Current Treatment

Despite the introduction of anti-TNF-a antagonist therapies, such as Remicade/infliximab for steroid refractory and fistulating CD, the treatment of IBD has not substantially changed in the last decades (Table 3). Front-line therapy in the management of patients with mild-to-moderate UC and CD, and as a maintenance therapy to prevent disease relapse in UC, are the 5-ASAs (e.g., mesalazine, sulfasalazine, and olsalazine). The 5-ASAs appear to exert their anti-inflammatory activity by inhibiting activation of NFkB. For disease in the distal bowel, multiple delayed and sustained release formulations, as well as prodrugs such as olsalazine, have been designed to release the majority of an oral dose directly in the distal ileum/colon, thus preventing topical exposure in the proximal small intestine. For rectal disease, rectal foams are also administered. The most recently introduced prodrug, balsalazide (1), contains azo bonds that are cleaved by colonic bacterial azo-reductases and release the active 5-ASA mesalazine locally.

Although mild disease can be treated successfully with 5-ASAs, many patients eventually require corticosteroids to control symptoms. Oral glucocorticoids (e.g., prednisolone) are some of the most effective therapies for inducing clinical remission in patients with active CD and UC. However, the adverse effects (including obesity, osteoporosis, hypertension, and adrenal suppression) of chronic corticosteroid treatment are both extremely undesirable and invariably culminate in the development of clinically challenging, steroid-refractory disease. Budesonide (2) is a highly effective second-generation oral corticosteroid, but was engineered with metabolic vulnerability, to enable a topical mode of action coupled with extensive first-pass metabolism and low systemic exposure. Despite this potential improvement in safety burden for this class of agents, approximately 30% of patients will also be unable to discontinue steroid therapy without disease exacerbation, and approximately 20% will become steroid resistant or will not respond to steroids.

Table 3 Standard treatment options for active inflammatory bowel disease

Active disease

CD treatment

Active disease

UC treatment

Mild-moderate Oral aminosalicylate Metronidazole Oral corticosteroids

Azathioprine or 6-mercaptopurine (6-MP) Severe Oral or intravenous corticosteroids

Intravenous Remicade/infliximab

Fistulating Metronidazole or antibiotic therapy

Intravenous Remicade/infliximab Azathioprine or 6-MP Maintenance Oral aminosalicylate Metronidazole Methotrexate Azathioprine or 6-MP

Mild-moderate Distal

Extensive colitis Moderate-severe Distal

Extensive colitis Severe or fulminant

Maintenance Distal

Extensive colitis

Oral or topical aminosalicylate Topical corticosteroids Oral aminosalicylate

Oral or topical aminosalicylate Oral or topical corticosteroids Oral corticosteroids

Intravenous corticosteroids or cyclosporin

Topical or oral aminosalicylate Azathioprine or 6-MP

Oral aminosalicylate Azathioprine or 6-MP

Outside of the approval and use of 5-ASAs, corticosteroids, and immunosuppressants, emerging treatments for IBD have become increasingly dominated by biological approaches. For instance, the use of anti-TNF-a antagonists such as Remicade/infliximab and Enbrel has revolutionized the treatment of clinically challenging steroid-refractory and fisulating CD; similar data are still awaited for utility in UC. Notwithstanding the rapid clinical efficacy observed with this class of agents, approximately 30% of CD patients do not respond to anti-TNF-a drugs and there are concerns over their long-term safety profile (opportunistic infections, increased carcinoma risk, immunogenicity).

The chronic use of immunosuppressants, e.g., azathioprine (3), cyclosporin (4), methotrexate (5), and occasionally mycophenolate mofetil (6) and tacrolimus (7), also requires constant monitoring both for levels of drug and for side effects.40 Thiopurines, such as 6-mercaptopurine and azathioprine, are metabolized to 6-thioguanine, blocking the nucleotide binding site and activity of G-protein Racl and inducing T cell apoptosis. While azathioprine is highly effective at inducing and maintaining disease remission, side effects include allergic reactions, pancreatitis, myelosuppression, nausea, infections, hepatoxicity, and malignancy. Bone marrow suppression is related to levels of 6-thioguanine, and therefore monitoring of complete blood counts at regular intervals is suggested. Of the other most commonly used immunosuppressants, methotrexate also induces myelosuppression and additionally it is associated with hepatoxicity, an increased risk of Epstein-Barr virus (EBV)-lymphoma, and opportunistic infections. Finally, cyclosporin is generally reserved for patients with severe UC that are refractory to steroids, but its chronic use is associated with renal insufficiency, hypertension, nausea, and opportunistic infections. As maintenance therapy for severe IBD, none of these agents is without considerable liabilities.

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