Ulcerative Colitis: Hanauer SB

Hanauer SB. · No affiliation provided · Nat Clin Pract Gastroenterol Hepatol. · Pubmed #18670441 No free full text.

This publication has no abstract.

Hanauer SB. · Department of Medicine and Clinical Pharmacology, University of Chicago, Chicago, Illinois, USA. · Inflamm Bowel Dis. · Pubmed #15905710 No free full text.

Abstract: Mesalamine has a well-established role in the management of ulcerative colitis. However, its role in the management of Crohn's disease (CD) is less clear. Studies evaluating its therapeutic value in CD have produced both positive and negative results. Meta-analyses have not clarified the situation, possibly because they have combined studies of different design. This debate critically examines the evidence for and against the use of mesalamine in CD.

Hanauer SB. · No affiliation provided · Gastrointest Endosc. · Pubmed #10650283 No free full text.

This publication has no abstract.

Hanauer SB. · Section of Gastroenterology and Nutrition, University of Chicago, Chicago, IL 60637, USA. · Aliment Pharmacol Ther. · Pubmed #18307645 No free full text.

Abstract: BACKGROUND: More than two-thirds of ulcerative colitis patients experience at least one relapse over a period of 10 years. Treatments that reduce the likelihood of relapses also reduce the risk of long-term complications. AIM: To review three topics: the current standard of treatment for ulcerative colitis, evolving concepts in treatment, and disease modification as a treatment goal of the future. RESULTS: Currently, 5-aminosalicylates are the standard treatment for the induction and maintenance of remission in mild-to-moderate ulcerative colitis patients. Evidence suggests that patients who take oral 5-aminosalicylates regularly are nearly six times more likely to experience regression in disease severity than those who do not. Additional treatment options such as corticosteroids, immunomodulators, biological therapies and ciclosporin are available for moderate-to-severe ulcerative colitis patients, or those who do not respond to 5-aminosalicylate. Surgery becomes pertinent for more than one-third of ulcerative colitis patients during the course of their disease. With the availability of a variety of therapies, advances in surgery and improved management strategies, a better understanding of patient treatment expectations can help improve the quality of care for ulcerative colitis patients. CONCLUSIONS: Disease modification is increasingly becoming a treatment goal in the management of ulcerative colitis. However, long-term studies are needed to examine further the disease modifying role of 5-aminosalicylates.

Kozuch PL, Hanauer SB. · Division of Gastroenterology and Hepatology, Department of Medicine, Thomas Jefferson University Hospital, Philadelphia, PA, USA. · World J Gastroenterol. · Pubmed #18200659 links to  free full text

Abstract: Crohn's disease (CD) and ulcerative colitis (UC) are chronic inflammatory diseases of the gastrointestinal tract. While a cure remains elusive, both can be treated with medications that induce and maintain remission. With the recent advent of therapies that inhibit tumor necrosis factor (TNF) alpha the overlap in medical therapies for UC and CD has become greater. Although 5-ASA agents have been a mainstay in the treatment of both CD and UC, the data for their efficacy in patients with CD, particularly as maintenance therapy, are equivocal. Antibiotics may have a limited role in the treatment of colonic CD. Steroids continue to be the first choice to treat active disease not responsive to other more conservative therapy; non-systemic steroids such as oral and rectal budesonide for ileal and right-sided CD and distal UC respectively are also effective in mild-moderate disease. 6-mercaptopurine (6-MP) and its prodrug azathioprine are steroid-sparing immunomodulators effective in the maintenance of remission of both CD and UC, while methotrexate may be used in both induction and maintenance of CD. Infliximab and adalimumab are anti-TNF agents approved in the US and Europe for the treatment of Crohn's disease, and infliximab is also approved for the treatment of UC.

Shah SB, Hanauer SB. · Section of Gastroenterology, Hepatology, and Nutrition, Department of Medicine, University of Chicago, Chicago, Illinois, USA. · Rev Gastroenterol Disord. · Pubmed #18192964 No free full text.

Abstract: Diarrhea continues to be a prevalent symptom in patients with inflammatory bowel disease (IBD), requiring a wide differential diagnosis to define the pathophysiologic mechanisms in individual patients. It is essential that physicians properly evaluate complaints of diarrhea by assessing both patient symptoms and potential physiologic impacts on fluid and electrolyte status. Underlying mechanisms of diarrhea with IBD are the location, extent, and severity of inflammation; malabsorption; altered motility; and iatrogenic causes such as medications, diet, and antibiotic-associated colitis (eg, Clostridium difficile). When treating diarrhea, physicians need to control inflammatory activity using appropriate treatment algorithms. Therapies include aminosalicylates, corticosteroids, immune modifiers, and, most recently, biologic treatment. Other medications, including loperamide, diphenoxylate, codeine sulfate, and tinctures of opium, slow motility and increase the absorption of fluids and nutrients. For iatrogenic issues, medications that cause diarrhea should be withdrawn and individual diets modified. Not all diarrheas in the IBD patient are the same; therefore, it is essential to tailor therapies according to presumed etiologies. Antidiarrheal agents are not recommended in extremely ill patients and those with known hypersensitivity or evidence of obstruction or colonic dilation, fever, or abdominal tenderness. Concomitant use of loperamide with diphenoxylate and atropine should be avoided in early pregnancy.

D'Haens G, Sandborn WJ, Feagan BG, Geboes K, Hanauer SB, Irvine EJ, Lémann M, Marteau P, Rutgeerts P, Schölmerich J, Sutherland LR. · University Hospital Gasthuisberg, Leuven, Belgium. · Gastroenterology. · Pubmed #17258735 No free full text.

This publication has no abstract.

Hanauer SB. · Professor of Medicine and Clinical Pharmacology Chief, Section of Gastroenterology, Hepatology and Nutrition, University of Chicago, 5841 S. Maryland Ave., MC 4076, Chicago, IL 60637, USA. · Aliment Pharmacol Ther. · Pubmed #16961743 No free full text.

Abstract: Sulfasalazine was the first aminosalicylate to be used for induction and maintenance therapy of ulcerative colitis (UC). Initial trials demonstrated a dose response that was compromised by dose-related intolerance. Recognition that the 5-aminosalicylic acid moiety (5-ASA, mesalazine) is the active ingredient of sulfasalazine has allowed the development of sulpha-free formulations of mesalazine and alternative azo-bond derivatives (olsalazine, balsalazide) that substantially reduce the dose-related (and allergic) consequences of the sulfapyridine moiety of sulfasalazine. Dose-ranging studies of mesalazine formulations for induction of remission have demonstrated increased efficacy of oral mesalazine up to 4-4.8 g/day, particularly in patients with more moderate disease activity. Combination therapy with oral and rectal mesalazine provide additional efficacy for patients with both distal and extensive colitis. The mesalazine formulations have dose-related benefits without dose-related side effects. In contrast, the azo-bond formulations are compromised by secretory diarrhoea at doses providing greater than 2-2.4 g/day of mesalazine. There are less data regarding dose-related benefits of aminosalicylates to maintain remissions in UC greater than 1.6 g/day of mesalazine, although the absence of dose-related side effects allows continuation of the same inductive dose through maintenance treatment without dose-related toxicity.

Hanauer SB. · University of Chicago, Section of Gastroenterology, Chicago, Illinois 60637, USA. · Colorectal Dis. · Pubmed #16594960 No free full text.

Abstract: Ulcerative colitis (UC) of moderate severity is a common presentation in gastroenterological practice and a number of treatment options exist to rapidly and effectively induce remission. This review highlights how novel formulations and dosing regimens can ensure treatment success at a greater convenience for the patient with no increased risk of adverse effects. 5-aminosalicyclic acid (5-ASA) is well tolerated with a low incidence of adverse effects, and has a significant role in the management of UC. Different formulations of oral 5-ASA are now available and allow targeted treatment to inflammatory areas of the small bowel and ascending colon. 5-ASA is often initiated at a low dose for patients with mild to moderately active UC and with increasing doses for those who fail or have a poor response. 5-ASA at high doses is increasingly being used as induction therapy for active UC, particularly in patients with recurrent and/or extensive disease. The recent ASCEND studies show that an induction dose of 5-ASA of 4.8 g daily in patients with moderate UC is significantly more effective and resolves symptoms faster compared with a daily dose of 2.4 g. The evidence provided by the ASCEND studies support the rationale for a 'top-down' dosing strategy for UC where more potent therapies are introduced at an earlier stage of moderately severe disease.

Hanauer SB. · Section of Gastroenterology, University of Chicago Medical Center, Chicago, Illinois 60637, USA. · Inflamm Bowel Dis. · Pubmed #16378007 No free full text.

Abstract: Ulcerative colitis (UC) and Crohn's disease (CD), the primary constituents of inflammatory bowel disease (IBD), are precipitated by a complex interaction of environmental, genetic, and immunoregulatory factors. Higher rates of IBD are seen in northern, industrialized countries, with greater prevalence among Caucasians and Ashkenazic Jews. Racial gaps are closing, indicating that environmental factors may play a role. IBD is multigenic, with the most clearly established genetic link between certain NOD2 variants and CD. Regardless of the underlying genetic predisposition, a growing body of data implicates a dysfunctional mucosal immune response to commensal bacteria in the pathogenesis of IBD, especially CD. Possible triggers include a chronic inflammatory response precipitated by infection with a particular pathogen or virus or a defective mucosal barrier. The characteristic inflammatory response begins with an infiltration of neutrophils and macrophages, which then release chemokines and cytokines. These in turn exacerbate the dysfunctional immune response and activate either TH1 or TH2 cells in the gut mucosa, respectively associated with CD and, less conclusively, with UC. Elucidation of immunological and genetic factors indicate multiple points at which the inflammatory cascade may be interrupted, yielding the possibility of precise, targeted therapies for IBD.

Hanauer SB. · University of Chicago, IL 60637, USA. · Nat Clin Pract Gastroenterol Hepatol. · Pubmed #16265041 No free full text.

Abstract: Evidence is accumulating that both genetic and environmental factors contribute to ulcerative colitis. The most consistent genetic associations have been shown for the MHC locus HLA Class II alleles, but the interleukin-1 family of genes and the multidrug resistance gene MDR1 have also been implicated as genetic susceptibility factors for the development of disease. In addition, there is a relationship between ulcerative colitis and bacterial flora, with an increased number of adherent Bacteroides spp. and Enterobacteriaceae spp. present in inflamed bowel segments. Conversely, cigarette smoking and appendectomy have both been shown to protect against the development of ulcerative colitis. Despite our improved understanding of the genetics and inflammatory mechanisms that underpin this disease, however, the etiology and pathogenesis of ulcerative colitis remain undefined. The diagnosis of ulcerative colitis is being aided by recent advances in diagnostic strategies, including the detection of fecal and serologic markers and the use of wireless capsule endoscopy, but, in the absence of a pathognomonic marker, the definition of this disease remains based on well-established clinical, endoscopic and histologic criteria. In particular, it is difficult to discriminate ulcerative colitis from other forms of colitis, including Crohn's disease, and there seems to be a growing overlap of pathophysiologic processes between ulcerative colitis and post-infectious irritable bowel syndrome. Patients who remain indeterminate between ulcerative colitis and Crohn's disease also continue to be a diagnostic challenge.

Lim WC, Hanauer SB. · Section of Gastroenterology and Nutrition, Department of Medicine, University of Chicago Medical Center, Chicago, Illinois, USA. · Rev Gastroenterol Disord. · Pubmed #15359211 No free full text.

Abstract: Aminosalicylates have been shown to exhibit a wide range of anti-inflammatory and immunomodulatory properties. Since the discovery of sulfasalazine's efficacy in ulcerative colitis and the subsequent development of sulfa-free mesalamine delivery systems, aminosalicylates have evolved to become an integral part of our therapeutic armamentarium and are now first-line therapies for the treatment of mildly to moderately active inflammatory bowel disease and for maintenance of remissions after successful induction therapy. Despite the substantial body of evidence supporting the use of aminosalicylates in ulcerative colitis and Crohn's disease, gaps in our evidence base and controversies surrounding aminosalicylates clinical application have emerged. In this review, issues of dose response and optimization of the treatment regimen in ulcerative colitis, the discrimination between oral mesalamine formulations in left-sided colitis, and their efficacy in active and quiescent Crohn's disease are discussed.

Hanauer SB. · Section of Gastroenterology, University of Chicago, IL 60637, USA. · Aliment Pharmacol Ther. · Pubmed #15352903 links to  free full text

Abstract: After the induction of remission, the second priority of therapy for ulcerative colitis is sustained clinical remission, defined as the absence of inflammatory symptoms (diarrhoea, bleeding, rectal urgency) and the maintenance of an intact mucosa, with the absence of ulcers, friability or significant granularity at endoscopy. The 'optimal' maintenance strategy will depend on the therapy needed to induce remission. Thus, the transition from induction to maintenance therapy will be determined by the intensity of acute therapy necessary to induce remission and the duration of therapy required to complete the resolution of clinical symptoms. There are few controlled clinical trials pertaining to maintenance after each induction regimen. However, experience dictates that aminosalicylates are efficacious after aminosalicylate-induced remissions, that steroids should be tapered according to the time required to induce remission, that patients requiring ciclosporin will benefit from the addition of long-term immunomodulation with azathioprine or mercaptopurine, and that many patients with distal colitis who require topical mesalazine (mesalamine) will continue to need topical therapy to maintain remission, albeit at reduced frequency. The expectations for maintenance therapy require patient adherence to the prescribed treatment regimen. Patients require education with regard to the long-term goals of maintenance therapy (e.g. prevention of relapse, reduction of long-term complications of disease activity or risks of acute therapy with steroids), and should be warned against the use of nonsteroidal anti-inflammatory drugs and cautioned about the cessation of smoking, when applicable, due to potential risks of relapse or chronic activity.

Hanauer SB. · University of Chicago, Section of Gastroenterology, IL 60637, USA. · Aliment Pharmacol Ther. · Pubmed #15352896 links to  free full text

Abstract: Aminosalicylate therapy for ulcerative colitis remains a foundational strategy for the induction and maintenance of remission for mild to moderate disease. Although it seems clear that topical mesalazine (mesalamine) is the most efficacious approach to distal ulcerative colitis, recent trials with orally delivered azo conjugates suggest that there may be an advantage over pH-released mesalazine as a first-line approach to active disease. No such comparisons are available for azo products and the prolonged-release formulation, Pentasa. However, recent meta-analyses have demonstrated that, although there is little difference in systemic exposure between marketed products, luminal concentrations may vary. In maintenance therapy, aminosalicylates remain the standard approach after aminosalicylate-induced remission. A number of gaps remain in the evidence base with regard to the optimal dosing of oral mesalazine as a maintenance agent, whether oral mesalazine can maintain remissions after rectal mesalazine induction, and the dose-response and efficacy of aminosalicylates after steroid- or ciclosporin-induced remissions. Although aminosalicylates have been advocated for several decades in Crohn's disease, a number of controversies have evolved since the original trials with sulfasalazine in active Crohn's disease. The original trials demonstrated benefits for sulfasalazine in colonic involvement, but controlled trial evidence for the role of sulfasalazine as maintenance therapy has not been as firmly established. In addition, although oral mesalazine has been demonstrated in controlled trials to be superior to placebo in mild to moderate disease, it is less efficacious than corticosteroids at inducing remissions. The maintenance benefits of mesalazine appear to be limited to patients 'induced into remission' with mesalazine and in some post-operative settings.

Lim WC, Hanauer SB. · Section of Gastroenterology, Department of Medicine, University of Chicago Hospitals, Chicago, Illinois, USA. · Rev Gastroenterol Disord. · Pubmed #15184826 No free full text.

Abstract: Ulcerative colitis and Crohn's disease, the idiopathic inflammatory bowel diseases (IBD), are thought to represent genetically determined, dysregulated immune responses to otherwise innocuous luminal antigens. Although progress in research has advanced our understanding of the immunopathogenesis and begun to elucidate genetic contributions toward susceptibility, limitations of current medical approaches continue to drive the search for better therapeutic agents. Most recently, the introduction of infliximab has heralded a new era of evolving biologically targeted treatments for IBD. Infliximab is currently the only biologic agent approved for the treatment of inflammatory and fistulizing Crohn's disease, but ongoing research continues to generate new biologic agents targeted at specific pathogenic mechanisms involved in the inflammatory process. Undoubtedly, with the success of infliximab, the role of biologic therapy will continue to expand in the future treatment of IBD.

Harrell LE, Hanauer SB. · Section of Gastroenterology and Nutrition, University of Chicago Medical Center, 5841 South Maryland Avenue, MC 4076, Chicago, IL 60637, USA. · Gastroenterol Clin North Am. · Pubmed #15177540 No free full text.

Abstract: The role of the aminosalicylates for induction therapy of mild moderate ulcerative colitis and as maintenance treatment has been substantiated by a large series of controlled clinical trials and confirmatory meta-analyses. Both sulfasalazine and newer derivatives are effective in preventing relapses. It remains to be determined whether certain high-risk groups of patients may benefit from higher doses of mesalamine induction or maintenance therapy. Mesalamine derivatives are also of benefit in the treatment of Crohn's disease. Sulfasalazine is likely not effective in the maintenance of Crohn's disease, although other mesalamine formulations continue to show some prophylactic activity after mesalamine induced remissions and for patients with disease of the ileum who have undergone surgical resection.

Hanauer SB. · Department of Medicine and Clinical Pharmacology, Section of Gastroenterology and Nutrition, University of Chicago, Illinois 60637, USA. · Gastroenterology. · Pubmed #15168369 No free full text.

Abstract: There continue to be evolutionary changes in the management of ulcerative colitis despite the fact that, aside from a variety of aminosalicylate formulations, no new therapies have been approved over the past few decades. Nevertheless, debates continue regarding the optimization of treatment with aminosalicylates and the short- and long-term benefits of immunomodulation in ulcerative colitis. This article focuses on the most recent clinical studies pertaining to the management of ulcerative colitis and explores both the advances and controversies pertaining to aminosalicylate therapy, corticosteroids, cyclosporine, and the purine antimetabolites. Novel therapeutic approaches--including preliminary experience with biological therapies directed at tumor necrosis factor and other cytokines, adhesion molecules, growth factors, and probiotics--will be reviewed. Recent data regarding potential chemoprevention in long-standing ulcerative colitis and management of postoperative complications and pouchitis will also be discussed.

Hanauer SB, Present DH. · Section of Gastroenterology and Nutrition, University of Chicago, Pritzker School of Medicine, Chicago, IL, USA. · Rev Gastroenterol Disord. · Pubmed #12776005 No free full text.

Abstract: Ulcerative colitis (UC) and Crohn's disease (CD), collectively known as inflammatory bowel disease (IBD), afflict an estimated one million Americans and produce symptoms that impair quality of life and ability to function. Progress in IBD management strategies has led to optimized approaches for achieving the two primary clinical goals of therapy: induction and maintenance of remission. Although surgery is indicated to treat refractory disease or specific complications, pharmacotherapy is the cornerstone of IBD management. The efficacy of aminosalicylates for induction of remission in mild to moderate UC and CD is well established, as is their role for maintenance of remission in UC. The sulfa-free mesalamine formulation offers an adverse effect profile similar to that of placebo, enabling the administration of higher, more effective doses. Although corticosteroids provide potent anti-inflammatory effects, their benefits are countermanded by the risk of intolerable and serious adverse effects, and they are ineffective for maintenance therapy. Other agents effective in inducing or maintaining remission are azathioprine, 6-mercaptopurine, infliximab, cyclosporine, methotrexate, and antibiotics. Ongoing clinical trials of experimental therapies will generate new tools for IBD treatment. Currently, a broad range of options allows physicians to tailor treatment to each patient's needs and preferences. Such considerations are essential for maximizing adherence to therapy.

Sandborn WJ, Hanauer SB. · Division of Gastroenterology and Hepatology, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA. · Aliment Pharmacol Ther. · Pubmed #12492730 links to  free full text

Abstract: AIM: : To quantify through systematic review the pharmacokinetic profiles of the oral delayed release and sustained release mesalazine (5-aminosalicylate, 5ASA) formulations (Asacol, Salofalk, Mesasal, Claversal, Pentasa) and pro-drugs (sulfasalazine, olsalazine, balsalazide) used in the management of ulcerative colitis. METHODS: : Selected articles had: (1) adult healthy volunteers or patients with ulcerative colitis and (2) quantification of pharmacokinetic data to include, at a minimum, urinary excretion of total 5ASA [5ASA plus N-Acetyl-5ASA (N-Ac-5ASA)]. DATA COLLECTION AND ANALYSIS: : Pharmacokinetic data (Tmax, Cmax, AUC, urinary excretion, faecal excretion) of 5ASA, its major metabolite N-Acetyl-5ASA, total 5ASA, and the parent pro-drug compounds was extracted. MAIN RESULTS: : The summary results for urinary excretion of total 5ASA over 24-96 h in all subjects (either mean or median) were: sulfasalazine mean 11-33% or median 22%; olsalazine mean 14-31% or median 16-27%; balsalazide mean 12-35% or median 20%; Asacol mean 10-35% or median 18-40%; Pentasa mean 15-53% or median 23-34%; Salofalk, Mesasal and Claversal mean 27-56% or median 31-44%. The summary results for faecal excretion of total 5ASA over 24-96 h in all subjects (either mean or median) were: sulfasalazine mean 23-75% or median 38%; olsalazine mean 47-50% or median 17-36%; balsalazide mean 46% or median 22%; Asacol mean 40-64% or median 20-56%; Pentasa mean 12-51% or median 39-59%; Salofalk, Mesasal and Claversal mean 37-44% or median 23-35%. CONCLUSIONS: : The systemic exposure to 5ASA, as measured by urinary excretion of total 5ASA, and the faecal excretion of total 5ASA is comparable for all oral mesalazine formulations and pro-drugs. Thus, selection of a mesalazine therapy for the treatment of ulcerative colitis should be based on other factors such as efficacy, dose-response, toxicity of the parent compound and its metabolites, compliance issues related to dose forms and dosing schedules, and costs.

Hanauer SB. · Section of Gastroenterology and Nutrition, University of Chicago, Pritzker School of Medicine, Chicago, IL, USA. · Rev Gastroenterol Disord. · Pubmed #12120183 No free full text.

Abstract: Significant advances have been made regarding our understanding of the etiopathogenesis of inflammatory bowel disease. This review focuses on the most recent applications of medical therapy for ulcerative colitis. Therapeutic approaches continue to evolve regarding inductive and maintenance strategies with oral and topical aminosalicylates, systemic and non-systemic corticosteroids, and cyclosporine and alternative immunomodulators. As further investigations continue to discern microbiological and immunoinflammatory targets, future therapies may include both probiotics and novel biological agents.

Hanauer SB, Dassopoulos T. · Department of Medicine, Section of Gastroenterology, University of Chicago, Chicago, Illinois, USA. · Annu Rev Med. · Pubmed #11160781 No free full text.

Abstract: Crohn's disease and ulcerative colitis are idiopathic inflammatory bowel diseases characterized by dysregulated intestinal immune responses in genetically susceptible hosts. Conventional approaches to the medical therapy of ulcerative colitis and Crohn's disease can now be directed at either induction or maintenance of remission to improve therapeutic efficacy while minimizing complications. Newer approaches have expanded the utility of conventional therapies by improving both safety and efficacy and highlight the importance of specific targets along the immunoinflammatory pathways. The combination of conventional and novel approaches now offers the potential of modifying the natural history of these diseases.

Stein RB, Hanauer SB. · Department of Medicine, University of Pennsylvania School of Medicine, Philadelphia, USA. · Drug Saf. · Pubmed #11085348 No free full text.

Abstract: 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-or has been well tolerated in clinical trials and early postmarketing experience. Additional trials are needed to assess long term adverse effects.

Rubin DT, Hanauer SB. · Section of Gastroenterology, The University of Chicago Hospitals, Illinois, USA. · Eur J Gastroenterol Hepatol. · Pubmed #10958212 No free full text.

Abstract: It is well established that smoking cigarettes is associated with Crohn's disease (CD) and that non-smoking is associated with ulcerative colitis (UC). Furthermore, there is convincing evidence that smoking cigarettes has a negative effect on the course of CD, and that smoking cigarettes may improve the disease severity or have a 'protective' effect in some patients with UC. Despite these well-described associations, the mechanism by which cigarette smoking affects CD and UC is not known. Researchers have studied the systemic effects, cellular and humoral immune effects, mucosal changes, and the intestinal permeability changes with inflammatory bowel disease (IBD) and smoking. To date, none of these studies adequately explains the observed clinical patterns. It has been assumed that nicotine is the active agent in these associations, but clinical trials of nicotine chewing gum and transdermal nicotine in UC have shown limited benefit, and have been complicated by significant side-effects. Topical delivery systems for nicotine therapy are currently under development and await future clinical trials.

Stein RB, Hanauer SB. · Department of Medicine, University of Pennsylvania School of Medicine, Philadelphia, USA. · Gastroenterol Clin North Am. · Pubmed #10372270 No free full text.

Abstract: CD and UC represent a spectrum of chronic IBD that present in protean ways and are accompanied by a variety of systemic sequelae. Sulfasalazine and the newer 5-aminosalicylates are important in the management of mild-to-moderate disease, whereas corticosteroids remain the primary therapy for most patients with moderate-to-severe disease (Tables 2-5). The toxicities associated with long-term steroid therapy, combined with their ineffectiveness as maintenance medications, have led to increased use of immunomodulators, such as azathioprine and 6-MP, for the treatment of steroid-dependent and steroid-resistant IBD. Infliximab is a novel therapeutic adjunct for chronically active and fistulizing CD that will herald a new era of biologic therapy for IBD. Meanwhile, CSA remains an alternative to urgent colectomy in severe UC unresponsive to corticosteroids and also for CD patients with severe disease or refractory fistulas. Finally, continued insights into the etiopathogenic pathways in IBD will provide evolving and innovative approaches until the eventual causes and cures are elucidated. In the meantime, clinicians should remain optimistic regarding current ability to reduce the morbidity and maintain the quality of life for patients suffering with these frustrating diseases.

Sandborn WJ, Hanauer SB. · Inflammatory Bowel Disease Clinic, Mayo Clinic and Mayo Foundation, Rochester, Minnesota 55905, USA. · Inflamm Bowel Dis. · Pubmed #10338381 No free full text.

Abstract: Tumor necrosis factor-alpha (TNFalpha), a proinflammatory cytokine, plays an important role in the pathogenesis of inflammatory bowel disease (IBD). Biotechnology agents including a chimeric monoclonal anti-TNF antibody (infliximab), a humanized monoclonal anti-TNF antibody (CDP571), and a recombinant TNF receptor fusion protein (etanercept) have been used to inhibit TNFalpha activity. Controlled trials have demonstrated efficacy for infliximab in moderately to severely active Crohn's disease (CD) and fistulizing CD sufficient to justify recent U.S. Food and Drug Administration (FDA) approval. Additional trials have been completed in rheumatoid arthritis (RA). Similarly, preliminary controlled trials have suggested efficacy for CDP571 in active CD and RA. Larger controlled trials have demonstrated efficacy for etanercept in RA patients who have failed disease modifying antirheumatic drug (DMARD) therapy leading to FDA approval for RA. Toxicities observed with anti-TNF therapies have included formation of human antichimeric antibodies (HACA) with associated acute and delayed hypersensitivity infusion reactions, human antihuman antibodies (HAHAs), and formation of autoantibodies with rare instances of drug-induced lupus. Several cases of non-Hodgkin's lymphoma also has been described. Future studies should evaluate optimal timing and duration of anti-TNF therapy, the utility of adjuvant medical treatments during anti-TNF therapy, and evaluate long-term safety and efficacy of the various anti-TNF agents.