In vitro effects of methotrexate on peripheral blood monocytes: modulation by folinic acid and S-adenosylmethionine

Article Abstract:

Methotrexate was originally used as an anticancer agent, but has more recently become useful in the treatment of rheumatoid arthritis. The drug is effective against cancerous cells because it prevents use by the cells of methyl groups (single-carbon compounds), donated by folic acid and important in the production of DNA and other compounds. The mechanism by which methotrexate modulates the inflammatory and other processes of rheumatoid arthritis is not known. Differing effects on immune cell functions have been reported. Several slow-acting antirheumatic drugs are known to modulate the function of monocytes, a type of white blood cell important in many chronic inflammatory disorders, but the effects of methotrexate on these cells has not been well studied. The effects of the drug on monocytes from healthy donors were evaluated. Monocytes are important in the body's reactions to cell damage or infection. Methotrexate inhibited two monocyte functions important in these reactions, chemotaxis (migration to foreign cells or damaged sites, guided by chemical attractants) and production of superoxide (a form of oxygen important in fighting foreign cells), and this inhibition was time- and dose-dependent. Folinic acid, the active form of folic acid, reversed the inhibitory effects of methotrexate. Effects of methotrexate were boosted by using culture medium (the solution used to support monocyte survival outside the body) that was low in methionine (a protein component that also is used in reactions to supply methyl groups), and this could be reversed by addition of methionine or of S-adenosylmethionine, a major methyl group donor. The study suggests that methotrexate probably exerts its anti-inflammatory effects by blocking methylation-dependent reactions that occur during inflammatory reactions. (Consumer Summary produced by Reliance Medical Information, Inc.)

Chemotaxis, Monocytes

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Exacerbation of rheumatoid arthritis in patients treated with methotrexate after administration of folinic acid

Article Abstract:

Methotrexate was originally used as an anticancer agent, and acts by mimicking and replacing folic acid, a vitamin important for cell reactions, in rapidly growing cells. It has recently been used in treatment of rheumatoid arthritis but has often caused gastrointestinal and bone marrow toxicity, sites of normal rapid cell turnover. Impaired cell replication here is chiefly due to depletion of cellular levels of tetrahydrofolate, the form of folic acid used in cell reactions. These stores can be replenished by treatment with folinic acid, and this may decrease toxicity of methotrexate therapy. However, this will be true only if intestinal and bone marrow cells are more sensitive to folinic acid availability than are the target disease cells. The best protocol for folinic acid therapy after methotrexate has not yet been established. The effects of treatment with 15 milligrams of folinic acid (about double the methotrexate dose) two hours after weekly methotrexate treatment were evaluated in 27 patients and compared with those of placebo (inert) treatment. The patients given folinic acid developed greater pain, joint involvement, duration of morning stiffness, and changes in a laboratory test indicative of inflammatory disease. Seven of 13 patients given folinic acid were withdrawn from therapy by 11 weeks, whereas none given placebo discontinued treatment. Folinic acid did not decrease the overall incidence of methotrexate toxicity. The study suggests that administration of a large dose of folinic acid within six hours of methotrexate exacerbated rheumatoid arthritis, while other findings suggested that administration three days or more after methotrexate was ineffective. (Consumer Summary produced by Reliance Medical Information, Inc.)

Health aspects, Complications and side effects, Drug therapy, Rheumatoid arthritis, Leucovorin, Folinic acid

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Production of IgM rheumatoid factor by normal lymphocytes after stimulation with preparations containing IgM rheumatoid factor from patients with juvenile rheumatoid arthritis

Article Abstract:

Some infectious and inflammatory disorders cause increased blood levels of rheumatoid factors (RFs), antibodies (immunoglobulins, Igs) that recognize and attack a part of the protein structure that is common to one subtype of Igs, the IgG class. In some diseases, the increased levels of RFs are reversible, while the elevations occurring in rheumatoid arthritis and juvenile rheumatoid arthritis are chronic and usually irreversible. The factors responsible for elevated RFs in these rheumatic diseases are uncertain. RFs are produced by B cells or lymphocytes, a type of white blood cell involved in immune function, and some studies suggest that a particular type of RF, IgM RF, may contribute to RF production by activating B cells. The effect of IgM RF on B cell activity was studied using RF obtained from the blood of nine female patients with juvenile rheumatoid arthritis. The levels of IgM RF from the patients strongly correlated with production of IgM RF by lymphocytes isolated from healthy adults. Nonspecific stimulation of lymphocytes by other techniques also caused IgM production, but much less IgM RF activity was present. In addition, lymphocytes stimulated with IgM RF also produced IgG, and this correlated with the levels of IgM RF. The results suggest that once IgM RF is produced, it can further increase IgM RF production by B lymphocytes, and this may contribute to the chronic production of RF in juvenile rheumatoid arthritis. (Consumer Summary produced by Reliance Medical Information, Inc.)

Measurement, Rheumatoid arthritis in children, Juvenile rheumatoid arthritis, Rheumatoid factor

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