Methotrexate adverse effects

Infliximab (Remicade) is a chimeric monoclonal antibody directed against TNF-a. Recently, its indications have been expanded to include psoriatic arthritis and treatment of adults with chronic severe plaque psoriasis. An advantage over other systemic psoriasis treatments is that infliximab does not adversely affect blood counts, hepatic enzyme levels, or kidney function. The recommended dose is 5 mg/kg as an IV infusion at weeks 0, 2, and 6, then every 8 weeks thereafter. For psoriatic arthritis, it may be used with or without methotrexate. Adverse effects include headaches, fever, chills, fatigue, diarrhea, pharyngitis, upper respiratory and urinary tract infec-... 

Methotrexate has been used successfully with cyclosporine, either concurrently34 or in rotation. Rotational therapy is particularly effective since it minimizes the serious adverse effects of both agents hepatotoxidty from methotrexate and hypertension and nephrotoxicity from cyclosporine. Having an overlapping treatment period may not be necessary and patients have been successfully switched after a 1-week washout period.21,35 This is a very useful combination of systemic agents in the longterm management of this chronic disease. 

III. The answer is d, (Hardman, pp 1247, L135.) Leucovorin prevents methotrexate from inhibiting dihydrofolate reductase and reverses all of its adverse effects except neurotoxicity... 

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. 

Sulfasalazine is an antiinflammatory agent that inhibits 5-lipoxygenase. It is used selectively as an alternative treatment, particularly in patients with concurrent psoriatic arthritis. When used alone, it is not as effective as methotrexate, PUVA, or acitretin. However, it has a relatively high margin of safety. The usual oral dose is 3 to 4 g/day for 8 weeks. Its adverse effects are similar to other sulfonamide antibiotics. 

Thioguanine is a purine analog that has been used as an alternative treatment for psoriasis when conventional therapies have failed. The typical dose is 80 mg twice weekly, increased by 20 mg every 2 to 4 weeks the maximum dose is 160 mg three times a week. Adverse effects include bone marrow suppression, GI complications (e.g., nausea, diarrhea), and elevation of liver fimction tests. 6-Thioguanine may be less hepatotoxic and therefore more useful than methotrexate in hepatically compromised patients with severe psoriasis. 

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. 

Berkun, Y., Levartovsky, D., Rubinow, A., et al. (2004) Methotrexate related adverse effects in patients with rheumatoid arthritis are associated with the A1298C polymorphism of the MTHFR gene. Annals of the Rheumatic Diseases. 63, 227-231. 

The adverse effects of methotrexate include gastrointestinal complaints, bone marrow suppression, alopecia and nephrotoxicity. The toxic effects of methotrexate may be terminated by administering the fully reduced folate coenzyme leucovorin (folinic acid). Leucovorin rescue permits the administration of high doses of methotrexate, for example in situations where partially resistance has occurred or to obtain cytotoxic concentrations of methotrexate in the CNS. 

The principal advantage of MMF over alternative systemic immunosuppressive agents (e.g., methotrexate, cyclosporine) is its relative lack of hepatotoxicity and nephrotoxicity. Adverse effects produced by MMF most commonly include nausea, abdominal cramps, diarrhea, and possibly an increased incidence of viral and bacterial infections. Whether MMF may be associated with an increased long-term risk of lymphoma or other malignancies is controversial however, any such risk is likely to be lower in patients treated for skin disease with MMF monotherapy than in transplant patients treated with combination immunosuppressive therapy. 

Therapeutic pyramid approach to inflammatory bowel diseases. Treatment choice is predicated on both the severity of the illness and the responsiveness to therapy. Agents at the bottom of the pyramid are less efficacious but carry a lower risk of serious adverse effects. Drugs may be used alone or in various combinations. Patients with mild disease may be treated with 5-aminosalicylates (with ulcerative colitis or Crohn s colitis), topical corticosteroids (ulcerative colitis), antibiotics (Crohn s colitis or Crohn s perianal disease), or budesonide (Crohn s ileitis). Patients with moderate disease or patients who fail initial therapy for mild disease may be treated with oral corticosteroids to promote disease remission immunomodulators (azathioprine, mercaptopurine, methotrexate) to promote or maintain disease remission or anti-TNF antibodies. Patients with moderate disease who fail other therapies or patients with severe disease may require intravenous corticosteroids, anti-TNF antibodies, or surgery. Natalizumab is reserved for patients with severe Crohn s disease who have failed immunomodulators and TNF antagonists. Cyclosporine is used primarily for patients with severe ulcerative colitis who have failed a course of intravenous corticosteroids. TNF, tumor necrosis factor. 

A 74-year-old woman with seronegative rheumatoid arthritis was given sulfasalazine followed by methotrexate, both of which were withdrawn because of adverse effects. She also took prednisone 10 mg/day. She developed acute abdominal pain and fever (38.7° C) with no chills. Her serum amylase was 269 IU/1, serum lipase... 

Adverse Effects. The major problems associated with methotrexate include hepatic and pulmonary toxicity. These problems are dose-related, however, and serious adverse effects tend to occur less frequently at... 

Many drugs produce both their desired effects and adverse effects by acting on a single receptor type in different tissues. Examples discussed in this book include digitalis glycosides, which act by inhibiting Na+/K+ ATPase in cell membranes methotrexate, which inhibits the enzyme dihydrofolate reductase and glucocorticoid hormones. 

Etodolac This drug has effects similar to those of the other NSAIDs. Gastrointestinal problems may be less common. However, other adverse effects such as fluid retention and abnormal kidney and liver function have been reported. Etodolac may increase the serum levels and thus raise the risk of adverse reactions caused by digoxin, lithium, methotrexate, and enhance the nephrotoxicity of cyclosporine. 

Adverse effects Long-term use of infliximab is associated with development of anti-infliximab antibodies unless the drug is used in combination with methotrexate. Infusion reactions such as fever, chill, pruritus, or urticaria have occurred. Infections leading to pneumonia, cellulitis, and other conditions have also been reported. Whether treatment with infliximab predisposes to lymphoma, a condition that occurs with immunosuppressive or immune-altering drugs, remains to be established. 

Methotrexate can be helpful in controlling relapses of Crohn s disease unresponsive to corticosteroid or azathioprine. It has also been used with benefit in ulcerative colitis. Its short- and long-term use are limited by a wide profile of adverse effects including bone marrow suppression and pulmonary and hepatic fibrosis (see p. 291). 

Most patients who receive asparaginase develop hver function abnormalities, which can be fatal (12). This adverse effect is of major concern in patients who are also taking other hepatotoxic drugs, such as methotrexate and mercaptopurine. Jaundice and increased serum bihr-ubin and transaminases occur often, and hepatomegaly and fatty deposits occur occasionally. 

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