Maintenance drugs for inflammatory bowel disease

Ulcerative colitis and Crohn's disease are chronic relapsing inflammatory disorders of the bowel that affect 2-4 per 1,000 people in Northern Europe. The course of these diseases is difficult to predict and relapses can occur many years after presentation. Various drugs (and/or surgery in Crohn's disease) are used to induce remission, and maintenance drug therapy is commonly given to prevent relapse once remission is achieved. Here, we consider maintenance drug treatment, in particular the size and duration of benefit and potential short-term and long-term risks associated with such therapy.     

Nonsteroidal anti-inflammatory drugs and inflammatory bowel disease: current perspectives.

Mechanisms underlying the gastric toxicity of nonsteroidal anti-inflammatory drugs (NSAIDs) have been extensively investigated, whereas those leading to intestinal damage are not completely understood. Several hypotheses have been put forward on the pathophysiology of intestinal damage by NSAIDs: enhanced intestinal permeability, inhibition of cyclooxygenase (COX), enterohepatic recirculation, and formation of adducts. The effects of COX-2 selective inhibitors, which appear to have better gastric tolerability when compared to nonselective NSAIDs, on normal and inflamed intestinal mucosa (as in Crohn's disease or ulcerative colitis) are still largely unexplored. If COX-2 inhibition plays a key role in suppressing the inflammatory process, recent evidence suggests that COX-2 products are involved in maintaining the integrity of intestinal mucosa, in the healing of gastrointestinal ulcers and in the modulation of inflammatory bowel disease (IBD). Animal models of intestinal inflammation have so far yielded conflicting results on the effects of COX-2 selective inhibitors on the intestinal mucosa. It is now clear that NSAIDs do not act through cyclooxygenase inhibition, but also have different targets such as nuclear factor-kappaB and/or peroxisome proliferator-activated receptors gamma. The peculiar pharmacological profile of each compound may help to explain the different impact of each NSAID on the inflammatory process and on IBD. Notably, the salicylic acid derivative 5-ASA is widely used in the treatment of IBD and is believed to act through nuclear factor-kappaB inhibition. Although the use of COX-2 selective inhibitors remains contraindicated in patients with IBD, studying their effects on intestinal mucosa may offer new insights into their subcellulars mechanisms of action and open new avenues for the development of novel therapies for IBD.     

Review article: biological activity markers in inflammatory bowel disease

BACKGROUND: Traditionally, inflammatory bowel disease activity is assessed by clinical activity indices that measure clinical symptoms and endoscopic indices that measure endoscopic inflammation. Biological markers are a non-invasive way of objectively measuring inflammation and can play an adjunctive or primary role in the assessment of disease activity. AIM: To review the data on biological markers for assessment of disease activity and prediction of relapse in inflammatory bowel disease. METHODS: To collect relevant articles, a PubMed search was performed from 1980 to 2006 using following search terms in combination: inflammatory bowel disease, biomarkers, inflammation, disease activity, relapse, acute phase reactants cytokines, interleukins, adhesion molecules, integrins, calprotectin and lactoferrin. RESULTS: Biological activity markers can be classified into serological, faecal and miscellaneous categories. Acute phase reactants levels correlate with disease activity and some can be used to help predict relapse. Cytokines and adhesion molecules are elevated in active disease inconsistently. Faecal markers are useful in assessment of disease activity and relapse. CONCLUSIONS: Acute phase reactants and faecal markers are useful to assess the disease activity in clinical practice. More data are required on cytokines and adhesion molecules. C-reactive protein, erythrocyte sedimentation rate, interleukins and faecal markers may be useful in predicting a relapse.     

Phosphodiesterase 4 inhibitors and inflammatory bowel disease: emerging therapies in inflammatory bowel disease

Crohn's disease and ulcerative colitis (UC) are common, chronic inflammatory bowel diseases (IBDs) characterized by episodes of life-altering symptoms such as diarrhea, bleeding, fecal urgency and incontinence, abdominal pain and cramps, and fever lasting weeks to months at a time. Existing treatments are 5-aminosalicyclates or immunosuppressants, but long-term control of IBD is a major problem for a large number of patients. Phosphodiesterase 4 (PDE4) is a key enzyme in cell homeostasis and inflammation and its inhibition has been useful in diseases such as asthma and chronic obstructive pulmonary disease, rheumatoid arthritis and multiple sclerosis. This review focuses on the role of oxidative stress in IBD and the PDE4 inhibitor OPC-6535 (tetomilast), an investigational agent for the treatment of UC. The authors detail the clinical development of the compound and report and provide insight into some of the unpublished data from the recently completed multicenter Phase III trials in UC.     

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.     

Potentiating effects of cigarette smoking on experi mental inflammatory bowel disease

AIM: Epidemiological and clinical reports have indicated a closerelationship between cigarette smoking and inflammatory boweldisease (IBD), such as the Crohn's disease (CD). We usedexperimental CD and cigarette smoking models to study theunderlying mechamisms. METHODS: Male SD rats wereexposed to cigarette smoke (0 ％, 2 ％, or 4 ％, Vol/vol ) givenonce daily for 1-h period for 4 d. Experimental CD was inducedby 2, 4,6-trinitrobenzene sulfonic acid (TNBS)-ethanol enema.     

Newer 5-aminosalicylic acid based drugs in chronic inflammatory bowel disease

Since the discovery that 5-aminosalicylic acid (5-ASA) is the active moiety of sulphasalazine in the treatment of chronic inflammatory bowel disease, several new 5-ASA based drugs have been developed. These consist either of slow- or delayed-release formulations of plain 5-ASA or sulpha-free azo compounds of 5-ASA. The different formulations and compounds have varying bioavailabilities, which makes it possible to use them alternatively in different clinical situations. A review of the literature is given, together with suggestions as to how the new drugs might be used in different clinical situations.     

QSAR methods for the discovery of new inflammatory bowel disease drugs

Introduction: Inflammatory bowel disease (IBD) represents an important class of chronic gastrointestinal tract disease. And although there are already several useful treatments to reduce and control the symptoms, there is still no cure. One drug discovery technique used is the computer-aided (in silico) discovery approach which has largely demonstrated efficacy. Computational techniques, when used in combination with traditional drug discovery methodology, greatly increase the chance of drug discovery in a sustainable and economical fashion.

Areas covered: This review aims to provide the most recent and important advances of in silico IBD drug discovery. While this review is mainly focused on QSAR methods, especially those based on molecular topology (MT), additional topics, such as docking or comparative field analysis are also addressed.

Expert opinion: IBD is a worldwide growing health concern that can only be currently treated in symptomatic and palliative way; thus, the search for new drugs is imperative. Computer-aided methods, which focus on the drug–receptor interaction, are essential tool in this regard. It is noted, however that a major problem is that although there are many known receptors associated with IBD, none of these have yet been found essential. The use of other approaches, including QSAR methodology, is certainly a complementary and attractive alternative; especially QSAR methods based on MT, which has proven successful in other drug discovery.     

Thiopurine methyltransferase activity and the use of azathioprine in inflammatory bowel disease

BACKGROUND: Azathioprine therapy is discontinued in one-third of patients with inflammatory bowel disease because of toxicity or a lack of clinical response. Patients with thiopurine methyltransferase (TPMT) deficiency are intolerant to azathioprine, whilst carriers are at increased risk of side-effects. AIM: To evaluate the importance of TPMT activity in the management of azathioprine therapy in inflammatory bowel disease. METHODS: Clinical response, adverse effects and haematological parameters were determined and correlated with TPMT enzyme activity and genotype in 106 patients with inflammatory bowel disease. RESULTS: Ninety-six patients had high TPMT activity, and 10 had intermediate activity. Nineteen patients (18%) were intolerant to azathioprine. Fifteen (16%) of those with high TPMT activity were intolerant, compared with five (50%) with intermediate activity [odds ratio (OR), 5.4; 95% confidence interval (CI), 1.5-19.8]. Complete remission was achieved in 63% of cases, and complete or partial remission in 79%. Interestingly, very high TPMT activity (> 14 units/mL red blood cells) was significantly associated with non-response, irrespective of the time on azathioprine (OR, 0.21; 95% CI, 0.07-0.68). TPMT gene mutations correlated with TPMT activity. CONCLUSIONS: Inflammatory bowel disease patients with intermediate TPMT activity have an increased risk of azathioprine toxicity. Conversely, very high TPMT activity predicts treatment failure. TPMT genotype predicted TPMT phenotype in this study.     

Risk-benefit assessment of drugs used in the treatment of inflammatory bowel disease.

Although the aetiology of inflammatory bowel disease remains elusive, many agents are available for the control of symptoms and inflammation. Knowledge of drug pharmacology, indications and side effects is essential to ensure the best possible clinical care while minimising toxicity and inappropriate use. Sulfasalazine consists of sulfapyridine linked to mesalazine (5-aminosalicylic acid) via an azobond. Its use is indicated in the treatment of mild to moderately active ulcerative colitis and in the prevention of relapse in patients with quiescent disease. Patients with mild to moderate colonic or ileocolonic Crohn's disease also benefit from this drug, as do a proportion of patients with isolated small bowel disease. Sulfasalazine has not been uniformly effective in preventing relapse in Crohn's disease, although many clinicians continue its use in patients who respond initially. A high incidence of side effects which limit therapy include intolerance, hypersensitivity reactions and impairment of male infertility. The newer aminosalicylates offer targeted delivery of mesalazine to the bowel, with fewer side effects. Topical mesalazine has proved extremely effective in patients with distal ulcerative colitis; oral forms are effective in the treatment of mild to moderately active ulcerative colitis and in relapse. Both types appear to be effective in the treatment of Crohn's disease, and possibly in preventing relapse. There is no current clinical advantage of one mesalazine preparation over another, nor is there an indication for their use in sulfasalazine-treated patients who have satisfactory response without adverse effects. Corticosteroids are indicated for more severe disease activity where the aminosalicylates have limited efficacy-specifically to induce remission in patients with severe or refractory ulcerative colitis or Crohn's disease. They should not be used to maintain disease remission or in the prevention of postoperative recurrence. Topical corticosteroids allow their local use in distal colitis with minimal systemic side effects. Long term use is limited by side effects, many of which are dose related, although alternate-day therapy may lessen the incidence. Immunosuppressive agents are beneficial for the treatment of refractory inflammatory bowel disease unresponsive to other medications, and may also facilitate the withdrawal of steroids in refractory patients. Mercaptopurine has an added benefit in the treatment of Crohn's disease fistulae; the role of cyclosporin in bowel disease has not been established and its use cannot currently be recommended. The potential toxicity of immunosuppressive agents warrants careful consideration of their use by both physician and patient. Metronidazole is indicated for the treatment of mild to moderate Crohn's disease, including perineal disease. Common side effects include peripheral neuropathy and nausea.(ABSTRACT TRUNCATED AT 400 WORDS)     

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: faecal markers in the assessment of activity in inflammatory bowel disease

The fundamental pathological process behind ulcerative colitis and Crohn's disease is intestinal inflammation. As the precise cause of this is not yet completely understood, current treatment strategies are aimed at reducing or eliminating the inflammation. Endoscopic examination and histological analysis of biopsy specimens remain the 'gold standard' methods for detecting and quantifying bowel inflammation; however, these techniques are costly, invasive, and repeated examinations are unpopular with patients. Disease activity questionnaires and laboratory 'inflammatory markers', although widely used, show an unreliable correlation with endoscopy and histology. New markers need to be developed to detect and quantify bowel inflammation. These would be of use diagnostically and also an aid to pharmacological treatment.     

Cancer in inflammatory bowel disease

The first case of cancer in inflammatory bowel disease (IBD) was reported at The Mount Sinai Hospital in 1925 in a patient with ulcerative colitis (UC). In 1956, carcinoma of the jejunum was described in a patient with regional enteritis (Crohn's disease [CD]). IBD cancers are preceded by dysplasia, and the relative risk increases with duration of the IBD. CD cancers are more proximally distributed than are UC cancers. Both tend to occur at the site of the overt disease and both develop at earlier ages (47 UC, 50 CD) than in the de novo colorectal cancer (70 years). The absolute cumulative colon cancer frequencies (8% UC, 7% CD) are identical after 20 years, emphasizing the importance of regular surveillance in both types of IBD. Moreover, the increased risk of colon cancer exists in patients with CD even when CD is confined to the small bowel, and patients with IBD have increased risks of developing extraintestinal and reticuloendothelial tumors in both CD and UC, as well as ano-vulval and malignant melanoma in CD. Colitic colorectal cancers are often diffuse, extensive, multiple and right-sided with insidious presentation. The prognosis is no worse after operation than that of de novo colon cancer. Most small bowel cancers in CD are adenocarcinomas, rather than sarcomas, and present at a younger age, more diffusely and more distally than de novo cancers, usually making them undiagnosable at a curable early stage; indeed, two-thirds present with intestinal obstruction. Strictures of the colon are common in patients with IBD, and they have a 10-fold risk for colon cancer, 30-fold for UC, and 6-fold for CD. The risk increases with disease duration. The indications for surgery are absolute, relative and incidental, and the procedures include segmental resection, total proctocolectomy, subtotal colectomy and palliative procedures.     

Macrophages in inflammatory bowel disease

Blood monocytes which differentiate into tissue macrophages, are unique in that they can not only initiate immune responses but can also be effector cells which contribute to the resolution of these responses. There is no single activation phenotype, and macrophages can be induced to differentiate into cells that either exacerbate or inhibit acute inflammation. Similarly, these cells can promote, deviate or suppress adaptive immune responses. This review focuses on the mechanisms that have been implicated in the recruitment, activation and differentiation of inflammatory monocytes/macrophages in chronic inflammatory bowel diseases, i.e. ulcerative colitis and Crohn's disease. These mechanisms might provide attractive targets for novel therapies.