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Mechanism
| • | synthetic analogue of folic acid |
| • | inactivates dihydrofolate reductase |
| • | mechanism of action in nonneoplastic skin disease is poorly understood, as are the diseases themselves |
| • | immunosuppressive effects are weak |
| • | strong evidence exists for direct action of methotrexate on psoriatic epidermal proliferation |
Adverse effects
Principles regarding adverse effects (AE’s):
| 2. | patients who experience AE’s early in therapy will probably continue to do so, and patients free of early complaints are likely to remain so long term |
| 3. | divided drug dosing is often helpful in reducing AE’s |
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HEPATOTOXICITY
| • | major limitation of therapy is induction of liver fibrosis |
| • | mechanism of liver damage unknown |
| • | LFT elevations develop frequently but have no value in predicting which patients will develop cirrhosis |
| • | those with less than 1.5g total dose have negligible incidence of fibrosis |
| • | only acceptable method for verifying methotrexate induced cirrhosis |
| • | risk of death is 1in 10,000 |
| • | AAD recommends bx after first 1.5g |
| • | others say bx once it is clear that patient is a candidate for long term treatment (i.e. disease adequately suppressed and AE’s tolerable) |
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BONE MARROW SUPPRESSION:
| • | “not uncommon” says Fitz |
| • | leucovorin = folinic acid rescue (bypasses inhibited enzyme; does not inhibit therapeutic efficacy) |
TERATOGENIC
indications
PSORIASIS:
| • | pustular psoriasis is particularly responsive |
| • | effectiveness in psoriatic arthritis less clear |
| • | divided into three doses (Q12º over 36º) weekly |
| • | (intent of divided dose is to maximize the exposure of proliferating psoriatic cells to the drug; also may be helpful in reducing side effects) |
PLEVA:
| • | exquisitely small doses to control the disease process (2.5 – 5mg/ week) |
PRP:
| • | higher doses (1.5 – 2X psoriatic doses) |
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