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BREAKTHROUGHS IN THE MANAGEMENT OF INFLAMMATORY BOWEL DISEASE
N H Banka
Consultant Gastroenterologist and Hepatologist, Bombay Hospital and Medical Research Centre, Formerly, Consultant gastroenterologist at Sir JJ Group of hospitals and Grant Medical College, Sir Hurkisondas Hospital and Nanavati Hospital.
Breakthroughs in newly developed agents have included not only new compounds and modes of delivery, but also entirely novel therapeutic modalities. Biologic therapies have begun to assume prominent role. Clinical observations, pilot studies and extrapolation of results from other Immuno-inflammatory diseases (Rheumatoid arthritis), provide important insights into mechanism of risk benefit, action and sample size estimates for the design and implementation of controlled trials. This is true for inflammatory bowel disease (IBD) where a constant flow of breakthroughs are reaching the professional and layman journals. However, even with the advent of regulatory approval of new treatments, such as Infliximab, the evidence base may be insufficient to predict the eventual optimisation of treatment strategies until years after the agents availability in the market.Aminosalicylates
The only "new" aminosalicylate is Balsalazide, which is a pro-drug. In recent trials this molecule has comparable efficacy and safety to mesalamine in the induction and maintenance of remission for ulcerative colitis.
Corticosteroids
Budesonide is marketed in different countries for the treatment of IBD. Potential therapeutic advantage over systemic steroids include a) an increased binding potency for the glucocoticoid receptor and b) increased "first-pass" hepatic metabolism. This drug can also be used to reach specific sites in the form of targeted delivery. The therapeutic efficacy has been similar to other steroids without inhibition of the hypothalamus-pituitary-adrenal axis. Budesonide enemas are not as efficacious as topical mesalamine.
Immunomodulators
Niether azathioprine nor mercaptopurine is considered a new therapy for IBD. Important and practical aspects of their usage remains to be defined in ulcerative colitis (UC) and Crohn's disease (CD). It could prove to be efficacious drug with initial steroid therapy and concurrent treatment with aminosalicylates.
A recent, small trial has suggested that intravenous cyclosporin without steroids may be efficacious for acute UC. Long term immunomodulation is beneficial after acute cyclosporin therapy with azathioprine. Other oral agents such as tacrolimus also have been evaluated in preliminary trials of UC and CD but controlled data is lacking.
Mycophenolate has also been studied but requires additional studies of safety and efficacy before it can be considered a standard approach.
Biologics
The introduction of infliximab into the US marketplace has been the first real advance for the treatment of IBD since the general acceptance of immunomodulation. Three controlled trials have set the expectations for these new therapies andpredict the eventual utility of infliximab. There was excellent efficacy for refractory disease but a gradual decline in efficacy over the ensuing 12 month period, particularly in patients who did not receive re-treatment. Similar results were obtained in fistulising CD.
Tight on the heals of infliximab are other anti-TNF strategies as an humanised version of a monoclonal anti-TNF (CDP571) and the potential use of eternacept, humanised soluble receptors for TNF. Most recently, thalidomide has also been explored in early trials for CD with optimistic reports of efficacy.
Molecular engineered formulations of human recombinant interleukin-10 and interleukin-11 have entered clinical trials in IBD as have anti-sense compounds targeting inhibition of adhesion molecules (ICAM-1). It is anticipated that monoclonal antibody and anti-sense technologies will continue to assess specific mediators such as NF kappa, gamma-interferon and interleukin-12. Evolving methods of influencing cytokine production and regulation, including the use of viral vectors are presently on the horizon.
Nicotine
The protective role of cigarette smoking against the development of UC has led to trials utilising nicotine as adjunctive therapy. A series of trials using nicotine patches has supported a role for nicotine therapy in the symptomatic management of UC. At present nicotine should not be used as a proven therapy for UC but may be considered in the patients whose UC aggravated after smoking cessation.
Short Chain Fatty Acids
Short chain fatty acids enhance the colonocyte-nutrient oxidation, thus improving the ongoing colonocyte dysfunction. It has been used as mixed SCFD or butyrate as enematas in distal UC. While in most studies there was a positive benefit, the overall response rate is not substantially different from placebo. At the present time this mode of therapy cannot be advocated for the routine management of UC.
Fish Oil, Omega-3 fatty Acids and Leukotriene Inhibitors
Trials involving omega-3 fatty acids were performed in the early and mid-1990s for refractory UC or as maintenance therapy. In these trials the clinical benefit was modest, at best, and these therapies have not been accepted within the current practice guidelines for UC. The development of an enteric coated fish oil preparation, recently effective in a Crohn's disease maintenance trial, may eventually offer an alternative therapeutic option in IBD.
The potential role of inhibition of 5-lipoxygenase and leukotriene B4 led to development of specific 5-lipoxygenase inhibitors. However, in contrast to asthma, specific inhibition of a distal mediator of inflammation has failed to provide adequate therapy for either active UC or prevention of relapse.
Heparin
Observations regarding a "paradoxical" improvement in colitis with heparin therapy and improvement in extraintestinal manifestations of IBD have led to the possibility that heparin may have a therapeutic role in IBD. While heparin does appear to be safe in the setting of UC it remains to be determined where heparin therapy will fall in the armamentarium for IBD and whether the new developments in low molecular weight heparin will provide similar therapeutic potential.
Probiotics
An intriguing area of therapy has been the potential for probiotic therapy for IBD. Recent european trials have begun to suggest efficacy for probiotic therapy for UC and CD. We anxiouslyawait further evidence for this expanding alternative approach.
Challenges in the field of IBD is not only identifying the novel agents, but also defining the end points and identifying the efficacy at the biologic level. Clinicians are only just beginning to recognize subclinical markers of response. Looking back at successes and failures in newer breakthroughs to treating IBD, it may be tempting, although extremely difficult to draw conclusions about pathogenesis. Even with a therapy as specific as anti-TNF antibody, it is not clear if the benefit is simple binding and clearing or deletion of the activated macrophage. Thus, when a therapy proves effective, do clinicians truly know how it works? In this context it is the write time to remember Sir William Osler's saying -"I always use the newest medicine first, Before its effectiveness wears off".
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