Refractory Inflammatory Bowel Disease

Opinion statement Therapeutic options for refractory colonic inflammation in patients with ulcerative colitis or Crohn’s disease have recently been augmented by the introduction of biologic therapies. Intravenous corticosteroids and cyclosporin A remain the standard therapies for severe ulcerative colitis. Monoclonal antibodies directed at tumor necrosis factor alfa (TNF-α) have proven to be most efficacious in patients with severe or refractory Crohn’s disease. Immunomodulatory therapy with azathioprine, 6-mercaptopurine, or methotrexate has demonstrated efficacy for maintenance of remission in patients with refractory ulcerative colitis or Crohn’s disease. The use of experimental biologic agents may be considered for those patients who fail to respond to or remain dependent on corticosteroids. Surgical intervention is indicated for patients with severe colitis who fail to respond to medical therapy or develop life-threatening complications such as perforation or toxic megacolon.     

Optimizing conventional therapy for inflammatory bowel disease

Recently, conventional therapies for inflammatory bowel disease (IBD) have not received the same amount of attention as biologic therapies, yet they remain the backbone of therapy for IBD because of their efficacy, safety, and relatively low cost. Advances in efficacy and safety continue because of modifications in drug dosing and monitoring. Higher doses of mesalamine per pill, together with once-daily dosing, may help to optimize drug delivery and patient compliance. Budesonide, an effective agent for both induction and short-term remission maintenance in Crohn’s disease, is devoid of many of the toxicities common to corticosteroids. Assessments of thiopurine methyltransferase and metabolite levels are helping to fine-tune dose optimization for the thiopurines azathioprine and 6-mercaptopurine. The oral calcineurin inhibitors tacrolimus and cyclosporine have been shown to have expanded roles in IBD, and methotrexate may be useful in some patients with refractory ulcerative colitis. Probiotics are showing promise for maintenance of remission in Crohn’s disease, ulcerative colitis, and pouchitis.     

Management of refractory ulcerative colitis

Opinion statement A physician’s approach to patients with ulcerative colitis (UC) who are refractory to standard first-line therapies must be thoughtful and systematic and include the individual’s physical and emotional state as the physician examines the various dietary, medical, and surgical options currently available. It is of foremost importance to confirm that the refractory patient’s symptoms are not simply due to dietary indiscretion, concomitant bowel infection (especially with Clostridium difficile), an incorrect diagnosis (eg, colitis due to infection, NSAIDs, ischemia, diverticulitis, or Crohn’s disease), or even a concomitant diagnosis (eg, celiac sprue, pancreatic insufficiency, functional bowel disorder, laxative or sorbitol intake). The ability to quickly assess the status of the colonic mucosa with flexible sigmoidoscopy aids in the ability to distinguish patients with refractory inflammation from those with other diagnoses. The initiation and optimization of the long-term purine analogues azathioprine (AZA) or 6-mercaptopurine (6-MP) remain the backbone of medical therapy for patients with refractory UC. For those unresponsive to corticosteroids, quicker induction of remission may necessitate infliximab, cyclosporine, or tacrolimus. Successful induction and maintenance with AZA, 6-MP, and/or infliximab should be followed by long-term therapy with these agents. Cessation of therapy often leads to relapse. Novel therapies under investigation hold the promise of offering more options for both the induction and maintenance of remission in refractory UC patients. Discussions of surgical intervention should not be put off as a last resort but rather included in the overall treatment plan offered to the patient.     

Postoperative management of ulcerative colitis and crohn’s disease

Approximately 10% to 30% of patients with ulcerative colitis and up to 70% of patients with Crohn’s disease will undergo surgery at some point during their lifetime. Although patients with ulcerative colitis are considered "cured" by surgery, patients who have undergone an ileal pouch anal anastomosis may develop pouchitis, cuffitis, pouch irritability, or even Crohn’s disease. Various therapies have shown success, including probiotics, in the prevention of pouchitis onset or relapse. Crohn’s disease historically recurs following surgery; prophylaxis against disease recurrence has been attempted with a variety of agents, with variable success. Innovative therapies holding promise for the future treatment or prevention of these conditions are under exploration.     

Inflammatory bowel disease in children

Opinion statement  

Is Indeterminate Colitis Determinable?

About 10% of patients with colitis due to inflammatory bowel disease have indeterminate colitis. Despite newer diagnostic tools, the frequency has not diminished over the past 33 years. The current preferred term among academicians is colonic inflammatory bowel disease unclassified (IBDU), although indeterminate colitis is the term endorsed for inclusion in the ICD-10 coding system. Indeterminate colitis is more frequent among children. The anti-Saccharomyces cerevisiae (ASCA) and perinuclear anti-cytoplasmic antibody (pANCA) are useful in distinguishing IBDU from ulcerative colitis and Crohn’s disease. However, current serologic and genetic studies, as well as endoscopic and imaging studies lack sufficient positive predictive values to make a definite diagnosis of Crohn’s colitis or ulcerative colitis. Patients with IBDU who undergo proctocolectomy with ileal pouch-anal anastomosis have more complications than patients with ulcerative colitis. Although some patients with indeterminate colitis eventually develop characteristic ulcerative colitis or Crohn’s disease, a subgroup are durably indeterminate.     

Positioning novel biologic,probiotic, and apheresis therapies for crohn’s disease and ulcerative colitis

Traditional medications for inflammatory bowel disease are small molecule drugs, most of which were developed for use in other diseases before being found to be efficacious for the treatment of ulcerative colitis or Crohn’s disease. Recently, several exciting alternative approaches to the medical treatment of inflammatory bowel disease have been developed. These include biologic, probiotic, and apheresis therapies that offer certain advantages over traditional drug therapy for inflammatory bowel disease. The purpose of this review is to assess the current state of knowledge about novel biologic, probiotic, and apheresis therapies and to analyze how best to incorporate these therapies into evolving management paradigms of inflammatory bowel disease.     

Current and future anti-TNF therapy for inflammatory bowel disease

Opinion statement Anti-tumor necrosis factor-α (anti-TNF) therapy has become a very important modality in the treatment of patients with inflammatory bowel disease. A number of anti-TNF medications have been investigated for this purpose, many via randomized controlled trials. Infliximab, the most studied of these agents, has shown impressive efficacy in the treatment of luminal and fistulizing Crohn’s disease, as well as ulcerative colitis. Adalimumab and certolizumab have shown similar efficacy in Crohn’s disease but have not yet been studied in ulcerative colitis. Less impressive results were seen in randomized controlled trials involving CDP-571, etanercept, or onercept for patients with Crohn’s disease. Thalidomide and CNI-1493 have been evaluated only preliminarily in small, open-label pilot studies in patients with Crohn’s disease. The future of anti-TNF therapy in inflammatory bowel disease is very bright, as exciting new developments continue to be made at a rapid pace.     

Safety of biologics in inflammatory bowel disease

Opinion statement Various biologic agents have been evaluated in patients with inflammatory bowel disease (eg, Crohn’s disease [CD]) and ulcerative colitis (UC). At present, only one, infliximab (humanized monoclonal anti-tumor necrosis factor-á antibody), is approved by the US Food and Drug Administration for induction and maintenance treatment in patients with active moderate to severe and/or fistulizing CD who are refractory to conventional therapy. Two recent trials, Active Ulcerative Colitis Trial (ACT) 1 and ACT 2, observed high efficacy of infliximab in inducting and maintaining clinical remission, mucosal healing, and corticosteroid-sparing effects in patients with moderate to severe UC. A plethora of randomized, double-blind, controlled and open-label, uncontrolled studies on large and small numbers of patients has assessed efficacy and safety of various biologic agents of potential use in treatment of inflammatory bowel disease. With respect to safety of biologic agents used for treatment, the most accurate data are available only in the case of infliximab. This is due to the fact that infliximab was evaluated in many more trials than any other biologic agent. Moreover, postmarketing experience also provides very valuable information about any side effects occurring during treatment with this agent.     

The Effect of Crohn’s Disease on Outcomes After Restorative Proctocolectomy

Purpose This study was designed to compare postoperative adverse events and functional outcomes after ileal pouch-anal anastomosis between patients with Crohn’s disease and those with non-Crohn’s disease diagnoses. Methods A literature search was performed to identify studies published between 1980 and 2005 comparing outcomes of patients undergoing ileal pouch-anal anastomosis for Crohn’s disease, ulcerative colitis, and indeterminate colitis. Random-effect, meta-analytical techniques were used and sensitivity analysis was performed. Results Ten studies comprising 3,103 patients (Crohn’s disease=225; ulcerative colitis=2,711; indeterminate colitis=167) were included. Patients with Crohn’s disease developed more anastomotic strictures than non-Crohn’s disease diagnoses (odds ratio, 2.12; P=0.05) and experienced pouch failure more frequently than patients with ulcerative colitis (Crohn’s disease vs. ulcerative colitis: 32 vs. 4.8 percent, P<0.001; Crohn’s disease vs. indeterminate colitis: 38 vs. 5 percent, P<0.001). Urgency was more common in Crohn’s disease compared with non-Crohn’s disease: 19 vs. 11 percent (P=0.02). Incontinence occurred more frequently in Crohn’s disease compared with non-Crohn’s disease patients: 19 vs. 10 percent (odds ratio, 2.4; P=0.01). Twenty-four-hour stool frequency did not differ significantly between Crohn’s disease, ulcerative colitis, or indeterminate colitis. Patients with isolated colonic Crohn’s disease were not significantly at increased risk of postoperative complications or pouch failure (P=0.06). Conclusions Patients with Crohn’s disease undergoing ileal pouch-anal anastomosis should be appropriately counseled toward poorer functional outcomes and higher failure compared with non-Crohn’s disease patients. It maybe possible to preoperatively select patients with isolated colonic Crohn’s disease who may benefit from ileal pouch-anal anastomosis with acceptable adverse outcomes. Presented at the meeting of the European Society of Coloproctology, Lisbon, Portugal, September 13 to 16, 2006.     

The Role of Tacrolimus in Inflammatory Bowel Disease: A Systematic Review

Therapeutic management of inflammatory bowel disease remains beyond the limits of conventional therapy in many cases. Novel therapies used include tacrolimus, a new powerful immunosuppressive drug, employed in some case reports and a few studies that have tried to evaluate its effectiveness in Crohn’s disease and ulcerative colitis with promising results, but its role in the management of inflammatory bowel disease remains controversial. We performed a systematic review that analyzed a total of 23 reported experiences in 286 patients with inflammatory bowel disease treated with tacrolimus. Although most of the published studies are uncontrolled, short, and heterogeneous, promising results have been obtained in fistulizing disease, unresponsive cases of both ulcerative colitis and Crohn’s disease, and even extraintestinal manifestations. The overall outcome was good enough to consider tacrolimus as a rationale therapeutic option. However, comparative studies with standard therapeutic options like infliximab are needed to assess the correct role that tacrolimus may play in these patients.     

Infliximab: Use in inflammatory bowel disease

Opinion statement Crohn’s disease (CD) and ulcerative colitis (UC) are chronic and often debilitating inflammatory bowel diseases (IBD) without medical cures. Despite the existence of multiple therapies, the medical treatment of these diseases often has proven insufficient and surgery is frequently required. However, as our understanding of the pathogenesis of these disorders and other immune-mediated inflammatory diseases (eg, rheumatoid arthritis and psoriasis) has grown, new and more specific biologic therapies have been developed that are proving more effective than traditional agents. Infliximab is a genetically engineered monoclonal antibody that targets the proinflammatory cytokine tumor necrosis factor-α (TNF-α) and represents the first effective biologic therapy for IBD and has largely revolutionized treatment. Infliximab initially was developed to be used in patients with moderate to severe luminal or fistulizing CD who are refractory to standard medical therapy. More and more practitioners now are using infliximab as first-line therapy because of its superior efficacy. Infliximab rapidly induces remission in CD, but when given chronically, it can provide long-term maintenance of remission. In addition, there are some data to support its use as a steroid-sparing agent and treatment for various extraintestinal manifestations of IBD and, although used predominantly to treat CD, recent data suggest that infliximab also may have a role in the management of UC. Overall, infliximab represents a clinically useful, cost-effective therapy that works well, even though careful patient monitoring is required to avoid rare but significant toxicities. The hope is that infliximab, together with other biologic agents that currently are in development, will allow us to modify the course of IBD, avoid complications such as strictures and abscesses, and reduce the need for surgery.     

Crohn’s disease of the esophagus

Opinion statement Esophageal damage is an uncommon manifestation of Crohn’s disease. The diagnosis should be considered in patients who have other intestinal manifestations of Crohn’s disease and present with esophageal symptoms. Diagnosis should be based on history, known extraesophageal Crohn’s disease, endoscopic evaluation with biopsy, and exclusion of gastroesophageal reflux disease. Mild disease should be treated with acid suppression and a short course of steroids. 5-amino-salicylates are not likely to be effective due to drug release characteristics. Patients who have moderate to severe disease should be treated aggressively with acid suppression, a longer course of steroids, and consideration of immunosuppressive therapy with 6-mercaptopurine or azathioprine. Infliximab or other anti-tumor necrosis factor therapy also can be considered in refractory patients to try to prevent the complications of stricturing and fistula formation. In those patients who develop strictures of the esophagus, treatment with balloon dilatation of the stricture followed by injection of a long-acting steroid such as triamcinolone will help to alleviate symptoms. Surgery may be required for severe, refractory symptoms, but it has a high morbidity in this population.     

CRP Correlates with Clinical Score in Ulcerative Colitis but Not in Crohn’s Disease

The aim of this study was to prospectively evaluate the correlation between clinical scoring systems and C-reactive protein (CRP) in inflammatory bowel disease. The modified Harvey-Bradshaw index was used in 40 patients (58 assessments) with Crohn’s disease, and the Lichtiger score in 29 patients (36 assessments) with ulcerative colitis. In ulcerative colitis, CRP was elevated in 14%, 42%, 64%, and 83%, respectively, of subjects with quiescent, mild, moderate, and severe disease. There was a linear correlation of log(CRP) with clinical score except for proctitis. In Crohn’s disease, CRP was elevated in 54%, 70%, 75%, and 100%, respectively, of subjects with quiescent, mild, moderate, and severe disease. We conclude that the clinical score has a good correlation with CRP in ulcerative colitis except for proctitis, whereas clinical score has a poor correlation with CRP in Crohn’s disease, particularly in those with clinically quiescent, fibrostenotic, and ileal disease.     

Choosing therapy on the basis of disease classifications in inflammatory bowel disease

Opinion statement Crohn’s disease and ulcerative colitis (UC) are heterogeneous disorders, and as such, the response to therapy is likewise heterogeneous. Therefore, stratification of patients into distinct phenotypes and potentially genotypes will lead to more definitive answers with respect to evaluation of novel and established therapies.     

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.     

Novel biological therapies for inflammatory bowel disease

Opinion statement The success of biological therapy is best advocated by infliximab (IFX), which has dramatically improved medical therapy for Crohn’s disease and now has been shown to be effective in the treatment of ulcerative colitis. Other anti-tumor necrosis factor (TNF) compounds have been tested in the treatment of Crohn’s disease and will soon appear in the therapeutic armament. However, neutralization of TNF does not seem to be the most important mechanism of action of these therapies. Apoptosis of activated T cells was demonstrated after IFX treatment, and this may be the key to its success. Thus, other therapies that induce apoptosis in activated T cells, such as visilizumab, have a great chance to be of benefit. Biological therapies applied in inflammatory bowel disease appear to be safe, although therapy-related adverse events clearly have been recognized.     

Insights in immunomodulatory therapies for ulcerative colitis and Crohn’s disease

Immunomodulators are a class of drugs that attenuate the underlying inflammatory processes of Crohn’s disease (CD) and ulcerative colitis (UC), the two major inflammatory bowel diseases (IBD). These agents play a prominent role in the management of refractory and steroid-dependent IBD. The immunomodulatory drugs in the IBD arsenal include azathioprine, 6-mercaptopurine, methotrexate, cyclosporine, and tacrolimus. Azathioprine and 6-mercaptopurine are considered firstline immunosuppressants due to their proven efficacy in both CD and UC and their safety profile, whereas cyclosporine occupies a niche as a surgery-sparing agent in the acute management of severe, steroid-refractory UC. Immunomodulators also appear to have a role as adjunctive therapy when used with infliximab or other biologic agents to reduce immunogenicity. Although data have been limited to observational studies, azathioprine and 6-mercaptopurine may be used during pregnancy.     

Family History and Serology Predict Crohn’s Disease after Ileal Pouch-Anal Anastomosis for Ulcerative Colitis

Purpose Approximately 5 to 10 percent of patients undergoing ileal pouch-anal anastomosis with a diagnosis of ulcerative colitis are subsequently diagnosed with Crohn’s disease. Preoperative predictors for Crohn’s disease post-ileal pouch-anal anastomosis have not been prospectively defined. Methods A total of 238 consecutive patients with ulcerative colitis or indeterminate colitis undergoing ileal pouch-anal anastomosis were prospectively enrolled into a longitudinal database. Clinical factors were assessed perioperatively. Serum drawn preoperatively was assayed for anti-Saccharomyces cerevisiae, antiouter membrane porin-C, anti-CBir1, and perinuclear antineutrophil cytoplasmic antibody using enzyme-linked immunosorbent assay. Crohn’s disease was defined by small bowel inflammation proximal to the ileal pouch or a perianal fistula identified at least three months after ileostomy closure. Predictors were assessed in a multivariate Cox proportional hazards model to predict the rate of Crohn’s disease after ileostomy closure. Results Sixteen patients (7 percent) were diagnosed with Crohn’s disease; median time to Crohn’s disease was 19 (range, 1–41) months. Significant factors for postoperative Crohn’s disease after ileal pouch-anal anastomosis included family history of Crohn’s disease (hazard ratio, 8.4; 95 percent confidence interval, 2.96–24.1; P < 0.0001) and anti-Saccharomyces cerevisiae immunoglobulin-A seropositivity (hazard ratio, 3.14; 95 percent confidence interval, 1.1–9.81; P = 0.04). Crohn’s disease developed in only 8 of 198 patients (4 percent) without these predictors vs. 8 of 40 patients (20 percent) in those with at least one of these factors (P = 0.002). The cumulative risk of Crohn’s disease among patients with two risk factors (67 percent) was higher than in patients with either risk factor (18 percent) or neither risk factor (4 percent, P < 0.001). Conclusions Patients with ulcerative colitis and indeterminate colitis with a family history of Crohn’s disease or preoperative anti-Saccharomyces cerevisiae immunoglobulin-A seropositivity are more likely to be diagnosed with Crohn’s disease after ileal pouch-anal anastomosis. Poster presentation of distinction at Digestive Disease Week, Washington, D.C., May 19 to 24, 2007, and Read at the meeting of The American Society of Colon and Rectal Surgeons, St. Louis, Missouri, June 2 to 7, 2007. Financial disclosures: Prometheus Laboratories Speakers’ Bureau (Eric A. Vasiliauskas, Konstantinos A. Papadakis, Marla Dubinsky, Andrew Ippoliti), shareholder (Carol Landers, Stephan R. Targan), and cofounder (Stephan R. Targan).     

Nutritional Treatments in Inflammatory Bowel Disease

Opinion statement