Use of Immunosuppressive Drugs in Hypersensitivity and Autoimmune Diseases
Glucocorticoid administration can be life-saving in certain acute disorders, such as bronchial asthma and autoimmune thrombocytopenic purpura and can induce significant improvement in chronic warm autoantibody hemolytic anemia, autoimmune chronic active hepatitis, autoimmune thrombocytopenic purpura, systemic lupus erythematosus, and a va-riety of chronic hypersensitivity conditions. Steroids are also part of most immunosup-pressive regimens used for preventing the rejection of transplanted organs.
2. Cytotoxic Agents and Cyclosporin A
Many nonneoplastic diseases either proven or presumed to be immunologically mediated have been treated with cytotoxic drugs. Results of controlled trials of azathioprine, methotrexate, and cyclophosphamide suggest that these cytotoxic drugs, when given in suf-ficient quantity, may be capable of suppressing disease activity and eliminate the need for long-term therapy with steroids.
Methotrexate is the most effective second-line drug for rheumatoid arthritis not con-trolled by NSAIDs. Methotrexate not only alleviates the signs and symptoms of rheuma-toid arthritis, but also may increase the hemoglobin and decrease the erythrocyte sedimen-tation rate (ESR) in patients. Methotrexate is usually given in weekly oral doses.
Cyclophosphamide has been demonstrated to be the only effective means of achiev-ing immunosuppression (and sometimes clinical cure) in certain steroid-resistant diseases, such as Wegener’s granulomatosis. Cyclophosphamide is also the drug of choice for the treatment of lupus glomerulonephritis and other vasculitides. In-terestingly, cyclophosphamide is better tolerated if given as monthly intravenous pulses rather than daily by mouth.
Azathioprine has also been used in the treatment of patients with SLE. Controlled studies demonstrated a number of beneficial effects, i.e., an increase in creatinine clear-ance, a decrease in proteinuria, and a decrease in mortality. However, a decrease in glomerular cell proliferation has been noted in renal biopsies of SLE patients receiving aza-thioprine and upon discontinuation of treatment severe exacerbations of the disease have been reported.
Cyclosporin A has not been as widely used in the treatment of autoimmune disorders as azathioprine, methotrexate, and cyclophosphamide, with the exception of type I (insulin-dependent) diabetes and myasthenia gravis. In these conditions, considerable clinical im-provement may be seen while cyclosporine is being administered, but relapses occur as soon as it is suspended.
Combinations of glucocorticoids and cytotoxic agents have been used in most diseases that were classically treated with glucocorticoids alone, and although controlled trials are still required to assess overall benefit in many of these diseases, it should be stated that their major advantage may be the possibility of reducing the dose of steroids when such drugs are added to corticosteroid therapy—the previously mentioned “steroid-sparing” effect.