Methotrexate immunosuppressive activity

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

Initially, the immunosuppressive agents, such as cyclophosphamide (32), azathioprine, and methotrexate, were developed to inhibit malignant cell proliferation. The immunosuppressant activity was discovered later and these agents were then applied to treat autoimmune diseases, where patients did not respond to high doses of steroids (51). The potential side effects associated with these agents have encouraged the search for unique immunosuppressants having more acceptable safety and efficacy profiles (62). Future approaches need to incorporate early treatment with immunotherapy... 

In general, these drugs are more toxic and are usually reserved for patients who have not responded to more traditional DMARDs such as methotrexate. Drugs with immunosuppressant activity may also be used in combination with more traditional DMARDs to provide optimal benefits in certain patients. Combination drug therapy in rheumatoid arthritis is addressed in the next section. 

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. 

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

Tacrolimus, an immunosuppressant that inhibits T-cell activation, is a useful alternative in severe recalcitrant psoriasis. Although it is not FDA approved for this indication, patients have received oral doses of 0.05 mg/kg daily, with increases up to 0.15 mg/kg daily, depending on results. Adverse effects include diarrhea, nausea, paresthesias, hypertension, tremor, and insomnia. 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 he 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 fohc 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. 

Randomized controlled trials of azathioprine, methotrexate, cladribine, intravenous immunoglobulin and cyclophosphamide have not shovm definite modification to the aggressive course of PP MS (Leary and Thompson, 2005). However, these immunosuppressant therapies continue to be evaluated in patients with active aggressive MS. 

Treatment of acute CVHD is often unsuccessful and the resulting complications can be fatal. Patients undergoing allogeneic HSCT are given prophylactic immunosuppressive therapy which inhibits T-cell activation and/or proliferation. The most commonly used CVHD prophylaxis regimens are cyclosporine or tacrolimus and methotrexate. 

Immunosuppressants, such as azathioprine, ciclosporin and methotrexate, can be used to treat severe inflammatory disease. Their use depends on their ability to inhibit the activity and proliferation of lymphocytes and other leukocytes and because of this they are very toxic to the bone marrow. Other adverse effects are nausea, leukopenia, blurred vision, rashes and hair loss. 

Patients with rheumatoid arthritis have elevated levels of TNF-a in their joints, whereas patients with Crohn s disease have elevated levels of TNF-a in their stools. In one trial, infliximab plus methotrexate improved the signs and symptoms of rheumatoid arthritis more than methotrexate alone. Patients with active Crohn s disease who had not responded to other immunosuppressive therapies also improved when treated with infliximab, including those with Crohn s-related fistulae. Infliximab is approved in the United States for treating the symptoms of rheumatoid arthritis, and is used in combination with methotrexate in patients who do not respond to methotrexate alone. It also is approved for treatment of symptoms of moderate to severe Crohn s disease in patients who have failed to respond to conventional therapy, and in treatment to reduce the number of draining fistulae in Crohn s disease patients. About 1 of 6 patients receiving infliximab experiences an infusion reaction characterized by fever, urticaria, hypotension, and dyspnea within 1 to 2 hours after antibody administration. Serious infections also have occurred in infliximab-treated patients, most frequently in the upper respiratory and urinary tracts. The development of antinuclear antibodies, and rarely a lupus-like syndrome, have been reported after treatment with infliximab. 

The most important clinical use of dactinomycin is in the treatment of rhabdomyosarcoma and Wilms tumor in children, where it is curative in combination with primary surgery, radiotherapy, and other drugs, particularly vincristine and cyclophosphamide. Antineoplastic activity has been noted in Ewing s tumor, Kaposi s sarcoma, and soft-tissue sarcomas. Dactinomycin can be effective in women with advanced cases of choriocarcinoma in combination with methotrexate. Dactinomycin also has been used as an immunosuppressant in renal transplants. 

Aside from its antineoplastic activity, methotrexate also has been used with benefit in the therapy of psoriasis. Additionally, it inhibits cell-mediated immune reactions and is employed as an immunosuppressive agent to suppress graft-versus-host disease in allogenic bone marrow and organ... 

Genestier L, Paillot R, Foumel S, et al. Immunosuppressive properties of methotrexate apoptosis and clonal deletion of activated peripheral T cells. J Clin Invest 1998 102 322-328. 

Clinically, the most common symptoms include dyspnea and pleuritic chest pain (38). Chest radiography reveals elevated hemidiaphragms. Some improvement has been noted using inhaled p agonists and theophylUine. A more global evaluation of SLE disease activity usually leads to an increase in immunosuppressive therapy using corticosteroids, methotrexate, cyclosporine, mycophenalate, cyclophosphamide, or azathioprine, with subsequoit improvement in symptoms (38). 

As it was mentioned in the previous sections, the active principle of Fostamatinib disodium (88) is Tamatinib (92), which is formed by enzymatic hydrolysis of 88 in the intestine. As in the case of lymphoma, the effect of 88 in autoimmune diseases is related to inhibition of Spleen tyrosine kinase (Syk) by 92 [241, 242]. As Syk has the central role in transmission of activating signals within B cells, inhibition of this enzyme lowers expression of a number of pro-inflammatory cytokines and hence leads to immunosuppression [243], Fostamatinib has shown significant efficacy in the treatment of patients with rheumatoid arthritis not responding to Methotrexate (272) (a drug which is used conventionally in therapy), although a number of adverse events were observed [244], If these results are confirmed once Phase III studies are completed, it may hnd a place in the treatment of patients with rheumatoid arthritis with poor response to conventional therapy (Fig. 11). 

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