Thrornboxanes in inflammatory bowel disease—pathogenic and therapeutic implications

Recent work suggests that thromboxanes may play a major pathogenic role in inflammatory bowel disease. Thromboxanes are produced in excess not only in inflamed mucosa but also in Crohn's disease, by uninflamed bowel and by isolated intestinal and peripheral blood mononuclear cells. Their cellular source is likely to include platelets, neutrophils, endothelial and epithelial cells as well as mononuclear cells, possible stimuli to their overproduction being chemotactic peptides, lipopolysaccharide, leucotrienes, platelet activating factor, interleukin-1, bradykinin and angiotensin II . The pro-inflammatory effects of thromboxanes are both direct (diapedesis and activation of neutrophils, mucosal ulceration, reduction of suppressor T-cell activity) and indirect (vasoconstriction, platelet activation). Although corticosteroids and aminosalicylates inhibit thromboxane synthesis, this action does not necessarily explain their therapeutic effect in inflammatory bowel disease. Selective thromboxane synthesis inhibitors and receptor antagonists, however, ameliorate experimental colitis in animals. Picotamide and ridogrel are dual thromboxane pathway blockers already used in man. Drugs of this type could prove useful not only for the prevention of systemic thrombo-embolism but also for suppressing intestinal mucosal inflammation in patients with inflammatory bowel disease.     

Review article: helminths as therapeutic agents for inflammatory bowel disease

Over the last decade major advances have been made in our understanding of the mechanisms and mediators of inflammation that hold the promise of the development of new therapies for inflammatory disease. While much is to be gleaned from the application of new technologies, assessment of the age-old host-parasite relationship may also provide insights on how to counter pathological inflammatory events. In the case of inflammatory bowel disease [particularly Crohn's disease, which is associated with T helper 1 (Th1) events] it is proposed that infection with parasitic helminths would be beneficial: the paradigm being that of immune deviation, where Th2 cytokines mobilized in response to the helminth will prevent or antagonize the disease-promoting Th1 events in the gut. The situation is unlikely to be this simple. Here we review and critique the data in support of helminth therapy for inflammatory bowel disease, drawing attention to the gaps in knowledge and presenting a view on how the field may be advanced. While the concept of helminth therapy may be superficially unappealing, this review may convince the reader of the value of more extensive analyses of the impact of helminth infection on enteric inflammation.     

Review article: steroid resistance in inflammatory bowel disease - mechanisms and therapeutic strategies

BACKGROUND: Steroid resistance in inflammatory bowel disease presents a difficult clinical challenge. The advent of biological therapies coupled with an increasing understanding of the pathogenesis of inflammatory bowel disease has provided new therapeutic options. METHODS: We review the available literature of the mechanisms behind steroid resistance. In addition, we outline some of the options available for treating those patients who fail to respond adequately to glucocorticoids. RESULTS: Approximately 30% of patients prescribed glucocorticoids will not achieve clinical remission. Many such patients are offered immunosuppressive or, recently, biological agents. However, these agents are ineffective in a large proportion of patients. Immunosuppressive agents only bring 40-60% of patients into remission, and biological agents typically induce remission in just 40% of patients. In this review, the possible explanations for glucocorticoid resistance are discussed. Recent evidence suggests that in many patients it is mediated by interleukin-2. Basiliximab, a biological agent that interrupts interleukin-2 signalling, has shown significant benefit in early clinical studies. CONCLUSIONS: Patients who fail to respond to steroid therapy should have alternative agents introduced in a timely fashion. Steroid refractory inflammatory bowel disease remains a difficult condition to treat, but new therapies and managements are emerging.     

Review article: Osteoporosis and inflammatory bowel disease

Studies using dual-energy X-ray absorptiometry have suggested a high prevalence of osteoporosis in inflammatory bowel disease. However, population-based data on fracture incidence suggest only a small increased risk of fracture amongst patients with inflammatory bowel disease compared with the general population. Therefore, it would be helpful to identify patients with inflammatory bowel disease at particularly high risk for fracture so that these risks might be modified or interventions might be undertaken. The data on calcium intake as a predictor of bone mineral density are conflicting. Although there are data suggesting that a one-time survey to determine current calcium intake will not help to predict bone mineral density in inflammatory bowel disease, persistently reduced calcium intake does appear to lead to lower bone mineral density. In the general population, body mass is strongly correlated with bone mineral density, which also appears to be true in Crohn's disease. Hence, subjects with inflammatory bowel disease and considerable weight loss, or who are obviously malnourished, could be considered for bone mineral density testing, and the finding of a low bone mineral density would suggest the need for more aggressive nutritional support. Although vitamin D is undoubtedly important in bone health, vitamin D intake and serum vitamin D levels do not correlate well with bone mineral density. Sex hormone deficiency can also adversely affect bone health, although a well-developed strategy for sex hormone measurements in patients with inflammatory bowel disease remains to be established. Ultimately, the determination of genetic mutations that accurately predict fracture susceptibility may be the best hope for developing a simplified strategy for managing bone health in inflammatory bowel disease. The therapy of osteoporosis in inflammatory bowel disease has been adapted from other osteoporosis settings, such as post-menopausal or corticosteroid-induced osteoporosis. To date, there remains no therapy proven to be efficacious in inflammatory bowel disease-related osteoporosis; however, calcium and vitamin D supplementation and bisphosphonates have their roles.     

Review article: aminosalicylates in inflammatory bowel disease

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.     

Review article: thiopurines in inflammatory bowel disease

BACKGROUND: In the past 10-20 years, knowledge of both thiopurine pharmacology and -pharmacogenetics has been extended dramatically and used to develop new strategies to improve efficacy and reduce toxicity. AIM: To review thiopurine efficacy, toxicity, pharmacology, pharmacogenetics, interactions in patients with inflammatory bowel disease. Special attention was paid to new strategies for optimization of pharmacotherapy. METHODS: To collect relevant scientific articles, a Pubmed search was performed from 1966 through January 2006 with the following key words (MeSH terms preferentially) in multiple combinations: 'azathioprine', '6-mercaptopurine', '6-MP', '6-thioguanine', '6-TG', 'thiopurine(s)', 'metabolites', 'level(s)', 'TDM', 'TMPT', 'ITPA', 'genotype(s)', 'phenotype(s)', 'inflammatory bowel disease', 'Crohn('s) disease', 'ulcerative colitis'. RESULTS: Strategies for optimization of pharmacotherapy include therapeutic drug monitoring of thiopurine metabolites, geno- or phenotyping crucial enzymes in thiopurine metabolism like thiopurine S-methyltransferase and inosine triphosphate pyrophosphatase, and the use of thioguanine as such. CONCLUSIONS: Thiopurine S-methyltransferase genotyping and therapeutic drug monitoring are useful instruments for individualizing thiopurine pharmacotherapy of inflammatory bowel disease. Inosine triphosphate pyrophosphatase genotyping may be helpful in case of unexplainable myelotoxicity. In case of azathioprine- or mercaptopurine-intolerance, thioguanine seems a promising alternative. However, more knowledge needs to be gathered about its potential hepatotoxicity.     

Review article: the role of non-biological drugs in refractory inflammatory bowel disease

Background Up to one‐third of patients with inflammatory bowel disease (IBD) do not respond to, or are intolerant of conventional immunosuppressive drugs. Although biological agents are alternative treatments, they may not be suitable or available to some patients. Aim To review the evidence for use of nonbiological drugs in the treatment of patients with IBD refractory to corticosteroids or thiopurines. Methods A literature search was performed using PubMed for English language publications with predetermined search criteria to identify relevant studies. Results Published evidence from uncontrolled series and controlled clinical trials has been used to produce a practical approach relevant to clinical practice which incorporates the indication, optimal dose, and side effects of various therapies including tacrolimus, methotrexate, thalidomide, tioguanine, mycophenolate mofotil, leucocyte apheresis, nutritional therapy, antibiotics, probiotics, allopurinol, rectal acetarsol and ciclosporin in the treatment of patients with refractory ulcerative colitis and Crohn’s disease. Approaches to optimise thiopurine efficacy are also discussed. Conclusions Patients with IBD refractory to corticosteroids or thiopurines may respond to alternative anti‐inflammatory chemical molecules, but the evidence base for many of these alternatives is limited and further trials are needed.     

Review article: bone disease in inflammatory bowel disease

Inflammatory bowel disease (IBD) is associated with an increased incidence of osteoporosis. Osteoporosis with osteoporotic pain syndromes, fragility fractures and osteonecrosis accounts for significant morbidity and impacts negatively on the quality of life. It is generally agreed that there is a need to increase awareness for inflammatory bowel disease-associated osteoporosis. However, the best ways in which to identify at-risk patients, the epidemiology of fractures and an evidence-based rational prevention strategy remain to be established. The overall prevalence of IBD-associated osteoporosis is 15%, with higher rates seen in older and underweight subjects. The incidence of fractures is about 1 per 100 patient years, with fracture rates dramatically increasing with age. While old age is a significant risk factor, disease type (Crohn's disease or ulcerative colitis) is not related to osteoporosis risk. Corticosteroid use is a major variable influencing IBD-associated bone loss; however, it is difficult to separate the effects of corticosteroids from those of disease activity. The recommendations in inflammatory bowel disease are similar to those for postmenopausal osteoporosis, with emphasis on lifestyle modification, vitamin D (400-800 IE daily) and calcium (1000-1500 mg daily) supplementation and hormone replacement therapy (oestrogens/selective oestrogen receptor modulators in women, testosterone in hypogonadal men). Bisphosphonates have been approved for patients with osteoporosis (T-score < 2.5), osteoporotic fragility fractures and patients receiving continuous steroid medication. Data on the recently Food and Drug Administration-approved osteoanabolic substance parathyroid hormone and on osteoprotegerin are promising in terms of both steroid-induced and inflammation-mediated osteoporosis, the key elements of inflammatory bowel disease-associated bone disease.     

Review article: topical corticosteroids in inflammatory bowel disease

It would be ideal to treat inflammatory bowel disease with topical corticosteroids that are either not absorbed through the mucosa, or have a substantial first-pass hepatic metabolism. The topical use of hydrocortisone, prednisolone-21-phosphate or betamethasone is often associated with systemic side-effects. Newer corticosteroid preparations (prednisolone metasulphobenzoate, tixocortol pivalate, fluticasone propionate, beclomethasone dipropionate and budesonide) are usually associated with minimal systemic corticosteroid activity. This article reviews the clinical activity and safety of these newer preparations.     

Review article: nutrition and adult inflammatory bowel disease

Major advances in the understanding of the aetio-pathogenesis and genetics of inflammatory bowel disease have been accompanied by an escalation in the sophistication of immunomodulatory inflammatory bowel disease therapeutics. However, the basic 'triple' therapy (5-aminosalicylates, corticosteroids, azathioprine) and nutrition have maintained their central role in the management of patients with inflammatory bowel disease over recent decades. This review provides an overview of the supportive and therapeutic perspectives of nutrition in adult inflammatory bowel disease. The objective of supportive nutrition is to correct malnutrition in terms of calorie intake or specific macro- or micronutrients. Of particular clinical relevance is deficiency in calcium, vitamin D, folate, vitamin B12 and zinc. There is justifiably a growing sense of unease amongst clinicians and patients with regard to the long-term use of corticosteroids in inflammatory bowel disease. This, rather than arguments about efficacy, should be the catalyst for revisiting the use of enteral nutrition as primary treatment in Crohn's disease. Treatment failure is usually related to a failure to comply with enteral nutrition. Potential factors that militate against successful completion of enteral nutrition are feed palatability, inability to stay on a solid-free diet for weeks, social inconvenience and transient feed-related adverse reactions. Actions that can be taken to improve treatment outcome include the provision of good support from dietitians and clinicians for the duration of treatment and the subsequent 'weaning' period. There is evidence to support a gradual return to a normal diet through exclusion-re-introduction or other dietary regimen following the completion of enteral nutrition to increase remission rates. We also review the evidence for emerging therapies, such as glutamine, growth factors and short-chain fatty acids. The future may see the evolution of enteral nutrition into an important therapeutic strategy, and the design of a 'Crohn's disease-specific formulation' that is individually tailored, acceptable to patients, cost-effective, free from adverse side-effects and combines enteral nutrition with novel pre- and pro-biotics and other factors.