Immunomodulator Therapy
Thiopurines and methotrexate are commonly used as immunomodulator therapies. Their mechanisms of action, metabolism, efficacy, and side effects are described here.
Thiopurines
Action and Metabolism. The thiopurine analogues azathioprine and 6-mercaptopurine (6-MP) gained widespread acceptance as established treatments for IBD in the early 1980s, although azathioprine's efficacy in healing fistulas had been reported over a decade prior. These medications work through multiple mechanisms to control the dysregulated immune response in IBD. The active thiopurine metabolite 6-thioguanine nucleotide is a purine antagonist and therefore interferes with DNA and RNA synthesis. The reduction in DNA and RNA synthesis inhibits the proliferation of T and B lymphocytes.
The variation of thiopurine metabolism among patients guides therapy for both azathioprine and 6-MP. Azathioprine is converted to 6-MP by a nonenzymatic reaction occurring within erythrocytes. Primary understanding of this metabolism begins with the thiopurine S-methyltransferase (TPMT) enzyme (Figure 2). There is significant genetic variation in TPMT enzymatic activity, and determining enzyme activity before initiation can help guide dosing. TPMT testing, however, does not preclude the need for monitoring for hepatotoxicity or leukopenia. While enzyme testing is expensive, it has been shown to reduce long-term costs from inappropriate dosing.
(Enlarge Image)
Figure 2.
A simplified approach to azathioprine (AZA) metabolism. Thiopurine methyltransferase (TPMT) breaks down 6-mercaptopurine (6-MP) into the hepatotoxic metabolite 6-methylmercaptopurine (6-MMP). Besides TPMT metabolism, there are 2 other major pathways from 6-MP that should be considered. One is driven by the hypoxanthine phosphoribosyl transferase (HPRT) enzyme, leading to 6-thioguanine nucleotide (6-TGN), the metabolite responsible for both the therapeutic benefit in inflammatory bowel disease and myelosuppression. The other pathway is driven by xanthine oxidase (XO), leading to production of 6-thiouric acid (6-TU), an inactive metabolite. 6-TIMP, 6-thioinosine monophosphate.
Efficacy. Azathioprine and 6-MP promote clinical remission and steroid sparing in patients. A recent Cochrane Database Systemic Review showed an odds ratio of 2.43 (95% confidence interval [CI], 1.62–3.64) for response in patients with Crohn's disease who were treated with azathioprine or 6-MP compared with placebo. The steroid sparing effect was significant, with an odds ratio of 3.69 (95% CI, 2.12–6.42). Earlier data estimated that one half to two thirds of patients will respond to thiopurine treatment. Thiopurines have a delayed onset of action, requiring at least 3 to 4 months for a clinical effect to occur.
Side Effects. The side effect profiles of azathioprine and 6-MP are significant, and 9.3% of patients develop adverse effects serious enough to stop therapy (Table 1). Allergic reactions include fever, rash, arthralgias, and pancreatitis; these occur independent of dose and resolve with discontinuation of the drug. Acute pancreatitis can be seen in 3% to 7% of patients, typically during the first month of treatment. Chronic pancreatitis attributable to azathioprine or 6-MP has not been reported. Switching between azathioprine and 6-MP may help obviate side effects. However, patients who develop acute pancreatitis while taking either agent should be considered intolerant to both medications.
Myelosuppression is an important and potentially lethal complication of thiopurine therapy, and the white cell line is most commonly affected. Although typically associated with low TPMT enzyme activity, myelosuppression can also occur with normal enzymatic activity. Hepatotoxicity can be seen in up to 2% of patients and is typically caused by increased synthesis of 6-methylmercaptopurine (Figure 2). Both myelosuppression and hepatotoxicity are dose-dependent responses, and management consists of dose reduction and possibly drug cessation.
For many patients and physicians, the most alarming adverse effect associated with thiopurine therapy is malignancy; the strongest associations have been linked with lymphoma and nonmelanoma skin cancer. A recent analysis of almost 20,000 French patients suggested that the risk of lymphoma in patients with IBD who were receiving thiopurines increased from 0.26 to 0.9 per 1000 patient-years, with a multivariate hazard ratio of 5.28 (95% CI, 2.01–13.9). Furthermore, there have been 36 case reports of hepatosplenic T-cell lymphoma associated with thiopurine use, which most commonly occurs in young men and is usually fatal; 20 of these cases were associated with the concomitant use of biologic therapy, and 16 involved thiopurine use alone. A study of patients taking thiopurines for >1 year showed a relative risk of 4.27 (95% CI, 3.08–5.92) for the development of nonmelanoma skin cancer. The risk was also high in patients taking anti-tumor necrosis factor (TNF) biologics and further increased in those taking dual therapy with thiopurines and anti-TNF biologics. Patients should ensure regular use of sunscreen during sun exposure and have annual skin exams by their primary care provider or dermatologist.
Except for special circumstances, thiopurines should not be used with xanthine oxidase inhibitors such as allopurinol or febuxostat. Furthermore, caution must be exercised with concomitant use of warfarin (may decrease the efficacy of warfarin) or angiotensin-converting enzyme inhibitors (may increase the risk of myelosuppression). However, both warfarin and angiotensin-converting enzyme inhibitors can be continued with thiopurines as long as blood work is monitored.
Methotrexate
Action. Methotrexate was pioneered for the treatment of rheumatoid arthritis in the 1950s. It should be considered an alternative to thiopurines. A clinical decision to use methotrexate is influenced by its side effect profile, namely teratogenicity, and its intramuscular or subcutaneous forms of administration. Methotrexate has numerous anti-inflammatory effects, including blocking production of interleukin (IL)-1, IL-2, IL-6, and IL-8.
Efficacy. Randomized controlled trials have shown the efficacy of methotrexate in the induction and maintenance of remission in Crohn's disease. Based solely on existing data, methotrexate cannot be considered a major treatment for ulcerative colitis. For active ulcerative colitis, a single randomized controlled trial including 67 patients showed similar remission rates after 4 months between the oral methotrexate group and the placebo group. However, this study was limited in size and its use of oral methotrexate. In clinical practice, methotrexate is frequently successful in treating ulcerative colitis. A large randomized controlled trial is currently ongoing to determine the efficacy of high-dose subcutaneous methotrexate in patients with ulcerative colitis. A clinical response can be expected within 8 weeks of starting therapy.
Side Effects. Although usually well-tolerated, the side effect profile of methotrexate includes nausea, stomatitis, diarrhea, hair loss, leukopenia, interstitial pneumonitis, and hepatic fibrosis (Table 1). Nausea is the most common side effect and usually improves with time. It is frequently managed supportively with ondansetron. Furthermore, daily folic acid can reduce nausea as well as stomatitis. Although the risk of hepatic fibrosis is low in patients with IBD, cirrhosis is the most worrisome adverse effect of methotrexate. The risk of cirrhosis is directly related both to the cumulative exposure to methotrexate as well as the presence of other risk factors for liver disease. Therefore, patients with a history of excessive alcohol use and nonalcoholic fatty liver risk factors (eg, diabetes, obesity, hyperlipidemia) should avoid methotrexate. Elevated aminotransferase levels do not always correlate with the presence of hepatic fibrosis, and a liver biopsy should be considered if there is reasonable clinical suspicion for hepatic fibrosis, particularly if the cumulative dose has exceeded 1.5 g. Methotrexate has high abortifacient and teratogenic effects, and patients should be counseled appropriately.
In general, potentially hepatotoxic and myelosuppressive medications should be avoided with methotrexate. Furthermore, the concurrent use of nonsteroidal anti-inflammatory drugs can increase methotrexate concentrations, thus increasing the risk of methotrexate toxicity.