Methotrexate immunosuppressants

Methotrexate is the most common treatment for resistant and widespread psoriasis. Its main actions are cytotoxic and immunosuppressant. Methotrexate inhibits an enzyme (dihydrofolate reductase) necessary for the synthesis of purine nucleotides (adenine and guanine), which are components of DNA. This results in a reduction in DNA synthesis and particularly affects rapidly dividing cells. 

Maintenance of remission of Crohn s disease may be achieved with oral or topical aminosalicylate derivatives, immunosuppressants (such as azathioprine, 6-mercaptopurine, and methotrexate), or infliximab. 

Patients with CD are at high risk for disease relapse after induction of remission. Within 2 years, up to 80% of patients suffer a relapse therefore, most patients should be evaluated for indefinite maintenance therapy. Maintenance of remission of CD may be achieved with oral or topical aminosalicylate derivatives, immunosuppressants (such as azathioprine, 6-mercaptopurine, and methotrexate), or infliximab. 

The answer is c. (Katzung, pp 608-609, 932-9.13.) Methotrexate is classified as an anti metabolite with therapeutic uses in cancer chemotherapy and as an immunosuppressive agent indicated in the treatment of severe active classical rheumatoid arthritis. Leucovorin is related to methotrexate in that it is an antagonist of its actions. It can supply a source of reduced folate for the methylation reactions that are prevented by methotrexate. 

The major types of drug therapy used in IBD include aminosalicylates, glucocorticoids, immunosuppressive agents (azathioprine, mercaptopu-rine, cyclosporine, and methotrexate), antimicrobials (metronidazole and ciprofloxacin), and agents to inhibit tumor necrosis factor-a (TNF-a) (anti-TNF-a antibodies). 

Ciclosporin, a calcineurin inhibitor, is a potent immunosuppressant useful in the prevention of rejection in organ transplants and grafting procedures. Ciclosporin is markedly nephrotoxic. Vincristine is a vinca alkaloid cytotoxic agent fluorouracil and methotrexate are both antimetabolite cytotoxic agents and bleomycin is a cytotoxic antibiotic. 

Q85 Methotrexate is an antimetabolite of folic acid and has immunosuppressant properties. Methotrexate may be used in Crohn s disease. 

Methotrexate is an antimetabolite of folic acid and has immunosuppressant properties. It inhibits the enzyme dihydrofolate reductase that is required for the synthesis of purines and pyrimidines. It is used in malignant disease, Crohn s disease, rheumatic disease and psoriasis. Folic acid is given with methotrexate to reduce the occurrence of side-effects particularly the risk of mucositis. 

HI. Disruption of cell metabolism with inhibition of proliferation. At dosages below those needed to treat malignancies, some cytostatics are also employed for immunosuppression, e.g., azathioprine, methotrexate, and cyclophosphamide (p. 298). The antiproliferative effect is not specific for lymphocytes and involves both T- and B-cells. 

Presumably, any cytotoxic substance that destroys bone marrow and lymphoid tissue may be used as an immunosuppressant. Among these drugs, the most widely used primarily for autoimmune diseases are vincristine, methotrexate, and cytarabine. However, their use should be considered experimental. Only methotrexate is seriously and sufficiently recognized as an initial drug for treating rheumatoid arthritis. 

Hypersensitivity to polyoxyethylated castor oil (injection only see Warnings and Administration and Dosage), cyclosporine, or any component of the products Gengraf and Neoral in psoriasis or RA patients with abnormal renal function, uncontrolled hypertension, or malignancies Gengraf and A/eora/concomitantly with PUVA or DVB, methotrexate or other immunosuppressive agents, coal tar or radiation therapy in psoriasis patients. 

Also the immunosuppressives cyclosporine, aza-thioprine and methotrexate have been shown to be effective treatment modalities in active Crohn s disease. 

For immunosuppressive effects methotrexate is most frequently used in RA but also azathioprine and cyclosporin are employed. Methotrexate doses for this indication can be lower than those used for cancer chemotherapy but significant toxicity such as nausea, cytopenias and mucosal lesions, and with longterm therapy slowly progressive hepatotoxicity may still be seen. 

Clinical applications include childhood acute lymphoblastic leukemia, choriocarcinoma, osteosar-com, non-Hodgkin s lymphoma and Burkitt s lymphoma. However methotrexate is also frequently used as an immunosuppressant in diseases such as psoriasis, rheumatoid arthritis and others. 

Cytotoxic agents which are used both for the treatment of cancer as for their immunosuppressive activity include cyclophosphamide, methotrexate, chlorambucil, vincristine, vinblastine and dactinomycin. 

The present primary mode of therapy for these diseases involves the use 5-amino-salicylate (5-ASA) products. Often patients require additional medications, including corticosteroids, to help induce remission and various immune modulators, such as azathioprine, 6-mercaptopurine or methotrexate, to maintain remission. In Crohn s disease certain antibiotics, such as metronidazole and ciprofloxacin, and infliximab Remi-cade), an anti-tumor necrosis factor-a(TNFa) antibody, also have been used. The pharmacology of antibiotics, immunosuppressive drugs, and corticosteroids is discussed in Chapters 43,57, and 60, respectively. 

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. 

Methotrexate is one of the few anticancer drugs that can be safely administered intrathecally for the treatment of meningeal metastases. Its routine use as prophylactic intrathecal chemotherapy in acute lymphoblastic leukemia has greatly reduced the incidence of recurrences in the CNS and has contributed to the cure rate in this disease. Daily oral doses of methotrexate are used for severe cases of the nonneoplastic skin disease psoriasis (see Chapter 41), and methotrexate has been used as an immunosuppressive agent in severe rheumatoid arthritis. 

The treatment of collagen disease is based on immunosuppressive therapies. Immunosuppressive agents, such as corticosteroids, are widely used. In addition, cytotoxic agents (azathioprine, cyclophosphamide, and methotrexate) have also been administered. 

B. Indications and nse Remicade is indicated for the reduction of the symptoms of moderate to severe Crohn s disease in patients who have not responded well to traditional treatments, including corticosteroids and other immunosuppressants, and antibiotics, and to close enterocuta-neous fistulas. Remicade, with concomitant methotrexate, is indicated for the reduction in signs and symptoms, and inhibiting the progression of structural damage due to RA in patients who have had an inadequate response to methotrexate alone. 

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