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Postoperative recurrence (POR) frequently occurs in patients with Crohn's disease, but current medications have proven of little benefit for this indication. In this Review, Dario Sorrentino outlines the definition, the main modalities of diagnosis and the risk factors for POR. The various medications and approaches used to prevent POR are also discussed and an algorithm for prevention of POR is proposed. Postoperative recurrence of Crohn's disease is a frequent and often severe sequela of the disease. Until a few years ago it was deemed inescapable, as all the conventional medications used to treat the disease have been proven of little benefit in preventing recurrence after surgical treatment. In the past few years, anti-TNF agents given immediately after surgery have shown a remarkable efficacy in the prevention of disease recurrence. Large, randomized, controlled trials are currently underway to confirm these findings. Anti-TNF treatment of endoscopic lesions that occur after surgery seems to be less effective than using TNF antagonists to prevent recurrence. However, although the data are limited, this treatment strategy seems to be still superior to all the other prevention strategies that are not based on anti-TNF agents. Limited data are available on long-term outcomes of patients treated with anti-TNF agents after surgery. They suggest that these medications are safe and effective after many years of treatment. In addition, these agents might prevent recurrence even at doses lower than those used in patients with Crohn's disease who have not had surgery. Key Points Recurrence of Crohn's disease after surgery is frequent and often severe Existing medications used to treat patients with Crohn's disease, such as mesalazine, antibiotics and immunomodulators, have proven of little benefit for this indication In recent years, a number of studies have shown anti-TNF agents to be extremely effective, either given preventively immediately after surgery or to treat mucosal recurrence that has already taken place Large randomized studies are seeking to confirm these findings Current, albeit limited, evidence indicates that anti-TNF agents might be effective in the long term, even at doses lower than those used in patients who have not had surgery

BackgroundInflammatory 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.AimsThis study aimed to examine the response to antibiotics and risk of IBD therapy escalation in Toxin+ versus Toxin-PCR+ patients.MethodsIBD 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.ResultsAmong 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.ConclusionsToxin+ 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.

The impact of diagnostic delay in inflammatory bowel disease, including Crohn's disease (CD) and ulcerative colitis (UC), on disease course remains uncertain. This study examines factors that may influence time to diagnosis and disease outcomes in a U.S. patient cohort.MethodsWe retrospectively collected data on patient characteristics, time to diagnosis, disease phenotype, and complications in 177 patients with inflammatory bowel disease (110 CD and 67 UC) diagnosed at our institution from 2008 to 2015. Factors potentially affecting time to diagnosis were analyzed. Association between disease complications (perianal disease, intestinal strictures, surgery, fistula, abscess, and perforation) and time to diagnosis was tested by multivariable analysis.ResultsThe median time to diagnosis was longer for patients with CD compared with patients with UC (median 9.5 versus 3.1 months; P < 0.001). The median time from symptom onset to initial physician visit was similar for patients with CD and patients with UC (1 month). However, the median time from symptom onset to specialist evaluation was longer for patients with CD compared with patients with UC: 7 months (interquartile range: 3–23) versus 3 months (interquartile range: 1–8), respectively (P < 0.001). In CD, ileal disease and hematochezia were positively and negatively correlated, respectively, with longer time to diagnosis (P < 0.05). Compared with patients with time to diagnosis ≤4 months, patients with time >26 months had increased overall complications (odds ratio, 8.22; P = 0.007) and intestinal strictures (odds ratio, 8.96; P = 0.012) at time of diagnosis. Such correlation persisted at follow-up.ConclusionsTime to diagnosis was long in CD. Physician-related delay in diagnosing CD was associated with increased overall complications and intestinal strictures (See Video Abstract, Supplemental Digital Content 1, http://links.lww.com/IBD/B646).

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.

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.

In patients with postoperative recurrence of Crohn's disease endoscopic and clinical remission can be maintained for up to 1 year with low infliximab doses (3 mg/Kg). However, in theory low-dose infliximab treated patients could develop subtherapeutic trough levels, infiximab antibodies, and might loose response to therapy. To verify this hypothesis infliximab pharmacokinetics and clinical/endoscopic response were checked in a group of patients treated in the long term with low infliximab doses. Infliximab antibodies, infliximab levels, highly-sensitive CRP and fecal calprotectin were measured during the 8-week interval in 5 consecutive patients in clinical (Crohn's Disease Activity Index < 150) and endoscopic (Rutgeerts scores 0-1) remission after one year of therapy with infliximab 3 mg/Kg. For comparison with reported standards, infliximab pharmacokinetics and inflammatory parameters were also tested in 6 Crohn's disease patients who did not undergo surgery and who were in clinical remission while on infliximab 5 mg/Kg. Patients on low infliximab dose also underwent colonoscopy after 18 additional months of therapy. Highly sensitive CRP and fecal calprotectin increased in all patients during the 8-week interval. Infliximab trough levels were lower in patients treated with the low dose compared to controls (mean±SE: 2.0±0.3 vs 4.75±0.83 μg/mL respectively p<0.05). Infliximab antibodies were present in two of the subjects treated with low infliximab dose and in none of the controls. However, in low dose-treated patients after 18 additional months of therapy endoscopy continued to show mucosal remission and none of them developed clinical recurrence or side effects. Patients treated with low infliximab doses had lower trough levels compared to patients treated with 5 mg/Kg and some developed antibodies to infliximab. However, low infliximab doses sustained clinical and endoscopic remission for a total of 30 months of treatment.

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.