Insights into the treatment of inflammatory bowel disease in pregnancy.

Patients diagnosed with inflammatory bowel disease (IBD) are most commonly diagnosed in late adolescence or early adulthood, with half of patients being diagnosed before age 32, thus impacting peak years of reproduction and family planning. While controlled IBD has no negative effects on the ability to conceive, there is overall a trend towards voluntary childlessness due to patients' concerns for adverse fetal outcomes from underlying IBD and from adverse medication effects. Active disease at the time of conception is associated with worsening disease activity during pregnancy and carries a higher risk of poor fetal outcomes. It is therefore important to maintain remission during pregnancy, which is often achieved with pharmacologic therapy. The goal of this paper is to provide a comprehensive review of the current literature and safety data for pharmacologic treatment of IBD in pregnancy, in breastfeeding women, and in men planning to have children.

Using Adalimumab to Treat Autoimmune Enteropathy.

Autoimmune enteropathy is a rare condition seen in adults with limited therapeutic options available. It manifests with profuse diarrhea and malnourishment. The diagnosis is made through a combination of clinical, serologic, and histologic parameters. The cornerstone of therapy revolves around nutritional optimization and immunosuppression, most commonly in the form of corticosteroids. Alternate therapies, such as antitumor necrosis factor agents, can be considered if there is an inadequate response to steroids. We report a case of autoimmune enteropathy that was successfully treated with adalimumab, a rare treatment for an infrequent disease.

Immunosuppressive therapies for inflammatory bowel disease.

Inflammatory bowel disease (IBD) is comprised of Crohn's disease and ulcerative colitis, both chronic inflammatory intestinal disorders of unknown etiology characterized by a waxing and waning clinical course. For many years, the drug therapy was limited to sulfasalazine and related aminosalicylates, corticosteroids and antibiotics. Studies suggesting that the pathophysiology of these disorders relates to a disregulated, over-active immune response to indigenous bacteria have led to the increasing importance of immunosuppressive drugs for the therapy of IBD. This review details the mechanisms of action, clinical efficacy, and adverse effects of these agents.

Abdominal phlegmons in Crohn's disease: outcomes following antitumor necrosis factor therapy.

BACKGROUND: An abdominal phlegmon is an inflammatory mass that can develop in the setting of penetrating Crohn's disease (CD). Anti-tumor necrosis factor (TNF) antibody therapy is typically avoided in CD complicated by phlegmon because of concern for peritoneal infection but may offer an effective alternative to surgical resection after infection has been controlled with antibiotics. The aim of this study was to examine outcomes for patients with CD who developed an abdominal phlegmon that was subsequently treated with an anti-TNF antibody. METHODS: We retrospectively reviewed the records of all CD patients attending Beth Israel Deaconess Medical Center between 2004 and 2010 with an abdominal phlegmon who were treated with an anti-TNF antibody in order to evaluate the safety and efficacy of this treatment regimen. RESULTS: There were 13 patients with CD complicated by a phlegmon treated with antibiotics and an anti-TNF antibody at our center between 2004 and 2010. Ten were male. Median time (interquartile range) from diagnosis to development of the phlegmon was 5.9 (1.9-22.7) years. The phlegmon was associated with an abscess in 12 patients. In addition to anti-TNF therapy, all patients were treated with broad-spectrum antibiotics. Anti-TNF therapy was effective without complications in all subjects. Two patients eventually had surgery more than a year after initiating anti-TNF treatment. CONCLUSIONS: Penetrating CD complicated by phlegmon formation may be safely and effectively managed with a combination of antibiotics and anti-TNF therapy. Larger, prospective trials are required to confirm these initial findings.

Efficacy and safety of drugs for ulcerative colitis.

IMPORTANCE OF THE FIELD: Ulcerative colitis (UC) is a chronic inflammatory disorder of the colon that carries considerable burden and morbidity for patients and presents a constant challenge in management for gastroenterologists. Continued advances in medical therapies provide a range of treatment options for patients, but with this is the need to balance the potential benefits of a particular medication with its side effect profile in both the short and the long term. AREAS COVERED IN THIS REVIEW: This article will review the current drugs used in the treatment of UC, including 5-amninosalicylates, antibiotics, steroids, immunomodulators and biologics, with particular attention to their indications, efficacy and toxicity profile. WHAT THE READER WILL GAIN: The reader will gain a comprehensive understanding of the various medical therapies used in the treatment of UC with focus on efficacy and toxicity profiles, allowing providers to choose appropriate medical therapies for their patients. TAKE HOME MESSAGE: The particular agent used depends upon the extent and severity of disease, with mild-to-moderate disease treated with conventional therapy including 5-amninosalicylates. Steroids are used in the short term to bring active disease into remission, and the more aggressive immunomodulators and biologics are reserved for more severe disease given their toxicity profiles.

Patient considerations in the management of ulcerative colitis: role of once-daily MMX mesalamine.

Mesalamine and its derivatives are effective and well-tolerated therapies for ulcerative colitis. However, patient adherence to traditional mesalamine-based therapy is poor, and is often limited by heavy pill burdens and frequent dosing intervals. This can lead to ineffective disease control, impaired quality of life, and preventable morbidity and mortality. Previous studies have suggested that a once-daily mesalamine regimen would be strongly adhered to in the outpatient setting, but at that time no such formulation of mesalamine existed. In 2007, clinical trial data showed a novel, once-daily, multi-matrix (MMX) formulation of mesalamine to be effective in both remission induction and remission maintenance. This breakthrough in drug delivery allowed the unification of an effective therapeutic with a formulation that enables outpatients to be increasingly adherent to their medication. In theory, this might result in improved outpatient disease control and a decreased number of flares. As the use of MMX mesalamine increases, studies examining the outpatient community adherence rate need to be performed.

Update on the role of modified release mesalamine in the management of ulcerative colitis and Crohn's disease.

5-aminosalicyclates (5-ASA) remain a key first-line therapy for patients with ulcerative colitis (UC). A range of 5-ASA preparations is available and Eudragit-S(®) coated modified release formulations of mesalamine, such as Asacol(®), remain among the most popular choices. We here review the current understanding of the mechanism of action of 5-ASA in inflammatory bowel disease. We evaluate evidence supporting the efficacy and safety of modified release mesalamine for both induction and remission maintenance in UC, including a review of the data from the recent ASCEND studies. We also examine the controversial issue of the role of mesalamine in treatment of Crohn's disease (CD) and highlight data supporting its use following surgically induced remission of CD. Evidence supporting the use of mesalamine as prophylaxis for colorectal cancer and dysplasia will be considered. Finally, recent developments in our understanding of how to use modified release mesalamine in a safe and cost-effective manner are evaluated, including discussion of the importance of studying patient non-adherence as a key component of future studies in this area.

Ulcerative colitis: current treatment strategies and future prospects.

Ulcerative colitis (UC) is a disease of unknown etiology characterized by inflammation of the mucosa and occasionally the submucosa of the colon. Conventional drug therapy for UC involves use of aminosalicylates, corticosteroids, azathioprine/6-mercaptopurine, cyclosporine and anti-tumor necrosis factor therapy. Alternative therapies include probiotics, nicotine and fish oil. Drugs like tacrolimus, rosiglitazone and Trichuris suis ova are being evaluated for use in UC patients. With the new biologic agents, new treatment options for UC continue to evolve. In this article we will discuss the conventional drugs, the alternative therapies and the management strategies according to the severity and extent of UC.

Steroid-refractory severe ulcerative colitis: what are the available treatment options?

Approximately 15% of patients with ulcerative colitis will experience a severe episode requiring hospitalization. Although intravenous corticosteroids are the current first-line therapy for these patients, about 30% of patients do not respond to corticosteroids and require either an alternative anti-inflammatory agent or surgery. Ciclosporin has proven its efficacy in a number of controlled trials in this setting and is characterized by high early response rates. Patients who respond to ciclosporin and avoid colectomy are more likely to retain their colon if they bridge to immunomodulators in the medium term. Infliximab has also demonstrated efficacy in reducing early colectomy rates and longer term data are awaited. Other agents, such as tacrolimus and basiliximab, and leukocytapheresis, have been studied in small trials and may be alternative options. Key issues remain as to what should be first- and second-line therapies, when surgery should be undertaken, and the risk of switching between immunosuppressants in these critical patients.

MMX mesalamine: a novel high-dose, once-daily 5-aminosalicylate formulation for the treatment of ulcerative colitis.

BACKGROUND: 5-Aminosalicylate (5-ASA) agents are the first-line therapy for ulcerative colitis (UC). A high-dose, once-daily formulation of 5-ASA known as MMX mesalamine has recently been approved for the treatment of UC. OBJECTIVE: To summarize current data on MMX mesalamine and to discuss its impact on management of UC. METHODS: A systematic review of published literature was performed on PubMed using the search terms 'MMX mesalamine' and 'Lialda'. Abstracts presented at US gastroenterology conferences between 2006 and 2007, were also reviewed. RESULTS: MMX mesalamine uses a novel multi-matrix delivery system to achieve a sustained release of 5-ASA throughout the colon. Clinical trials have demonstrated MMX mesalamine 2.4 g/day or 4.8 g/day to be superior to placebo in inducing remission in active mild to moderate UC. The drug is well tolerated with a safety profile comparable to other oral 5-ASA agents. With a high-dose formulation of 1.2 g 5-ASA per tablet, MMX mesalamine can be administered conveniently at two to four pills once a day. CONCLUSION: MMX mesalamine is the first and only approved once-daily 5-ASA treatment option for patients with UC. It is efficacious for the induction of remission in mild to moderate UC and has a favorable safety profile. With the advantage of low pill burden and easy dosing schedule, it may potentially improve patient compliance and treatment success.

The risks and the benefits of mesalazine as a treatment for ulcerative colitis.

Mesalazine is a 5-aminosalicylic acid compound that is the primary treatment for mild-to-moderate ulcerative colitis. In both oral and topical formulations it has demonstrated efficacy in both induction of active colitis and maintenance of remission, regardless of the extent of inflammation. In addition, there is indirect evidence of a role in the chemoprophylaxis of colorectal cancer in these patients. Mesalazine is generally well tolerated by patients, although serious adverse effects have been reported. In particular, worsening of colitis, interstitial pneumonitis and nephritis are of concern to clinicians. Fortunately these reactions are mostly reversible with cessation of therapy.

Anti-tumour necrosis factor therapy for ulcerative colitis: evidence to date.

Infliximab, the chimeric monoclonal antibody directed against tumour necrosis factor (TNF)-alpha, has profoundly changed therapy for Crohn's disease (CD). However, for ulcerative colitis (UC), before the publication of ACT 1 and ACT 2 (Active Ulcerative Colitis Trials 1 and 2), there were only a few open-label and controlled trials that evaluated the role of infliximab in the treatment of UC. Results from these earlier studies were equivocal and ambiguous. However, the ACT 1 and ACT 2 trials were large, randomised and placebo-controlled, and have shown that infliximab is significantly more efficacious than placebo in treating both corticosteroid-responsive and -refractory moderate to severe UC. Data from these two studies showed that in patients with moderate to severe UC, treatment with infliximab (5 and 10 mg/kg), compared with placebo, led to significantly higher rates of clinical response, clinical remission and mucosal healing. However, a significant proportion of patients who were receiving oral corticosteroids at the start of the trials, remained on corticosteroids despite infliximab therapy. Additionally, the safety profile of the drug was found to be similar to what has been reported in clinical studies of infliximab in patients with CD. On the basis of currently available data, we use infliximab as a remission-inducing agent in patients who have moderate to severe UC and are either refractory to or intolerant of mesalazine (5-ASA) products and immunomodulators. Moreover, infliximab seems to be a reasonable therapeutic modality for remission maintenance in those patients with UC in whom mesalazine products and immunomodulators have failed. Although data are limited, infliximab may be considered as a remission-inducing agent in patients with moderate to severe UC which is refractory to oral corticosteroids. However, the role of infliximab in the treatment of UC patients who are dependent on oral corticosteroids is still unclear and, therefore, should be considered only in patients who cannot be successfully transitioned to or are intolerant of oral immunomodulators. Furthermore, infliximab may be an alternative to ciclosporin (cyclosporin) in hospitalised patients with severe to moderately severe but not fulminant UC who do not respond to intravenous corticosteroids. At present, there is insufficient evidence to advocate using infliximab as a first-line agent for UC patients with mild or moderate to severe disease. Future randomised, controlled trials with clearly defined patient populations should further help to clarify the definitive role of infliximab in the therapeutic scheme for UC.

Combined oral and topical mesalazine treatment for extensive ulcerative colitis.

BACKGROUND: A 32-year-old white Jewish woman was referred to our clinic in October 2002 for a second opinion on the management of her active extensive ulcerative colitis that did not respond to oral mesalazine (mesalamine) 3.6 g/day. The severity of symptoms had affected her plans to have children. INVESTIGATIONS: Laboratory investigations, including perinuclear antineutrophil cytoplasmic antibodies and antibodies to Saccharomyces cerevisiae, stool cultures, and sigmoidoscopy to 40 cm from the rectum, with biopsies. DIAGNOSIS: Moderate-to-severe active extensive ulcerative colitis, unresponsive to mesalazine at 3.6 g/day. MANAGEMENT: Oral mesalazine 4.8 g/day and 4 g mesalazine enemas nightly.

The Role of Antibiotics in Inflammatory Bowel Disease.

Broad-spectrum antibiotics are the mainstay of therapy for patients with Crohn's disease (CD) who present with localized peritonitis due to a microperforation bacterial overgrowth secondary to chronic strictures. They are essential adjuncts to drainage therapy for CD-associated abscesses and for complicated perineal disease. The lack of well-designed, placebo-controlled trials has led to much skepticism about the efficacy of antibiotics as primary therapy for CD. However, a careful review of the experience with antibiotics, including clinical observations and controlled trials, leads to the conclusion that antibiotics have a role as primary therapy in active uncomplicated CD. The efficacy of their response must be considered in well-defined subsets of patients. Ciprofloxacin and metronidazole, the two most widely studied antibiotics, are effective therapy for patients with active ileocolonic and colonic disease and have been shown to reduce recurrence rates after ileocolonic resection. The benefits of these drugs are less clear for patients with uncomplicated ileal disease. Additionally, ciprofloxacin and metronidazole may also serve as an adjunct to immunomodulator therapy. The role of antimycobacterial therapy in treatment of CD is an attractive alternative, and hopefully this therapy will be further clarified when results of ongoing trials become available. In toxic patients with fulminant ulcerative colitis (UC), with or without megacolon, broad-spectrum antibiotics should be a part of the treatment program. In less severely ill patients requiring hospitalization, antibiotics may be given to cover for the potential of a superimposed infection until the workup for infection, including Clostridium difficile is completed. There may be a subset of patients with severe nontoxic colitis with persistent fever and bandemia after steroid therapy who respond to antibiotics, but to date controlled trials have not shown efficacy in this group. Antibiotics should not be routinely used for mild to moderately ill patients with UC, although a trial of ciprofloxacin is not unreasonable prior to colectomy for otherwise refractory patients. The use of rifaximin in UC requires further evaluation in larger studies.

Abdominal epilepsy.

Abdominal epilepsy is an uncommon syndrome in which gastrointestinal complaints, most commonly abdominal pain, result from seizure activity. It is characterized by (1) otherwise unexplained, paroxysmal gastrointestinal complaints, (2) symptoms of a central nervous system disturbance, (3) an abnormal electroencephalogram with findings specific for a seizure disorder, and (4) improvement with anticonvulsant medication. We review the history of the syndrome and analyze all 36 cases reported in the English literature from the last 34 years. The most common gastrointestinal symptoms include abdominal pain, nausea and vomiting, while the most common neurological symptoms include lethargy and confusion. After exclusion of more common etiologies for the presenting complaints, workup should proceed with an electroencephalogram. Where the diagnosis is seriously considered, neurological consultation should be considered. Treatment typically begins with anticonvulsant medication, and resolution of symptoms with therapy helps to confirm the diagnosis.

Smoking and immunomodulators do not influence the response or duration of response to infliximab in Crohn's disease.

OBJECTIVE: Clinical predictors for infliximab response are still unknown. Identifying predictors of response to infliximab in Crohn's disease may improve our selection of patients. METHODS: Two hundred patients with luminal (61%) or fistulous (39%) Crohn's disease and at least 6 months of follow-up following a total of 416 infliximab infusions were evaluated. Clinical response and duration of response were the primary endpoints. RESULTS: Patients with fistulous disease had a higher response rate (83% versus 70%, P = 0.044) and a significantly longer duration of response compared with patients with luminal disease (17.4 versus 10.1 wks, P = 0.017). For luminal disease, nonsmokers and smokers had similar response rates (74% versus 64%, P = 0.5) and similar durations of response (9.4 wks versus 8.4 wks P = 0.6) while patients taking concurrent immunomodulators had similar response rates compared with those not taking immunomodulators (74% versus 71%, P = 0.9) and similar durations of response (10.4 wks versus 10.6 wks, P = 0.9). For fistulous disease, response rates (89% versus 83% P = 0.9) and duration of response (16.9 wks versus 10.1 wks, P = 0.10) were similar between nonsmokers and smokers and concurrent immunomodulators had no effect on response (89% versus 86%, P = 0.9) or duration of response (19.8 wks versus 15.4 wks, P = 0.46). Multivariable analysis confirmed that neither smoking, corticosteroids, immunomodulator therapy, gender, age, age of disease onset, disease duration, nor luminal disease location significantly influenced response or duration of response. CONCLUSIONS: Patients with fistulous disease had a higher response rate and a significantly longer duration of response compared with patients with luminal disease. However, among patients with luminal or fistulous disease, neither smoking nor immunomodulators had any effect on response or duration of response.

Postoperative maintenance of Crohn's disease remission with 6-mercaptopurine, mesalamine, or placebo: a 2-year trial.

BACKGROUND & AIMS: No therapy has been shown to reliably prevent the evolution of postoperative recurrence of Crohn's disease. The aim of the current trial was to compare 6-mercaptopurine (6-MP) and mesalamine with placebo for the prevention of clinical, endoscopic, and radiographic recurrence of Crohn's disease after resection and ileocolic anastomosis. METHODS: Five centers randomized 131 patients to receive 6-MP (50 mg), mesalamine (3 g), or placebo daily in a double-blind, double-dummy trial. Patients had clinical assessments at 7 weeks and then every 3 months; colonoscopy at 6, 12, and 24 months; and small bowel series at 12 and 24 months. End points were clinical, endoscopic, and radiographic recurrence rates at 24 months. RESULTS: Clinical recurrence rates (intent to treat) by life-table analysis at 24 months were 50% (95% confidence interval [CI], 34%-68%), 58% (95% CI, 41%-75%), and 77% (95% CI, 61%-91%) in patients receiving 6-MP, mesalamine, and placebo, respectively. Endoscopic recurrence rates were 43% (95% CI, 28%-63%), 63% (95% CI, 47%-79%), and 64% (95% CI, 46%-81%), and radiographic recurrence rates were 33% (95% CI, 19%-54%), 46% (95% CI, 29%-66%), and 49% (95% CI, 30%-72%), respectively. 6-MP was more effective than placebo ( P < 0.05) at preventing clinical and endoscopic recurrence over 2 years. Patient withdrawals resulted in 69% of the study population evaluable for the clinical recurrence end point. CONCLUSIONS: 6-MP, 50 mg daily, was more effective than placebo at preventing postoperative recurrence of Crohn's disease and should be considered as a maintenance therapy after ileocolic resection.