proinflammatory cytokines and TLRs in DCs from IBD patients.

Knowledge Gaps in the Management of Postoperative Crohn's Disease: A US National Survey.

BACKGROUND: Postoperative recurrence (POR) of Crohn's disease (CD) is common. Guidelines on POR management have recently been issued, but clinical practice may vary. AIMS: To examine the current clinical practice of POR management in the USA METHODS: A web-based survey was sent to all members of the American Gastroenterological Association and the American College of Gastroenterology. The survey consisted of multiple-choice questions with clinical scenarios to assess how participants manage POR. RESULTS: A total of 189 responses were received from practices in 34 states. 44% of participants were from academic settings. The median number of CD patients seen each month was 20-30 patients per participant. The majority of participants considered smoking, prior intestinal surgery, penetrating disease, perianal fistula, early disease onset, and long extent of disease as high-risk factors for POR. To diagnose and grade endoscopic recurrence, 57% of participants used an endoscopic scoring system; 86% defined clinical recurrence using a combination of symptoms and endoscopic findings; and 79% of participants routinely performed colonoscopy after surgery. In high-risk patients, 65% offered medical prophylaxis-most often biologics and/or immunomodulators-immediately after surgery, while 34% offered medical prophylaxis regardless of the patient's risk of POR. 64% of participants never stopped medical prophylaxis once initiated. CONCLUSIONS: Most gastroenterologists routinely perform colonoscopy to guide POR management. The majority of these providers continue medical prophylaxis indefinitely regardless of subsequent endoscopic findings. Further research is needed to determine the risks and benefits of continuing versus deescalating therapy in patients with potentially surgically induced remission.

Infliximab Reduces Endoscopic, but Not Clinical, Recurrence of Crohn's Disease After Ileocolonic Resection.

BACKGROUND & AIMS: Most patients with Crohn's disease (CD) eventually require an intestinal resection. However, CD frequently recurs after resection. We performed a randomized trial to compare the ability of infliximab vs placebo to prevent CD recurrence. METHODS: We evaluated the efficacy of infliximab in preventing postoperative recurrence of CD in 297 patients at 104 sites worldwide from November 2010 through May 2012. All study patients had undergone ileocolonic resection within 45 days before randomization. Patients were randomly assigned (1:1) to groups given infliximab (5 mg/kg) or placebo every 8 weeks for 200 weeks. The primary end point was clinical recurrence, defined as a composite outcome consisting of a CD Activity Index score >200 and a ≥70-point increase from baseline, and endoscopic recurrence (Rutgeerts score ≥i2, determined by a central reader) or development of a new or re-draining fistula or abscess, before or at week 76. Endoscopic recurrence was a major secondary end point. RESULTS: A smaller proportion of patients in the infliximab group had a clinical recurrence before or at week 76 compared with the placebo group, but this difference was not statistically significant (12.9% vs 20.0%; absolute risk reduction [ARR] with infliximab, 7.1%; 95% confidence interval: -1.3% to 15.5%; P = .097). A significantly smaller proportion of patients in the infliximab group had endoscopic recurrence compared with the placebo group (30.6% vs 60.0%; ARR with infliximab, 29.4%; 95% confidence interval: 18.6% to 40.2%; P < .001). Additionally, a significantly smaller proportion of patients in the infliximab group had endoscopic recurrence based only on Rutgeerts scores ≥i2 (22.4% vs 51.3%; ARR with infliximab, 28.9%; 95% confidence interval: 18.4% to 39.4%; P < .001). Patients previously treated with anti-tumor necrosis factor agents or those with more than 1 resection were at greater risk for clinical recurrence. The safety profile of infliximab was similar to that from previous reports. CONCLUSIONS: Infliximab is not superior to placebo in preventing clinical recurrence after CD-related resection. However, infliximab does reduce endoscopic recurrence. ClinicalTrials.gov ID NCT01190839.

Non-cirrhotic portal hypertension in inflammatory bowel disease.

With the increasing incidence and prevalence of inflammatory bowel diseases (IBD), its complications and associated morbidity also continue to rise. One of these is non-cirrhotic portal hypertension. There is an increasing need of recognizing and understanding the pathophysiology of this condition in the clinical setting of IBD, especially in long standing cases. Due to multiple potential factors, patients with IBD appear to be at a higher risk of developing portal hypertension even in the absence of liver cirrhosis. Portal hypertension is usually diagnosed when complications (such as ascites, variceal bleeding) develop, especially when patients have already experienced multiple complications of the disease. Hence, a high level of vigilance for the detection of portal hypertension at an early stage is needed. This review discusses the known epidemiology, clinical characteristics, clinical presentation, modalities of diagnosis and the potential treatments of the different forms of non-cirrhotic portal hypertension associated with IBD. The concomitant presence of portal hypertension can significantly impact the overall clinical picture and disease burden in IBD. Hence, increased awareness of this condition at an early stage might help tailor a comprehensive and individualized therapeutic plan of care for these patients.

Early diagnosis and treatment of postoperative endoscopic recurrence of Crohn's disease: partial benefit by infliximab--a pilot study.

BACKGROUND: Current data indicate that infliximab-given immediately after surgery-may be very effective in preventing postsurgical recurrence of Crohn's disease. However, it is unknown whether a similar benefit would result from early diagnosis and treatment, rather than prevention of endoscopic recurrence. AIMS: The primary outcome of this study was to clarify whether infliximab, given after diagnosis of postoperative endoscopic recurrence of Crohn's diseases (Rutgeerts score ≥ 2) can induce endoscopic remission (score <2) at 54 weeks. The secondary outcomes were improvement in the endoscopic score and clinical recurrence at 54 weeks. METHODS: In this prospective open label multicenter pilot study 43 patients with ileocolonic Crohn's disease subjected to curative surgery underwent colonoscopy 6 months after surgery. Patients with endoscopic recurrence (Rutgeerts score ≥2) were treated with either mesalamine 800 mg tid or infliximab 5 mg/kg bw on a maintenance basis. Colonoscopy was performed after 54 weeks of therapy. RESULTS: A total of 24/43 patients were diagnosed with endoscopic recurrence at 6 months. Thirteen were treated with infliximab and 11 with mesalamine. None of the 11 mesalamine-treated patients had endoscopic remission at 54 weeks. Two had clinical recurrence at 8 and 9 months. Fifty-four percent of patients treated with infliximab had endoscopic remission at 54 weeks (P = 0.01) while 69% had an improvement in the endoscopic score. None had clinical recurrence. CONCLUSIONS: Treatment of postsurgical endoscopic lesions by infliximab appears superior to mesalamine. However, a sizeable proportion of patients did not fully benefit from this strategy.

Timely Monitoring of Inflammation by Fecal Lactoferrin Rapidly Predicts Therapeutic Response in Inflammatory Bowel Disease.

BACKGROUND: Fecal lactoferrin (FL) levels may mirror drug-induced changes in inflammation in ulcerative colitis and Crohn disease in a timely way and could be used to assess loss of response (LOR) to biologics. METHODS: This study is a retrospective outcome review in 61 patients on adalimumab, infliximab, or vedolizumab managed in our center and followed for 6 to 24 months. Patients were 1) in clinical remission or 2) were experiencing possible LOR. RESULTS: For group 1, in 71% of 31 patients, FL slowly increased during the therapeutic interval (R2 = 0.769; P < 0.001), thus reflecting increasing inflammation as drug concentrations decreased. In the remaining patients, FL was undetectable throughout the therapeutic interval because of a stronger suppression of inflammation. For group 2, in 30 patients negative for infections, FL levels measured 1 to 3 days after infusion/injection compared to preadministration values either increased (nonresponders)-in these patients the medication was switched to another class; partially decreased (partial responders)-the therapeutic interval was shortened; or were normal throughout (responders)-causes for symptoms unrelated to disease activity were found for all. After FL-based management, 3-month standardized clinical scores were normalized in both partial responders (0.58 ±â€…0.21 vs 0.13 ±â€…0.09; P < 0.001) and nonresponders (0.81 ±â€…0.17 vs 0.12 ±â€…0.08; P < 0.001), and FL levels dropped by up to 99%. CONCLUSIONS: Levels of FL reflect drug-induced changes in mucosal inflammation in a timely way, thus enabling rapid assessment of therapeutic response in patients with ulcerative colitis and with Crohn disease. In patients with suspected LOR, FL levels before and after infusion/injection accurately separated responders, partial responders, and nonresponders. The strategy proposed here is simple, accurate, and easily applicable to clinical practice.

Wireless Capsule Endoscopy for Diagnosis and Management of Post-Operative Recurrence of Crohn's Disease.

Despite aggressive medical therapy, many patients with Crohn's disease require surgical intervention over time. After surgical resection, disease recurrence is common. Ileo-colonoscopy and the Rutgeerts score are commonly used for diagnosis and monitoring of post-operative endoscopic recurrence. The latter is the precursor of clinical recurrence and therefore it impacts prognosis and patient management. However, due to the limited length of bowel assessed by ileo-colonoscopy, this procedure can miss out-of-reach, more proximal lesions in the small bowel. This limitation introduces an important uncertainty when evaluating post-operative relapse by ileo-colonoscopy. In addition, the Rutgeerts score 'per se' bears a number of ambiguities. Here we will discuss the pros and cons of ileo-colonoscopy and other imaging studies including wireless capsule endoscopy to diagnose and manage post-operative recurrence of Crohn's disease. A number of studies provide evidence that wireless capsule endoscopy is a potentially more accurate as well as less invasive and less costly alternative to conventional techniques including ileo-colonoscopy.

Noncanonical NF-κB Signaling Upregulation in Inflammatory Bowel Disease Patients is Associated With Loss of Response to Anti-TNF Agents.

Objectives: Targeting tumor necrosis factor (TNF) with biologic agents, such as infliximab and adalimumab, is a widely used and effective therapeutic strategy in inflammatory bowel disease (IBD). Unfortunately, a significant number of patients fail to respond or lose response over time to these agents. Previous studies have defined multiple complex roles for canonical NF-κB signaling in the pathogenesis of IBD. However, preliminary evidence suggests that the lesser defined noncanonical NF-κB signaling pathway also contributes to disease pathogenesis and response to anti-TNF agents. The objective of this study was to evaluate this hypothesis in Crohn's disease (CD) and ulcerative colitis (UC) patients. Design: A total of 27 subjects with IBD (19 with CD and 8 with UC) and 15 control subjects were tested. Clinical criteria, patient history, and endoscopic disease activity were factors used to categorize patients and define therapeutic response. Biopsy specimens were collected during colonoscopy and expression was determined for 88 target genes known to be associated with noncanonical NF-κB signaling and IBD. Results: Noncanonical NF-κB signaling was significantly upregulated in IBD patients and was associated with increased gastrointestinal inflammation, epithelial cell death, lymphocyte migration, and Nod-like receptor signaling. Furthermore, noncanonical NF-κB signaling was further upregulated in patients unresponsive to anti-TNF agents and was suppressed in responsive patients. MAP3K14, NFKB2, CCL19, CXCL12, and CXCL13 were significantly dysregulated, as were genes that encode pathway regulators, such as CYLD, NLRP12, and BIRC2/3. Conclusion: Our study identifies a previously uncharacterized role for the understudied noncanonical NF-κB signaling pathway in the pathogenesis of IBD and anti-TNF therapy responsiveness. The genes and pathways identified may ultimately prove useful in IBD management and could potentially be used as biomarkers of drug response.

Low-dose maintenance therapy with infliximab prevents postsurgical recurrence of Crohn's disease.

BACKGROUND & AIMS: Infliximab might prevent postsurgical recurrence of Crohn's disease. However, it is unclear whether long-term therapy is necessary and whether alternative strategies could be applied to minimize potential side effects and reduce the costs of treatment. METHODS: We performed a prospective cohort study in 12 consecutive patients, treated immediately after surgery with maintenance infliximab (5 mg/kg), who did not have clinical or endoscopic evidence of disease recurrence after 24 months; they were followed up for an additional year. Infliximab treatment was then discontinued; patients with disease recurrence, based on endoscopy (Rutgeerts score, >or=2), were given lower doses of infliximab (starting with 1 mg/kg) to re-establish mucosal integrity. Surrogate markers of disease activity (fecal calprotectin [FC], C-reactive protein, and erythrocyte sedimentation rate) were assessed after each infliximab dose. RESULTS: None of the patients had clinical or endoscopic recurrence of Crohn's disease 3 years after surgery. However, discontinuation of infliximab caused endoscopic recurrence after 4 months in 10 of 12 patients (83%). All 10 patients then were treated again with infliximab, which, at a dose of 3 mg/kg every 8 weeks, restored and maintained mucosal integrity for 1 year. Among the surrogate markers, FC levels correlated with endoscopic scores (Wald test, P < .0001). CONCLUSIONS: Long-term maintenance therapy with infliximab is required to maintain mucosal integrity in patients after surgery for Crohn's disease. However, a dose of 3 mg/kg (a 40% reduction from the standard dose) was sufficient to avoid disease recurrence, determined by endoscopy, in all patients at 1 year. FC levels correlate with mucosal status at different infliximab doses.