Azathioprine ulcerative colitis

Maintenance of remission of ulcerative colitis may be achieved with oral or topical aminosalicylates. Immunosuppressants such as azathioprine or 6-mercaptopurine can be used for unresponsive patients or those who develop corticosteroid dependency. 

Immunosuppressive agents such as azathioprine and mercaptopurine (a metabohte of azathioprine) are sometimes used for the treatment of IBD. These agents are generally reserved for cases that are refractory to steroids and may be associated with serious adverse effects such as lymphomas, pancreatitis, or nephrotoxicity. Cyclosporine has been of short-term benefit in acute, severe ulcerative colitis when used in a continuous infusion. 

Azathioprine is effective in preventing relapse of ulcerative colitis for periods exceeding 4 years. However, 3 to 6 months may be required for beneficial effect. For patients who initially respond to infliximab, continued administration of 5 mg/kg every 8 weeks as maintenance therapy is an alternative for steroid dependent patients. 

IX.b.3.3. Immunosuppressants. As in ulcerative colitis low doses of azathioprine (2 mg/kg) are effective in preventing recurrence, but have little value in treating acute disease. 

Sulfasalazine (Azulfidine) is approved for the treatment of rheumatoid arthritis and ulcerative colitis. It is also used to treat ankylosing spondylitis and Crohn s disease. Comparisons of sulfasalazine with other DMARDs suggest that it is more effective than hydroxychloroquine, azathioprine, and oral gold compounds. It is at least as effective as intramuscular gold and penicillamine. It has a greater degree of toxicity than hydroxychloroquine but less than gold compounds and penicillamine. After 5 years, approximately 75% of patients have discontinued sulfasalazine therapy, primarily because of a lack of efficacy as opposed to intolerable side effects. 

Therapeutic pyramid approach to inflammatory bowel diseases. Treatment choice is predicated on both the severity of the illness and the responsiveness to therapy. Agents at the bottom of the pyramid are less efficacious but carry a lower risk of serious adverse effects. Drugs may be used alone or in various combinations. Patients with mild disease may be treated with 5-aminosalicylates (with ulcerative colitis or Crohn s colitis), topical corticosteroids (ulcerative colitis), antibiotics (Crohn s colitis or Crohn s perianal disease), or budesonide (Crohn s ileitis). Patients with moderate disease or patients who fail initial therapy for mild disease may be treated with oral corticosteroids to promote disease remission immunomodulators (azathioprine, mercaptopurine, methotrexate) to promote or maintain disease remission or anti-TNF antibodies. Patients with moderate disease who fail other therapies or patients with severe disease may require intravenous corticosteroids, anti-TNF antibodies, or surgery. Natalizumab is reserved for patients with severe Crohn s disease who have failed immunomodulators and TNF antagonists. Cyclosporine is used primarily for patients with severe ulcerative colitis who have failed a course of intravenous corticosteroids. TNF, tumor necrosis factor. 

Azathioprine and 6-MP are important agents in the induction and maintenance of remission of ulcerative colitis and Crohn s disease. Although the optimal dose is uncertain, most patients with normal thiopurine-S-methyltransferase (TPMT) activity (see below) are treated with 6-MP, 1-1.5 mg/kg/d, or azathioprine, 2-2.5 mg/kg/d. After 3-6 months of treatment, 50-60% of patients with active disease achieve remission. These agents help maintain remission in up to 80% of patients. Among patients who depend on long-term glucocorticoid therapy to control active disease, purine analogs allow dose reduction or elimination of steroids in the majority. 

Timmer A et al Azathioprine and 6-mercaptopurine for maintenance of remission in ulcerative colitis. Cochrane Database Syst Rev 2007 Ian 24(1) CD000478. 

Clinical Use. Azathioprine (Imuran) is a cytotoxic agent that is structurally and functionally similar to certain anticancer drugs, such as mercaptopurine.22,30 Azathioprine is primarily used to prevent the rejection of transplanted organs, especially in patients with kidney transplants. Azathioprine may also be used to suppress immune responses in a wide range of other conditions, such as systemic lupus erythematosus, dermatomyositis, inflammatory myopathy, hepatic disease, myasthenia gravis, and ulcerative colitis. As presented in Chapter 16, azathioprine is also used as an antiarthritic disease-modifying agent. 

Steroids do not have a role in the maintenance of remission with ulcerative cohtis because they are ineffective. Steroids should he gradually withdrawn after remission is induced (over 3 to 4 weeks). If they are continued, the patient will he exposed to steroid side effects without likelihood of benefits. Azathioprine is effective in preventing relapse of ulcerative colitis for periods exceeding 4 years. However, 3 to 6 months may be required for beneficial effect. For patients who initially respond to infliximab, continued administration of 5 mg/kg every 8 weeks as maintenance therapy is an alternative for steroid dependent patients. 

Ciclosporin may induce remission in some patients with severe ulcerative colitis unresponsive to corticosteroid. The drug is given in a dose of 2-4 mg/kg i.v. until remission is attained. Renal function should be monitored closely as ciclosporin is nephrotoxic (see p. 620). For maintenance therapy azathioprine (see below) is often substituted. Ciclosporin use only delays surgery for many patients after 1 year 50% will have relapsed and undergone colectomy. 

Methotrexate can be helpful in controlling relapses of Crohn s disease unresponsive to corticosteroid or azathioprine. It has also been used with benefit in ulcerative colitis. Its short- and long-term use are limited by a wide profile of adverse effects including bone marrow suppression and pulmonary and hepatic fibrosis (see p. 291). 

Patients with inflammatory bowel disease unresponsive to azathioprine or intolerant of it may benefit from mycophenolate mofetil. Of 12 patients so treated, three had minor adverse effects (headache, nausea, arthralgia). Three with ulcerative colitis developed rectal bleeding while taking mycophenolate mofetil. Histological features of the mucosa were highly... 

Hawthorne AB, Logan RFA, Hawkey CJ. Randomized controlled trial of azathioprine withdrawal in ulcerative colitis. BMJ 1992 305 20-22. 

Azathioprine is indicated in renal homotransplantation (five-year patient survival rate of 35%) in rheumatoid arthritis (for patients with severe, active, and erosive disease not responding to conventional therapies) and in chronic ulcerative colitis, myasthenia gravis, and Behcet s syndrome (adverse effects may offset its limited value). As with other cytotoxic drugs, azathioprine can affect rapidly growing cells, resulting in leukopenia, thrombocytopenia, and gastrointestinal toxicity. In addition, hepatotoxicity (cholestasis) has been reported. Many of the general problems of immunosuppression, such as increased risk of infections, can also occur. 

Methotrexate generally is reserved for patients whose IBD is either steroid-resistant or steroid-dependent. In Crohn s disease, it both induces and maintains remission, generally with a more rapid response than that seen with mercaptopurine or azathioprine. Only limited studies have examined the role of methotrexate in ulcerative colitis. 

The client diagnosed with severe ulcerative colitis is prescribed azathioprine (Imuran), an immunosuppressant. Which assessment data concerning the medication would warrant immediate intervention by the nurse ... 

Chouraqui JP, Serre-Debeauvais F, Armari C, Savariau N. Azathioprine toxicity in a child with ulcerative colitis interaction with mesalazine. Gastroenterology (1996) 110 (4 Siqjpl), A883. 

Observational studies Patients with Crohn s disease (n = 14) or ulcerative colitis (n = 15) with previous hypersensitivity reactions to azathioprine were given gradually increasing doses of mercaptopurine from 0.5 to 1.0-1.5 mg/kg/day [108 "]. In nine patients mercaptopurine was withdrawn in the first 2 weeks because of early hypersensitivity reactions the other 20 patients tolerated it. 

Of 135patients with Crohn s disease (n — 88) or ulcerative colitis (n = 47), 65 stopped taking it because of adverse events after 25 (8-92) days the other 70 patients tolerated mercaptopurine and were followed up for 736 (362-1080) days [109 ]. Mercaptopurine was tolerated in 12 of 17 patients with hepatotoxicity and in 13 of 19 with arthral-gia/myalgia during azathioprine treatment. Previous abdominal surgery was more common in those who had adverse reactions to mercaptopurine (39/65 vs. 27/70), and thiopurine methyltransferase activity was higher in those who were tolerant of mercaptopurine. 

In a retrospective study of 31 patients (14 with Crohn s disease and 17 with ulcerative colitis), in whom azathioprine (mean dose 2.2 mg/kg/day) was withdrawn because of liver damage (cytolytic in 32%, cholestatic in 39%, and mixed in 29%), mercaptopurine (mean dose 1.3 mg/kg/day) jvaj used instead [IIT]. In 27 patients there was no further liver damage of these, 24% tolerated full doses of mercaptopurine. In four patients liver damage recurred 1-3 months after the onset of exposure to mercaptopurine. 

Yiasemides E, Thom G. Azathioprine hypersensitivity presenting as a neutrophilic dermatosis in a man with ulcerative colitis. Australas J Dermatol 2009 50(1) 48-51. 

Reznik Y, Dao T, Coutant R, et al (2004) Hepatocyte nuclear factor-1 alpha gene inactivation cosegregation between liver adenomatosis and diabetes phenotypes in two maturity-onset diabetes of the young (MODY)3 families. J Clin Endocrinol Metab 89 1476-1480 Russmann S, Zimmermann A, Krahenbuhl S, et al (2001) Veno-occlusive disease, nodular regenerative hyperplasia and hepatocellular carcinoma after azathioprine treatment in a patient with ulcerative colitis. Eur J Gastroenterol Hepatol 13 287-290... 

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