Methotrexate anemia with

Methotrexate, an antimetabolite, is indicated for moderate to severe psoriasis. It is particularly beneficial for psoriatic arthritis. It is also indicated for patients refractory to topical or UV therapy. Methotrexate can be administered orally, subcutaneously, or intramuscularly. The starting dose is 7.5 to 15 mg per week, increased incrementally by 2.5 mg every 2 to 4 weeks until response maximal doses are approximately 25 mg/wk. Adverse effects include nausea, vomiting, mucosal ulceration, stomatitis, malaise, headache, macrocytic anemia, and hepatic and pulmonary toxicity. Nausea and macrocytic anemia can be ameliorated by giving oral folic acid 1 to 5 mg/day. Methotrexate should be avoided in patients with active infections and in those with liver disease. It is contraindicated in pregnancy because it is teratogenic. 

Hydroxyurea inhibits cell synthesis in the S phase of the DNA cycle. It is used selectively in the treatment of psoriasis, especially in those with liver disease who would be at risk of adverse effects with other agents. However, it is less effective than methotrexate. The typical dose is 1 g/day, with a gradual increase to 2 g/day as needed and as tolerated. Adverse effects include bone marrow toxicity with leukopenia or thrombocytopenia, cutaneous reactions, leg ulcers, and megaloblastic anemia. 

Unexpectedly severe (sometimes fatal) bone marrow suppression, aplastic anemia, and Gl toxicity have occurred with coadministration of methotrexate (usually in high dosage) along with some NSAIDs (see Precautions. Drug Interactions). 

Hematologic - Methotrexate can suppress hematopoiesis and cause anemia, aplastic anemia, pancytopenia, leukopenia, neutropenia, and/or thrombocytopenia. Use with caution, if at all, in patients with malignancy and preexisting hematopoietic impairment. 

Folic acid deficiency can be caused by drugs. Methotrexate and, to a lesser extent, trimethoprim and pyrimethamine, inhibit dihydrofolate reductase and may result in a deficiency of folate cofactors and ultimately in megaloblastic anemia. Long-term therapy with phenytoin can also cause folate deficiency, but only rarely causes megaloblastic anemia. 

Pancytopenia, thrombocjdopenia, and anemia can occur during leflunomide treatment (21,66-68). The risk of pan-cjdopenia is increased when it is used in combination with methotrexate and in elderly patients. Its course can be fatal and the time of onset ranges from 11 days to 4 years (66). Anemia has been reported in renal transplant recipients (28). 

Significant hematological abnormalities occur in 10-24% of patients who take methotrexate. Mild to moderate leukopenia is the most frequent, followed by thrombocytopenia. Isolated thrombocytopenia and anemia are uncommon (SEDA-22, 416) (36). In a retrospective study in 315 patients, 13 had thrombocytopenia, two of whom also had pancytopenia (37). Thrombocytopenia correlated with the weekly dosage of methotrexate administered on the same day as NSAIDs, and methotrexate was safely reintroduced in patients who developed thrombocytopenia as a result of concomitant administration of... 

In a double-blind, placebo-controlled study of the safety and efficacy of methotrexate therapy combined with glucocorticoids in patients with giant cell arteritis over 24 months, adverse events were defined as a new diagnosis of any condition during treatment (39). The combination of methotrexate plus prednisolone reduced the number of relapses and improved the course of the disease. Methotrexate was withdrawn in three patients who had adverse events that were clearly drug-related. One had leukopenia, anemia, and mucositis, one developed pancytopenia, and one oral ulcers. These patients were not taking folic acid or folinic acid supplements. 

Common side effects seen with methotrexate include mucositis, leukopenia, thrombocytopenia, and anemia. At normal doses, methotrexate is primarily excreted unchanged... 

Methotrexate is associated with nausea and vomiting as well as mucosal ulceration, stomatitis, malaise, headaches, macrocytic anemia, and pulmonary toxicity. Nausea and macrocytic anemia can be ameliorated by administering oral folic acid in doses of 1 to 5 mg/day. 

Bone marrow toxicity that leads to leukopenia, anemia, and thrombocytopenia has been shown to be induced by methotrexate. A serious long-term adverse effect is hepatotoxicity. Consequently, methotrexate should typically be avoided in patients with liver disease. Risk factors for hepatotoxicity include a history of excessive alcohol consumption, hepatitis, persistent elevated liver function tests, and family history of inheritable liver disease. ... 

Several drugs (e.g., sulfasalazine, trimethoprim-sulfamethoxazole, and methotrexate) have been reported to cause a fohc acid deficiency megaloblastic anemia. These drugs either interfere with folate absorption or inhibit the dihydrofolate reductase enzyme necessary for conversion of dihydrofolate to its active tetrahydrofolate form (see Chap. 102, on drug-induced blood dyscrasias). 

Folic acid deficiency may occur either following prolonged usage of methotrexate or in patients with preexisting folic acid deficiency. Folinic acid may be administered to overcome the folic-acid-deficiency-related megaloblastic anemia. 

FOLATE DEFICIENCY Folate deficiency is a common complication of diseases of the small intestine, which interfere with the absorption of dietary folate and the recirculation of folate through the enterohepatic cycle. In acute or chronic alcohohsm, daily intake of dietary folate may be severely restricted, and the enterohepatic cycle of the vitamin may be impaired by toxic effects of alcohol on hepatic parenchymal cells this is the most common cause of folate-deficient megaloblastic erythropoiesis. However, it also is the most amenable to therapy, inasmuch as the reinstitution of a normal diet is sufficient to overcome the effect of alcohol. Disease states characterized by a high rate of cell turnover, such as hemolytic anemias, also may be complicated by folate deficiency. Additionally, drugs that inhibit dihydrofolate reductase (e.g., methotrexate and trimethoprim) or that interfere with the absorption and storage of folate in tissues (e.g., certain anticonvulsants and oral contraceptives) can lower the concentration of folate in plasma and may cause a megaloblastic anemia. 

Inasmuch as TTP, one of the four triphosphate nucleotides needed for DNA synthesis, is formed through the methylation of UMP to TMP which is then further phosphorylated, one may expect that a reduction in methyl transfer would reduce the levels of TTP and thereby cause interference with DNA synthesis and maturation of the red cell. Yet, the pools of TTP in lymphocytes were normal in untreated patients deficient in vitamin Bi2- In contrast, in patients treated with methotrexate a marked drop in the TTP pool is found [166]. A drop in thymidylate synthetase activity in phytohemagglutinin stimulated lymphocytes of patients with pernicious anemia has been described. 

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