Treatment of Ulcerative Colitis

Wojciech Blonski; Anna M. Buchner; Gary R. Lichtenstein

Disclosures

Curr Opin Gastroenterol. 2014;30(1):84-96. 

In This Article

Azathioprine and 6-mercaptopurine

The guidelines by the American Gastroenterological Association from 2006 and the American College of Gastroenterology from 2010 recommend the use of immunomodulators such as azathioprine (AZA) or 6-mercaptopurine in patients with severe flares of ulcerative colitis requiring treatment with corticosteroids or another course of corticosteroids within a year as well as in moderately active ulcerative colitis not responsive to oral corticosteroids and not requiring intravenous therapy with corticosteroids.[15,18] The recommended daily dose of AZA is 2–3 mg/kg and of 6-mercaptopurine is 1–1.5 mg/kg.[18]

The metabolism of AZA/6-mercaptopurine depends on two enzymes including thiopurine methyl transferase (TPMT) that catalyzes formation of inactive metabolite of 6-mercaptopurine, namely 6-methylmercaptopurine (6-MMP)[31] and hypoxanthine phosphoribosyltransferase that participate in the conversion of AZA/6-mercaptopurine into active metabolites, 6-thioguanine nucleotides (6-TGN).[31] The low activity of TPMT is associated with increased levels of 6-TGN that increase risk of bone marrow toxicity.[32] In addition, increased levels of 6-MMP may be associated with the development of hepatotoxicity (6-MMP >5700 pmol/8 × 108).[32] Based on a meta-analysis of 12 studies, patients with 6-TGN levels above 230–260 pmol/8 × 108 are three times more likely to be in clinical remission when compared with individuals with 6-TGN levels below these levels [pooled odds ratio (OR) = 3.3; 95% CI 1.7–6.3; P < 0.001].[31]

Treatment with AZA alone has not been demonstrated to be efficacious in inducing remission of an ulcerative colitis flare. No benefit of AZA (2.5 mg/kg/day) added to oral corticosteroids therapy in treating active disease was noted in a small double-blind trial in which remission rates after 1 month were comparable between patients receiving AZA with corticosteroids and those receiving corticosteroids with placebo (78 vs. 68%, P = ns).[33] Another small double-blind trial observed significant improvement in clinical and endoscopy findings after 3-month treatment with AZA at the daily dose of 2.5 mg/kg among patients with active proctocolitis, its efficacy was comparable with sulfasalazine with improvements rates of 60 and 80%, respectively (P < 0.10).[34]

It was determined in placebo[35,36] or 5-ASA[37] controlled studies that AZA has an effect on corticosteroids sparing in patients with corticosteroid-dependent ulcerative colitis. Corticosteroid dependence has been defined as a relapse of disease within 30 days after discontinuation of corticosteroids or during reduction of corticosteroids dose that precludes corticosteroids discontinuation for more than 1 year.[38] Therapy with AZA with a daily dose ranging from 1.5 to 2.5 mg/kg for up to 6 months allowed for reduction in dose of corticosteroids or discontinuation of corticosteroids without relapse of the disease.[35–37] Maintenance immunotherapy of corticosteroid-dependent ulcerative colitis with AZA was found to be equally efficacious to combination therapy with AZA and 5-ASA with relapse rates after 2 years of treatment of 19 and 18%, respectively, in a randomized, observer-blind trial.[39] Data from a prospective open-label observational trial of the cohort of 42 patients with corticosteroid-dependent ulcerative colitis have suggested that AZA given at a daily dose of 2–3 mg/kg allows for up to 3-year constant effective maintenance of remission without corticosteroids.[40] The rates of sustained corticosteroid-free remission were the largest among patients with a duration of ulcerative colitis less than 3 years prior to AZA therapy with OR of 3.12 (95% CI 1.89–7.64).[40]

Furthermore, a Cochrane meta-analysis updated in 2012 determined that therapy with AZA for at least 12 months is superior to placebo with a significantly lower risk of failure to maintain remission (RR = 0.68; 95% CI 0.54–0.86).[41] AZA or 6-mercaptopurine may be effective as maintenance therapy for patients who have failed or cannot tolerate mesalamine or SASP and for patients who require repeated courses of steroids. However, more research is needed to evaluate superiority over standard maintenance therapy, especially in the light of a potential for adverse events with the use of AZA. Based on pooled data, treatment with these agents (AZA/6-mercaptopurine) was associated with nearly three-fold increased risk of any adverse event (RR = 2.82; 95% CI 0.99–8.01) when compared with AZA/6-mercaptopurine-nonexposed individuals with significant bone marrow suppression (4%) and acute pancreatitis (2%) being the most frequent.[41] Indefinite continuation of treatment with AZA/6-mercaptopurine is associated with a potential risk of developing lymphoma. According to the meta-analysis by Kandiel et al.[42], there is a four-fold increased risk of lymphoma (RR = 4.18; 95% CI 2.07–7.51) in patients with inflammatory bowel disease treated with AZA/6-mercaptopurine. This might have been because of AZA/6-mercaptopurine's effect, severity of IBD or combination of both factors.[42] The meta-analysis of three population-based studies[43–45] determined that the overall incidence of hepatosplenic T-cell lymphoma (HSTCL) was 1.32 cases per 100 000 person-years with a number needed to harm of 1 : 75 488 patients per year.[46]

Discontinuation of thiopurine therapy reduced the risk of lymphoma. Thiopurines remain a mainstay therapy for steroid-dependent ulcerative colitis patients. Other options include the use of anti-TNF therapy with agents such as infliximab, adalimumab (ADA) and golimumab. However, all measures need to be undertaken to reduce the potential risk of treatments including careful selection of patients including avoiding treatment in certain populations at high risk such as older patients (because of the higher risk of lymphoma in patients over 65 years), assessment of TMPT genotype or enzyme activity before initiation of therapy with AZA/6-mercaptopurine (in order to identify individuals with low activity of this enzyme who might be particularly of increased risk for developing AZA/6-mercaptopurine-induced toxicity) with weight-based dose adjustment and careful laboratory monitoring.[47]

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