Immunosuppressives, arthritis

The first human kidney and bone marrow transplants using cyclosporine were reported in 1978. Oral or intravenous cyclosporine is an immunosuppressant for transplantation of these and other organs and investigations are underway for its possible use in a variety of autoimmune diseases including rheumatoid arthritis, severe psoriasis, and Crohn s disease. Dose-dependent nephrotoxicity (261—264) remains the primary limitation of the dmg and necessitates close monitoring of patients, including measurement of dmg levels in blood. Cyclosporine research has been reviewed (265—274). 

MTX is part of curative therapeutic schedules for acute lymphoblastic leukemias (ALL), Burkitt s lymphoma, and choriocarcinoma. It was also used in adjuvant therapy of breast cancer. High dose MTX with leucovorin rescue can induce about 30% remissions in patients with metastatic osteogenic sarcoma. MTX is one of the few antineoplastic drugs that can be safely administered intrathecally for the treatment of meningeal metastases and leukemic infiltrations (routine prophylaxis in ALL). In addition, MTX can be used as an immunosuppressive agent for the treatment of severe rheumatoid arthritis and psoriasis. 

In the pathogenesis of many chronic inflammatory diseases (e.g., rheumatoid arthritis, glomerulonephritis, colitis ulcerosa, Morbus Crohn, atopic dermatitis, psoriasis) autoimmune processes play an important role, too. Although first of all nonsteroidal antiinflammatory agents or glucocorticoids should be applied, immunosuppressive agents may also be indicated. 

Thiopurine methyltransferase (TPMT) catalyzes the S-methylation of thiopurine dmgs, such as 6-mercaptopurine (6-MP), 6-thioguanine and azathioprine, to inactive metabolites [29-32]. Thiopurines form part of the routine treatment for patients with acute lymphoblastic leukemia, rheumatoid arthritis, and autoimmune diseases such as SLE and Crohn s disease, and are used as an immunosuppressant following organ transplantation. 

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. 

Cyclosporine demonstrates immunosuppressive activity by inhibiting the first phase of T-cell activation. It also inhibits release of inflammatory mediators from mast cells, basophils, and polymorphonuclear cells. It is used in the treatment of both cutaneous and arthritis manifestations of severe psoriasis. The usual dose is between 2.5 and 5 mg/kg/day given in two divided doses. Adverse effects include nephrotoxicity, hypertension, hypomagnesemia, hyperkalemia, alterations in liver function tests, elevations of serum lipids, GI intolerance, paresthesias, hypertrichosis, and gingival hyperplasia. Cumulative treatment for more than 2 years may increase the risk of malignancy, including skin cancers and lymphoproliferative disorders. 

Corticosteroids do not heal illnesses, but they are widely used in various conditions when it is necessary to utilize their anti-inflammatory, immunosuppressant, and mineralo-corticoid properties. In addition, they are used in replacement therapy for patients who have adrenal insufficiency. Corticosteroids can be used in vital situations for asthma, severe allergic reactions, and transplant rejections. They are effective in noninfectious granulomatous diseases such as sarcoidosis, collagen vascular disease, rheumatoid arthritis, and leukemia. Steroids are used as lotions, ointments, etc. in treating a number of dermatological and ophthalmologic diseases. 

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. 

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. 

Infliximab is a monoclonal antibody against TNF-a (see Chapter 26, Section III.d.1). It has been approved for the treatment of psoriasis, Crohn s disease, ankylosing spondylitis, psoriatic arthritis, rheumatoid arthritis and ulcerative colitis. Similar immunosuppressants are etanercept, and adali-mumab. 

Darmawan J, Nasution AR, Rasker JJ, Zhao DB, Soorosh GS, Chen SL et al. Sustained clinical and radiological remission in DMARD refractory rheumatoid arthritis treated with step-down bridge combination therapy of five immunosuppressants without corticosteroids in a 6 years observation in Asia - WHO-ILAR COPCORD Stage II Treatment. APLAR J Rheumatol 2007 10 in press. 

Darmawan J, Rasker JJ, Nasution AR, Zhao DB, ChenS-L, Haq SA et al. WHO-ILAR COPCORD Stage II treatment of the autoimmune diseases with step-down bridge combination of five immunosuppressants (SBC-5-IMNs) in therapy of rheumatoid arthritis. Proceedings book of the 12th APLAR Congress of Rheumatology. Kuala Lumpur (Malaysia) 2006. 

Darmawan J, Rasker JJ, Nuralim H. Ten years radiographic outcome of rheumatoid factor positive rheumatoid arthritis patients, treated with aggressive immunosuppressive comhination therapy. J Rheumatol 2004 31 Suppl 69 66-9. 

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. 

---