A 50-year-old man presents with complaints of bilateral morning stiffness in his wrists and knees and painful joints on exercise. On physical examination, the joints are slightly swollen. The rest of the examination is unremarkable. His laboratory findings are also negative except for slight anemia, elevated erythrocyte sedimentation rate, and positive rheumatoid factor. X-ray of B/L knee was done. The patient was staed on weekly methotrexate to control the inflammation. What is the principle mechanism of action here?
The x-ray knee shows joint space narrowing, sclerosis and osteophytosis- suggestive of Osteoahritis. Methotrexate's principal mechanism of action at the low doses used in the rheumatic diseases probably relates to inhibition of amino-imidazolecarboxamide ribonucleotide (AICAR) transformylase and thymidylate synthetase. AICAR, which accumulates intracellularly, competitively inhibits AMP deaminase, leading to an accumulation of AMP. The AMP is released and conveed extracellularly to adenosine, which is a potent inhibitor of inflammation. As a result, the inflammatory functions of neutrophils, macrophages, dendritic cells, and lymphocytes are suppressed. There is some effect on dihydrofolate reductase and this affects lymphocyte and macrophage function, but this is not its principal mechanism of action. Methotrexate has direct inhibitory effects on proliferation and stimulates apoptosis in immunoinflammatory cells. Additionally, it inhibits proinflammatory cytokines linked to rheumatoid synovitis.
Inhibition of Dihydrofolate reductase enzyme
Increased extracellular levels of adenosine
Inhibition of assembly of microtubules in neutrophils impairing chemotaxis
Inhibition of cyclooxygenase enzyme
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