Among the first biological explanations put forth to explain the antiinflammatory action of methotrexate stems from the capacity of methotrexate to inhibit the regeneration of S-adenosyl methionine, the principal methyl donor in all cellular methylation reactions, from S-adenosyl homocysteine. Prior reports indicated that transmethylation reactions are required for the full inflammatory function of monocyte/macrophages, suggesting that inhibition of methylation reactions via methotrexate-mediated diminution of S-adenosyl methionine could explain the therapeutic effects of methotrexate.2 Moreover, inhibition of methylation reactions may result in the accumulation of intracellular polyamines, such as spermine and spermidine; these polyamines can be converted to lymphotoxic agents such as ammonia and hydrogen peroxide, thereby diminishing inflammation in RA. The hypothesis that methotrexate blocks inflammation by inhibiting the formation of methyltetrahydrofolate and causing the accumulation of polyamines was disproven in experiments using 3-deazo-adenosine. This agent is a specific methylation inhibitor but nevertheless fails to reduce inflammation in patients with RA despite inhibition of transmethylation reactions in their cells.3
Phillips and colleagues reported that methotrexate induces the formation of reactive oxygen species (ROS) in monocytoid and cytotoxic T-cell lines leading to their diminished function and death.4 These observations suggest another possible mechanism for the action of methotrexate. Since the effects on ROS required high concentrations of methotrexate and occurred primarily in rapidly dividing cells, their relevance to nondividing monocyte/macrophages is questionable. More recently, Spurlock and colleagues reported that methotrexate “primes” monocytes for apoptosis by a jun kinase–dependent mechanism that relies on methotrexate-dependent reactive oxygen species production and is reversed by tetrahydrobiopterin.5 Although the role of monocyte/macrophage apoptosis in suppressing inflammation in RA has not been demonstrated in vivo in either animals or patients, this work suggests an interesting mechanism by which methotrexate can act.
The doses of methotrexate used to treat RA are very low compared with those given for the treatment of cancer. Furthermore, it is clear from the once-weekly dosing schedule that the effects of the drug must be prolonged because serum methotrexate levels peak within six to 10 hours after an oral dose and are undetectable 24 hours after the dose. It has been known for many years that methotrexate is a “pro-drug”; methotrexate is taken up by cells and promptly polyglutamated by folylpolyglutamate synthase to long-lived methotrexate polyglutamates.6 The spectrum of enzymatic inhibition by methotrexate polyglutamates is different from the native agent, and the enzyme most potently inhibited by methotrexate polyglutamates is aminoimidazole carboxamidoribonucleotide (AICAR) transformylase, which catalyzes an intermediate step in de novo purine biosynthesis.
By regulating molecules key to osteoclast/osteoblast processes, methotrexate may reduce bone destruction in inflammatory arthritis, osteolysis, especially in combination with adenosine
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Although initially given as replacement therapy for patients with primary and secondary immunodeficiency states, intravenous immunoglobulin (IVIg) has proven to be effective in the treatment of various autoimmune and inflammatory disorders. This success has led to a dramatic increase in the use of IVIg, with its use as an antiinflammatory agent now vastly surpassing its use in the treatment of immunodeficiencies. Even so, the basis for the antiinflammatory activity of IVIg remains unclear.