Risk factors and prognostic value of acute severe lower gastrointestinal bleeding in Crohn’s disease

BACKGROUNDAcute severe lower gastrointestinal bleeding (LGIB) is an uncommon but challenging complication of Crohn’s disease (CD).AIMTo identify the predictors of acute severe LGIB and to evaluate the impact of acute severe LGIB on the subsequent clinical course in CD patients.METHODSA retrospective inception cohort study was conducted in 75 CD patients with acute severe LGIB and 1359 CD patients without acute severe LGIB who were diagnosed between February 1991 and November 2019 at Asan Medical Center, a tertiary university hospital in Korea. Multivariable analysis with Cox proportional hazard regression was performed to identify the risk factors for acute severe LGIB. A matched analysis using 72 patients with bleeding and 267 matched patients without within the cohort was also conducted to investigate whether acute severe LGIB is a predictor of clinical outcomes of CD. RESULTSMultivariable Cox regression analysis revealed that early use of thiopurines [hazard ratio (HR): 0.23, 95% confidence interval (CI): 0.12-0.48; P < 0.001] and female sex (HR: 0.51, 95%CI: 0.27-0.94; P = 0.031) were significantly associated with a lower risk of acute severe LGIB. The cumulative risks of behavioral progression and intestinal resection were not significantly different between the two matched groups (P = 0.139 and P = 0.769, respectively). The hospitalization rate was higher in the bleeding group than in the matched non-bleeding group (22.1/100 vs 13.2/100 patient-years; P = 0.012). However, if hospitalizations due to bleeding episodes were excluded from the analysis, the hospitalization rate was not significantly different between the bleeding group and the matched non-bleeding group (14.5/100 vs 13.2/100 patient-years; P = 0.631).CONCLUSIONEarly use of thiopurines may reduce the risk of acute severe LGIB. History of acute severe LGIB may not have a significant prognostic value in patients with CD.     

Clinical significance of endoscopic findings in the upper gastrointestinal tract in Crohn’s disease

Crohn’s disease is an inflammatory disorder that can affect the entire gastrointestinal tract but typically involves the ileocecal region. Before endoscopy was widely used, involvement of the esophagus, stomach, and duodenum was thought to be rare. Recent publications demonstrated that not only are upper gastrointestinal lesions common in Crohn’s disease (affecting up to 75% of the patients), but they also present characteristic endoscopic findings with potential clinical significance. It was suggested that lesions in the stomach with a bamboo joint-like appearance might be an endoscopic biomarker for Crohn’s disease. It was also found that this occurrence is related to a more severe disease course. Our review summarizes the literature, as well as our own observations and considerations, concerning the issue of upper gastrointestinal involvement in Crohn’s disease and its clinical meaning.     

Nonobstructing Crohn’s disease

Opinion statement Although our existing medical management improves the quality of life of the majority of patients with Crohn’s disease (CD), a substantial proportion of individuals still experience unpleasant symptoms from either the disease or therapy. Many patients ultimately require surgery. In the near future it is highly likely that new drugs will be available that are able to favorably modify the natural history of the disease.     

Rituximab-induced Crohn’s disease

The use of rituximab has significantly improved outcomes in patients with haematological malignancies and autoimmune disease. There are reports of rituximab-associated ulcerative colitis; however, we report for the first time, two cases of rituximab-induced Crohn’s disease in elderly patients treated for lymphoma. Both patients had evidence of inflammation, ulceration, and granulomas consistent with Crohn’s disease, and responded well to immunosuppression. The association of rituximab and ileocolitis suggests a protective effect of CD20?+?lymphocytes in the gut, and implicates their depletion to the development and exacerbation of inflammatory bowel disease.     

Fistula-associated anal carcinoma in Crohn’s disease

Introduction: Fistula-associated anal carcinoma in patients with Crohn’s disease (CD) is a rare condition. More recently, this entity has been increasingly reported likely due to increased recognition, and the incidence may be greater than once appreciated. There remains a paucity of data regarding the incidence, diagnosis, treatment, and outcome of fistula-associated anal carcinoma.

Area covered: This review evaluates the clinical features, pathology, treatment, and prognosis of fistula-associated anal carcinoma in patients with CD. A strategy for surveillance of this carcinoma is proposed by the authors based on the evidence obtained from this review.

Expert commentary: Clinicians caring for patients with CD and perianal involvement need to be aware of the rare yet extremely important association of long-standing perianal disease and fistula-associated carcinoma. Only through awareness, a high level of suspicion will be diagnosed in a timely manner. This involves a thorough history, a proper, and complete anorectal examination, along with early imaging and examination under anesthesia. Through this approach, it is hoped that early diagnose can be achieved in at-risk patients and change the significant morbidity and mortality associated with this diagnosis.     

Optimizing biological therapy in Crohn’s disease

Anti-TNF therapy has revolutionized the treatment of inflammatory bowel diseases, including both Crohn’s disease and ulcerative colitis. However, a significant proportion of patients does not respond to anti-TNF agents or lose response over time. Recently, therapeutic drug monitoring has gained a major role in identifying the mechanism and management of loss of response. The aim of this review article is to summarize the predictors of efficacy and outcomes, the different mechanisms of anti-TNF/biological failure in Crohn’s disease and identify strategies to optimize biological treatment.     

Surgical management in intestinal Crohn’s disease

The main strategy in surgical treatment of Crohn’s disease is resection of the diseased segment, despite possible development of postoperative nutritional impairment and lowered quality of life (QOL) caused by short bowel syndrome and early postoperative relapse. To overcome postoperative short bowel syndrome, minimal resection is highly recommended, and furthermore strictureplasty is now used in many institutions. Many reports have shown that strictureplasty is safe, has a low rate of surgical complications, and displays identical surgical results as intestinal resection. To apply this procedure to various types of Crohn’s disease, different derivatives of this procedure, such as Heineke–Mikulicz, Finney, Jaboulay, and double Heineke–Mikulicz type, as well as side-to-side isoperistaltic strictureplasty have evolved. In performing strictureplasty, the severity of stenosis is more important than the length of the stricture, because a simple but long stricture can be easily managed by any method of this procedure. Further, it is necessary to investigate the surgical specimens via histopathological analysis of frozen section when neoplastic change is suspected. Now, functional end-to-end anastomosis using a linear stapler has become the most frequently used method in intestinal surgery. Many studies have documented less leakage, morbidity, and anastomotic recurrence as well as shorter hospital stay following stapled anastomosis. As part of the postoperative maintenance treatment regimen, various drugs, such as masalamine, immunomodulators, and infliximab, have been shown to demonstrate positive efficacy when used solely or in combination. Endoscopic examination should be done regularly, and the maintenance treatment regimen should be adjusted according to the disease activity.     

Hyperhomocysteinemia in patients with Crohn’s disease

Background

Thromboembolic complications have been reported in patients with Crohn’s disease. Among the contributing factors, hyperhomocysteinemia has been described, although controversial data exist. The aim of our study was to assess the incidence of hyperhomocysteinemia in a nonselected group of patients with Crohn’s disease and to determine whether it might represent a risk marker for thrombosis in such patients.

Methods

Fifty consecutive patients were recruited, and clinical and laboratory variables were compared between those without and those with hyperhomocysteinemia. In the latter, gene mutations in N5-N10-methyltetrahydrofolate reductase were searched for, and clinical and laboratory variables were related to hyperhomocysteinemia. The presence/absence of thrombotic episodes in both groups was determined.

Results

Both groups had similar clinically active disease, with higher C-reactive protein values found in those with hyperhomocysteinemia. Hyperhomocysteinemia was found in 46 % of patients. Of these, 74 % had moderate, 13 % intermediate, and 13 % severe increase in serum homocysteine levels. No relationship was found between homocysteine levels, and age, vitamin B12 levels, folic acid levels, Crohn’s Disease Activity Index score, and CRP values. Gene mutations were found in 5 (22 %) patients, 2 homozygotes and 3 heterozygotes. None of the patients with or without hyperhomocysteinemia had episodes of venous or arterial thrombosis, or stroke.

Conclusions

Hyperhomocysteinemia is frequent in patients with Crohn’s disease, and it could be a cofactor for the pathogenesis of thrombotic episodes.     

The endoscopic findings of the upper gastrointestinal tract in patients with Crohn’s disease

Crohn’s disease (CD) is a type of chronic inflammatory bowel disease (IBD) associated with ulceration, and the main foci of the inflammation in CD patients are typically the terminal ileum and colon. However, in the upper gastrointestinal tract (GIT), including the esophagus, stomach and duodenum, inflammatory lesions are also detected as well, with a relatively high frequency (30–75%). Recent advances in imaging modalities, including endoscopy, have aided in the diagnosis of CD. Various lesions, including aphtha, erosion, ulcers, bamboo-joint-like appearance and notch-like appearance, are detected in the upper GI of CD patients. Of these lesions, the bamboo-joint-like appearance in the gastric cardiac region and notch-like appearance in the second portion of the duodenum are highly specific for CD, regardless of the disease activity at other sites. These two findings, particularly a bamboo-joint-like appearance, have therefore been considered as potential biomarkers for CD. Although proton pump inhibitors (PPIs) are administered as an initial treatment for upper GIT lesions of CD, the efficacy of this treatment remains controversial. The administration of mesalazine, steroids, immunosuppressant and biologic agents is expected to be effective for treating such lesions.     

Crohn’s disease complicated by adult-onset Still’s disease

A 31-year-old man with Crohns disease developed arthritis, spiking fever, and skin rash indistinguishable from that of adult-onset Stills disease. He was admitted to our hospital because of a periumbilical intestinal skin fistula. Crohns disease had been diagnosed in 1991, and had required intestinal resection twice, and schizophrenia had been diagnosed in 1993. He developed polyarthritis and spiking fever, accompanied by a macular skin rash on both forearms. Marked hepatosplenomegaly and bilateral pleural effusion were detected on computed tomography examination. These findings are indistinguishable from those of adult-onset Stills disease. Because his mental status had deteriorated following high-dose prednisolone on a previous admission, he was treated with an immunosuppressive agent on this occasion, with the treatment being successful. This is the first report of adult-onset Stills disease complicating Crohns disease. In patients with Crohns disease, polyarthritis and skin rash can easily be misdiagnosed as enteropathic arthritis with erythema nodosum associated with the Crohns disease. Although adult-onset Stills disease may not be fatal, early diagnosis is important because it can, in rare cases, result in life-threatening complications.     

IgA nephropathy in association with Crohn’s disease

Background Urological complications of inflammatory bowel disease are seen in up to 25% of patients, but renal parenchymal disease is rarely reported.Case report The authors describe a case of a 29-year-old man with clinical and radiological features of ileocaecal Crohns disease. He had previously been investigated for painless macroscopic haematuria and a renal biopsy had revealed IgA nephropathy. Despite medical treatment, regular exacerbations of Crohns disease were associated with deterioration in renal function and the development of haematuria. The patient eventually underwent surgical resection of the terminal ileum and caecum. His renal disease has remained quiescent for the last 5 years following resection.     

PTGER4 modulating variants in Crohn’s disease

Purpose

Variants modulating expression of the prostaglandin receptor 4 (PTGER4) have been reported to be associated with Cohn’s disease (CD), but the clinical impact remains to be elucidated. We analyzed these variants in a large German inflammatory bowel disease (IBD) cohort and searched for a potential phenotype association.

Methods

The variants rs4495224 and rs7720838 were studied in adult German IBD patients (CD, n?=?475; ulcerative colitis (UC), n?=?293) and healthy controls (HC, n?=?467). Data were correlated to results from NOD2 genotyping and to clinical characteristics.

Results

We found a significant association for the rs7720838 variant with overrepresentation of the T allele to CD (p?=?0.0058; OR 0.7703, 95 % CI 0.641–0.926) but not to UC. Furthermore, logistic regression analysis revealed that the presence of the T allele was associated with stricturing disease behavior in CD patients (p?=?0.03; OR 1.84, 95 % CI 1.07–3.16). Interestingly, the chance for developing stricturing disease behavior was enhanced if mutant alleles in both rs7720838 and NOD2 were present (OR 2.87, 95 % CI 1.42–5.81; p?=?0.003). No overall association to CD or UC was found for the rs4495224 variant.

Conclusions

The PTGER4 modulating variant rs7720838 increases susceptibility for CD and might resemble a risk factor for stricturing disease behavior.     

Role of gut microbiota in Crohn’s disease

Crohn’s disease (CD), a form of inflammatory bowel disease (IBD), provides a complex model of host–microbe interactions underpinning disease pathogenesis. Although there is not widespread agreement on the etiology of CD, there is evidence that microorganisms lead to the often severe inflammatory response characteristic of the disease. Despite several microbial candidates, no specific microbe has been considered pathogenic. Instead, the concept of the ‘pathogenic community’ has emerged from the evidence, whereby the stability of the microbial ecosystem of the healthy human gut is disrupted in response to host genetics and destabilized immunity, perhaps through changing public health practices leading to altered microbial exposures over time. We discuss the complex microbial ecosystem of the mammalian gut, the underlying genetic factors that predispose to CD, and how these gene variants may alter host–microbe interactions and propagate inflammation. Over the next 5 years, the increased understanding of genes involved in CD and the way in which individuals with variants of these genes respond differently to nutrients and drugs will enable the rational development of personalized therapies, using pharmacogenomic and nutrigenomic approaches.     

Vedolizumab in the treatment of Crohn’s disease

Vedolizumab, a recent addition to the therapeutic armamentarium in Crohn’s disease, is promising in efficacy, durability of remission and safety. It is the first gut selective biologic treatment, acting by targeting α4β7-integrin, a receptor expressed on activated lymphocytes and binding to MAdCAM1, a cell adhesion molecule selectively expressed in the circulatory system of the digestive tract, preventing trafficking of lymphocytes to the gut. The pivotal GEMINI studies have demonstrated the efficacy and safety of vedolizumab in achieving clinical response and clinical remission in patients with moderately to severely active CD who are naïve or have previously failed therapy with TNF-antagonists, immunomodulators or dependent on steroids. Vedolizumab had a favorable safety profile and specifically showed no evidence of PML, reactivation of latent TB or hepatitis B. Overall, the number of malignancies in the clinical trials was small; however, long-term exposure was limited. Vedolizumab can be given as a first-line therapy or following treatment failure, and was tolerated as part of combination therapy. More medications with similar and novel therapeutic mechanisms are anticipated in the coming years.     

Intestinal cancer in patients with Crohn’s disease

Background Surveillance of intestinal cancer in Crohn’s disease (CD) has often been advocated. To date, no clear evidence exists whether CD patients are at special risk for intestinal cancer. An increased incidence of small bowel adenocarcinoma is suggested. However, recent figures also suggest an increased risk of CD associated colorectal cancer. We report our experience with 10 cases of CD complicated by intestinal adenocarcinoma. Materials and methods Our institutional database included 330 patients treated for CD between 1988–2005. Data of patients that developed carcinoma within Crohn’s lesions of either small or large bowel were analyzed. Results Ten patients were diagnosed with CD complicated by carcinoma. In nine patients, cancer was present in the colorectum and in one, in Crohn’s ileitis. Tumors were in conjunction with fistulae in three and developed within strictures in five patients. Mean age at the time of diagnosis of CD was 43 years. Mean duration of CD until diagnosis of cancer was 14 years. Only five patients were diagnosed for cancer preoperatively. Staging revealed advanced tumors in almost all patients. Mean survival after surgery was 29 months (2–149 months). Conclusions Cancer risk in CD and especially in Crohn’s colitis may still be underestimated. Delayed diagnosis resulted in a poor prognosis. The value of colonoscopy as surveillance tool is questioned by the fact that in our patients, carcinoma was diagnosed in some patients preoperatively by routine colonoscopy. Therefore, additional markers should be identified to detect CD patients at risk.     

Prevention of postoperative recurrence in Crohn’s disease

Postoperative recurrence of Crohn’s disease is often inevitable. Certain risk factors such as smoking, young age, and a perforating disease behavior have been identified. Patients with an enhanced risk profile should be treated with mesalamine or with azathioprine, the latter of which has higher success rates. An endoscopic evaluation of the neoterminal ileum performed 6 to 12 months after surgery provides important prognostic information regarding the further clinical course of the disease and can be used as a guide to optimize medical therapy.     

Structural bowel damage in quiescent Crohn’s disease

BackgroundCrohn’s disease is associated with accumulation of progressive structural bowel damage (SBD) leading to the development of stenotic and penetrating complications. The data pertaining to the course of progression of SBD is scarce. The Lemann index (LI) is a novel tool for evaluation of SBD that incorporates pan-enteric clinical, endoscopic and imaging data.AimsTo evaluate the progression of SBD in quiescent CD patients.MethodsPatients with known quiescent small bowel Crohn’s disease (CD) for at least 3 months (CDAI < 220) were prospectively recruited and underwent repeated magnetic resonance enterographies (MRE) and video capsule endoscopies (VCE). Patients were assessed for SBD on initial and follow-up evaluation using relevant clinicopathological data, MRE and VCE results. Significant structural bowel damage (SBD) was identified as LI > 4.8, and progression of SBD as LI > 0.3.ResultsSixty one patients were enrolled in the study. Significant SBD was detected 13 (21.4%) on enrollment. Duration of disease (p = 0.036) and history of CD-related surgery (p = 0.0001) were associated with significant BD. Forty one patients underwent a follow-up MRE (14.8 ± 2.5 months apart). LI was similar at baseline and follow-up. There was a negligible change in LI between the evaluations.ConclusionsIn patients with quiescent Crohn’s disease, structural bowel damage was stable over a median of 14 months follow-up.