Robert B. Stein

An open-label trial of the PPARγ ligand rosiglitazone for active ulcerative colitis

OBJECTIVES:Previous research has demonstrated that ligands for the γ subtype of peroxisome proliferator-activated receptors (PPARs) reduce inflammation in two different murine models of colitis. This study was designed to examine the potential efficacy of rosiglitazone, a ligand for the γ subtype of PPARs, as a therapy for active ulcerative colitis.METHODS:Fifteen patients with mild to moderately active ulcerative colitis despite therapy with 5-aminosalicylic acid compounds were enrolled in an open-label study of rosiglitazone (4 mg b.i.d. p.o.) for 12 wk. Thirteen of 15 patients were receiving concomitant therapy with corticosteroids and/or immunomodulator medications. Disease activity was measured with the Disease Activity Index.RESULTS:After 12 wk of therapy, four patients (27%) had achieved clinical remission, of whom three (20%) also had an endoscopic remission. Four additional patients (27%) had a clinical response without achieving remission. Two patients were hospitalized with worsened disease activity, and one patient was withdrawn for nephrotic syndrome.CONCLUSIONS:These data suggest that ligands for the γ subtype of PPARs may represent a novel therapy for ulcerative colitis. A double blind, placebo-controlled, randomized trial is warranted.

Efficacy of anti-tumor necrosis factor therapy in patients with ulcerative colitis

OBJECTIVES:Tumor necrosis factor-α (TNF-α) is an important cytokine involved in the pathogenesis of inflammatory bowel disease. The monoclonal antibody to TNF-α, infliximab, is effective in treating Crohns disease. Preclinical studies suggest the importance of TNF-α in treating ulcerative colitis (UC). We report the effectiveness of infliximab for UC and examine factors predictive of response to medication.METHODS:Data from all UC patients receiving infliximab at four institutions were analyzed. Disease activity was determined by the Disease Activity Index.RESULTS:A total of 27 patients with active UC received inpatient (37%) and outpatient (63%) infliximab as single (52%) or multiple (two to 15) infusions (48%). Twelve patients (44%) achieved remission and six patients (22%) had partial response. Nine patients had no response; five subsequently underwent total colectomy. The median time to achieve response and remission was 4 days and the median duration 8 wk. Nine of the 18 patients who responded experienced 19 relapses; 18 of these relapses (95%) were successfully treated with repeat infusions. Steroid-refractory patients were less likely to respond to infliximab therapy than were steroid-responsive patients (33% vs 83%; p = 0.026). No other factors were predictive of response to infliximab. Two patients developed serious adverse events, including death in one case.CONCLUSIONS:Preliminary evidence suggest effectiveness of infliximab in the treatment of UC, including medically refractory severe disease. Individuals who are refractory to corticosteroids, however, may be unlikely to respond to infliximab. A randomized controlled trial is necessary to further investigate the efficacy of infliximab in patients with UC.

Comparative Tolerability of Treatments for Inflammatory Bowel Disease

Despite limited understanding of therapeutic aetiopathogenesis of ulcerative colitis and Crohn’s disease, there is a strong evidence base for the efficacy of pharmacological and biological therapies. It is equally important to recognise toxicity of the medical armamentarium for inflammatory bowel disease (IBD).Sulfasalazine consists of sulfapyridine linked to 5-aminosalicylic acid (5-ASA) via an azo bond. Common adverse effects related to sulfapyridine ‘intolerance’ include headache, nausea, anorexia, and malaise. Other allergic or toxic adverse effects include fever, rash, haemolytic anaemia, hepatitis, pancreatitis, paradoxical worsening of colitis, and reversible sperm abnormalities.The newer 5-ASA agents were developed to deliver the active ingredient of sulfasalazine while minimising adverse effects. Adverse effects are infrequent but may include nausea, dyspepsia and headache. Olsalazine may cause a secretory diarrhoea. Uncommon hypersensitivity reactions, including worsening of colitis, pancreatitis, pericarditis and nephritis, have also been reported.Corticosteroids are commonly prescribed for treatment of moderate to severe IBD. Despite short term efficacy, corticosteroids have numerous adverse effects that preclude their long term use. Adverse effects include acne, fluid retention, fat redistribution, hypertension, hyperglycaemia, psycho-neurological disturbances, cataracts, adrenal suppression, growth failure in children, and osteonecrosis. Newer corticosteroid preparations offer potential for targeted therapy and less corticosteroid-related adverse effects.Azathioprine and mercaptopurine are associated with pancreatitis in 3 to 15% of patients that resolves upon drug cessation. Bone marrow suppression is dose related and may be delayed.The adverse effects of methotrexate include nausea, leucopenia and, rarely, hypersensitivity pneumonia or hepatic fibrosis. Common adverse effects of cyclosporin include nephrotoxicity, hypertension, headache, gingival hyperplasia, hyperkalaemia, paresthesias, and tremors. These adverse effects usually abate with dose reduction or cessation of therapy. Seizures and opportunistic infections have also been reported.Antibacterials are commonly employed as primary therapy for Crohn’s disease. Common adverse effects of metronidazole include nausea and a metallic taste. Peripheral neuropathy can occur with prolonged administration. Ciprofloxacin and other antibacterials may be beneficial in those intolerant to metronidazole.Newer immunosuppressive agents previously reserved for transplant recipients are under investigation for IBD. Tacrolimus has an adverse effect profile similar to cyclosporin, and may cause renal insufficiency. Mycophenolate mofetil, a purine synthesis inhibitor, has primarily gastrointestinal adverse effects.Biological agents targeting specific sites in the immunoinflammatory cascade are now available to treat IBD. Infliximab, a chimeric antibody targeting tumour necrosis factor-α has been well tolerated in clinical trials and early postmarketing experience. Additional trials are needed to assess long term adverse effects.

Integrating anti-tumor necrosis factor therapy in inflammatory bowel disease: Current and future perspectives

Crohns disease and ulcerative colitis are two idiopathic inflammatory disorders of the GI tract. Manifestations of disease can be severe and lead to long term therapy with a variety of medications and/or surgery. Standard medical therapy consists of agents that either treat suppurative complications or modulate the inflammatory cascade in a nonspecific manner. Many specific chemokine and cytokine effectors that promote intestinal inflammation have been identified. Such work has led to experimental clinical trials with a variety of cytokine antagonists. Compounds directed against one such cytokine, tumor necrosis factor α (TNF), have demonstrated the greatest clinical efficacy to date. This is consistent with scientific observations that suggest a central role for TNF in the inflammatory cascade. Infliximab is a chimeric monoclonal antibody against TNF that has been demonstrated to be effective for the treatment of Crohns disease. Infliximab is Food and Drug Administration approved for the treatment of Crohns disease. There exist several other TNF antagonists in various phases of investigation, including the monoclonal antibody CDP 571, the fusion peptide etanercept, the phosphodiesterase inhibitor oxpentifylline, and thalidomide. The clinical efficacy of these agents and the role of TNF in the pathogenesis of inflammatory bowel disease is reviewed.

MEDICAL THERAPY FOR INFLAMMATORY BOWEL DISEASE

Despite advances in pharmacologic approaches, the treatment of ulcerative colitis and Crohns disease remains a challenge. Prior standards of therapy, sulfasalazine and corticosteroids, are gradually being replaced by mesalamine and alternative immune modulating agents. This article discusses the important pharmacologic properties, mechanisms of action, indications, and complications necessary to apply the expanding armamentarium in clinical practice.

Medical Therapy for Crohn's Disease: The State of the Art

Various medications are used to control the symptoms of Crohns disease. This article reviews the traditional medical therapies of Crohns disease, including aminosalicylates and corticosteroids, and the broad armamentarium of immune modulators and biologic agents that are becoming increasingly important in the management of Crohns disease.

Azathioprine or 6-mercaptopurine for inflammatory bowel disease: do risks outweigh benefits?

The treatment of Crohns disease and ulcerative colitis has evolved and has improved the quality of life of patients afflicted with these disorders. Immune modulators such as azathioprine and 6-mercaptopurine are an important class of medications used for the treatment of patients with inflammatory bowel disease. Controlled studies have demonstrated their efficacy in both induction and maintenance of remission in Crohns disease, and similarly, for the induction and maintenance of remission in patients with ulcerative colitis. These agents have had an increasing importance in the management of steroid-resistant, steroid-dependent diseases, and fistulizing Crohns disease. The primary limitations to these agents have been their slow onset of action and their side effect profile. Despite these limitations, these agents have demonstrated efficacy and have become paramount to the management of patients with these incurable potentially disabling disorders. The precise role of azathioprine/6-mercaptopurine, their limitations and their safety are reviewed in this paper.

ADVANCES IN INFLAMMATORY BOWEL DISEASE

Optimal management of patients with IBD requires a multidisciplinary approach involving primary care physicians, gastroenterologists, surgeons, radiologists, and nutritionists. The rapidly evolving medical armamentarium promises better quality of life for patients afflicted with these complex, chronic diseases. It is expected that future development of biologic agents will add to the therapeutic options, although it may complicate treatment algorithms. Surgical advancements, particularly in ileoanal anastomosis and bowel preservation by strictureplasty, have improved outcome dramatically. The focus on development of new therapies and refinement of older ones demands a constant attention to the latest peer-reviewed literature and that the clinician keep abreast of the various advancements that have been summarized here.

Nutrition in inflammatory bowel disease.

Clinical and basic research continues to expand our understanding of the complex pathogenesis of inflammatory bowel diseases. The potential roles played by fatty acid intake, serum leptin, and nitric oxide in the promotion of intestinal inflammation in Crohns disease and ulcerative colitis will be reviewed. In addition, important advances in the areas of bone disease, vitamin deficiency, growth failure, and home parenteral nutrition will be discussed.