Other cytotoxic agents, including methotrexate, vincristine, and cytarabine (see Chapter 54), also have immunosuppressive properties. Methotrexate has been used extensively in rheumatoid arthritis (see Chapter 36) and in the treatment of GVH disease. Although the other agents can be used for immunosuppression, their use has not been as widespread as the purine antagonists, and their indications for immunosuppression are less certain. The use of methotrexate (which can be given orally) appears reasonable in patients with idiosyncratic reactions to purine antagonists. The antibiotic dactinomycin has also been used with some success at the time of impending renal transplant rejection. Vincristine appears to be quite useful in idiopathic thrombocytopenic purpura refractory to prednisone. The related vinca alkaloid vinblastine has been shown to prevent mast cell degranulation in vitro by binding to microtubule units within the cell and to prevent release of histamine and other vasoactive compounds.
Pentostatin is an adenosine deaminase inhibitor that has been used mainly as an antineoplastic agent for lymphoid malignancies; it produces a profound lymphopenia. It is now frequently used for steroid-resistant GVH disease after allogeneic stem cell transplantation, as well as in preparative regimens prior to those transplants to provide severe immunosuppression to prevent allograft rejection.
Three other FDA-approved immunomodulators are used exclusively in the treatment of relapsing-remitting multiple sclerosis.
Dimethyl fumarate (DMF) is the methyl ester of fumaric acid. Its exact mechanism of action is unknown, but it appears to activate the nuclear factor (erythroid-derived 2)-like 2 (NRF-2) transcriptional pathway. Activation of the NRF-2 pathway results in reduction of the oxidative stress that contributes to demyelination; it also appears to help protect the nerve cells from inflammation. DMF is given orally. Lymphopenia may be significant, so blood counts must be monitored regularly and the drug may be withheld if active infection is present. Flushing is common with treatment initiation and usually improves with time. Other less common adverse effects include nausea, diarrhea, abdominal pain, increased hepatic enzymes, and eosinophilia.
Glatiramer acetate (GA) is a mixture of synthetic polypeptides and four amino acids (l-glutamic acid, l-alanine, l-lysine, and l-tyrosine) in a fixed molar ratio. Its mechanism of immunomodulation in multiple sclerosis is unknown. Studies suggest that GA downregulates the immune response to myelin antigens by induction and activation of suppressor T cells that migrate to the central nervous system. It is given as a subcutaneous injection (not intravenously) in variable dosages and schedules. Toxicities include skin hypersensitivity, and rarely lipoatrophy and skin necrosis at the injection site. Other adverse effects include flushing, chest pain, dyspnea, throat constriction, and palpitations, all of which are usually mild and self-limited.