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.     

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.     

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.     

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.     

Recent advances in understanding Crohn’s disease

Crohn’s disease is a chronic inflammatory bowel disorder resulting from an inappropriate innate and acquired immune response to commensal microorganisms in genetically susceptible individuals. This disease has a fluctuating course, with alternating periods of remission and relapses, and it is characterized by a remarkable clinical heterogeneity; it may be complicated by perianal fistulas, abscesses, and intestinal strictures leading to obstructions, besides several systemic manifestations. However, a complete resolution of the disease is currently not possible, yet Crohn’s disease can be managed with established and novel therapies, which achieve long-term remission and acceptable quality of life. This review is focused on novel advances in basic and clinical aspects of Crohn’s disease, although it also deals with new trends in diagnosis and treatment.     

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.     

Surgical intervention in children with Crohn’s disease

Introduction Crohn’s disease (CD) causes chronic inflammation of the gastrointestinal tract leading to extensive medical treatments and surgery with two thirds of patients having surgery over their lifetime. In this study, we reviewed the pediatric population at the British Columbia Children’s Hospital diagnosed with CD and examined their demographics and treatments, in particular assessing those who ultimately underwent surgery. Materials and methods Two hundred and eighty children (median age 11.9 years [CI 11.5–12.28]) diagnosed with CD from January 1994 to December 2003 were included. Demographic data were documented including age, ethnicity, duration of symptoms before diagnosis, treatment to date and surgical parameters. Comparison was made between operative and non-operative patients including involvement of disease, medical treatment, complications and recurrence of disease leading to repeat operations. Results Fifty-five (19.6%) children had surgical procedures. There was a significant increase in surgery in those patients who had not received immunomodulator therapy before surgery (odds ratio 1.95 [CI 1.02–3.73]). We also observed that those CD patients with extensive small intestinal involvement had lower likelihood of having surgery (odds ratio 0.386 [CI 0.145–1.033]). No significant difference was found between the two groups with regard to age of diagnosis (p = 0.41), duration of symptoms (p = 0.22), gender (p = 0.50) or ethnicity (p = 0.451). Conclusion There was an increased incidence of surgery in those patients who were not treated with immunomodulator therapy. In addition, children with extensive as opposed to isolated small intestinal disease were less likely to have surgery in childhood.     

Massive lower gastrointestinal hemorrhage in Crohn’s disease

Opinion statement  Acute lower gastrointestinal bleeding is an uncommon but potentially life-threatening complication of Crohn’s disease. Because of the relative infrequency of severe bleeding due to CD, reports of larger numbers of cases are few, and the medical literature provides insufficient information to direct management. Nevertheless, certain clear guidelines can be offered once other causes for GI blood loss have been excluded and the diagnosis of a Crohn’s-related bleed is likely. While the initial episode may abate spontaneously, the primary treatment is determined by the severity and persistence of bleeding as well as the risk for recurrence.

The role of antimicrobials in Crohn’s disease

This review summarizes literature regarding the role of antimicrobials for induction and maintenance of Crohn’s disease (CD) remission. PubMed was searched (1966 to October 2012) for controlled trials involving adults and written in English. Five of the 13 identified studies showed benefit with the use of ciprofloxacin, metronidazole and rifaximin for induction of remission. Eight studies showed no benefit using ciprofloxacin, metronidazole, combination of metronidazole and ciprofloxacin or clarithromycin and rifaximin. Four of the five studies showed benefit based on colonic location. Perianal CD with draining fistulas responded in one of two studies. Two studies in postileocolonic resection demonstrated benefit of metronidazole or ornidazole in reducing CD recurrence. Antimicrobials, especially metronidazole, are promising for inducing remission in patients with colonic CD and preventing recurrence in postileocolonic resection.     

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.     

Advances in medical therapy for Crohn’s disease

Therapeutic research in Crohn’s disease has been intensified in recent years. This has led to many novel approaches and insights into the mechanism of action of ‘classic’ drugs. Antibiotics remain valuable but do not offer benefit when used in addition to corticosteroids. Immunomodulators remain the cornerstone for maintenance therapy, although certain corticosteroid-dependent patients can be switched to maintenance therapy with topical steroids. Azathioprine and 6-mercaptopurine remain efficient beyond 4 years in patients with relapses and elevated C-reactive protein in spite of this therapy. Infliximab has shown efficiency in maintenance of active and fistulizing Crohn’s disease. In addition, ‘automatic reinfusion’ was found to be superior to ‘on-demand’ treatment. Infusion reactions and loss of response, most often caused by antibodies against infliximab, can be prevented with immunomodulators and corticosteroid infusions before dosing. Such alternative anti-tumor necrosis factor agents as adalimumab or CDP-870 may be less immunogenic. Other biologic agents, such as the anti-integrin monoclonal antibody natalizumab, were shown to be effective in maintaining remission and somewhat less so in induction of remission. Finally, much attention is being paid to alteration of the luminal flora with probiotics and helminth ova. Extracorporeal apheresis and even stem cell transplantation were found to be effective in isolated patients, but these therapies warrant further prospective and controlled investigation.     

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.     

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.     

Rifaximin and Crohn’s disease

In a recent article,Longman and Swaminath analyzed our paper on the use of rifaximin in patients with moderately active Crohn’s disease(CD).Here we report some considerations concerning their article.The exploratory post-hoc subgroup analysis showed that early-stage disease and,differently from that written by Longman and Swaminath,also colonic involvement seemed to be associated with a significant higher efficacy of rifaximin-EIR 800 mg twice daily.Early-stage disease is generally considered as the more easily treatable phase of CD,and the better response to rifaximin in Crohn’s colitis is in accordance with the high concentration of bacteria in the colon.In addition,patients with C reactive protein level>5 mg/L achieved remission more significantly than patients with normal values,thus suggesting that the symptoms were probably caused by inflammation instead of by non-inflammatory causes.We also analyze the role of rifaximin against gut bacteria and the clinical situations that could obtain the best results from antibiotics.     

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.     

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.     

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.