Allopurinol markedly reduces xanthine oxide catabolism of the purine analogs, potentially increasing active 6-thioguanine nucleotides that may lead to severe leukopenia. Allopurinol should not be given to patients taking 6-MP or azathioprine except in carefully monitored situations.
Methotrexate is another antimetabolite that has beneficial effects in a number of chronic inflammatory diseases, including Crohn’s disease and rheumatoid arthritis (see Chapter 36), and in cancer (see Chapter 54). Methotrexate may be given orally, subcutaneously, or intramuscularly. Reported oral bioavailability is 50–90% at doses used in chronic inflammatory diseases. Intramuscular and subcutaneous methotrexate exhibit nearly complete bioavailability.
The principal mechanism of action is inhibition of dihydrofolate reductase, an enzyme important in the production of thymidine and purines. At the high doses used for chemotherapy, methotrexate inhibits cellular proliferation. However, at the low doses used in the treatment of IBD (12–25 mg/wk), the antiproliferative effects may not be evident. Methotrexate may interfere with the inflammatory actions of IL-1. It may also stimulate increased release of adenosine, an endogenous anti-inflammatory autacoid. Methotrexate may also stimulate apoptosis and death of activated T lymphocytes.
Methotrexate is used to induce and maintain remission in patients with Crohn’s disease. Its efficacy in ulcerative colitis is uncertain. To induce remission, patients are treated with 15–25 mg of methotrexate once weekly by subcutaneous injection. If a satisfactory response is achieved within 8–12 weeks, the dose is reduced to 15 mg/wk.
At higher dosage, methotrexate may cause bone marrow depression, megaloblastic anemia, alopecia, and mucositis. At the doses used in the treatment of IBD, these events are uncommon but warrant dose reduction if they do occur. Folate supplementation reduces the risk of these events without impairing the anti-inflammatory action.
In patients with psoriasis treated with methotrexate, hepatic damage is common; however, among patients with IBD and rheumatoid arthritis, the risk is significantly lower. Renal insufficiency may increase risk of hepatic accumulation and toxicity.
A dysregulation of the helper T cell type 1 (Th1) response and regulatory T cells (Tregs) is present in IBD, especially Crohn’s disease. One of the key proinflammatory cytokines in IBD is tumor necrosis factor (TNF). TNF is produced by the innate immune system (eg, dendritic cells, macrophages), the adaptive immune system (especially Th1 cells), and nonimmune cells (fibroblasts, smooth muscle cells). TNF exists in two biologically active forms: soluble TNF and membrane-bound TNF. The biologic activity of soluble and membrane-bound TNF is mediated by binding to TNF receptors (TNFR) that are present on some cells (especially Th1 cells, innate immune cells, and fibroblasts). Binding of TNF to TNFR initially activates components including NF-κB that stimulate transcription, growth, and expansion. Biologic actions ascribed to TNFR activation include release of proinflammatory cytokines from macrophages, T-cell activation and proliferation, fibroblast collagen production, up-regulation of endothelial adhesion molecules responsible for leukocyte migration, and stimulation of hepatic acute phase reactants. Activation of TNFR may later lead to apoptosis (programmed cell death) of activated cells.