Toxicities of the PSIs can include profound myelosuppression (especially thrombocytopenia), hepatotoxicity, diarrhea, hypertriglyceridemia, pneumonitis, and headache. Because nephrotoxicity is of major concern when administering calcineurin inhibitors, and since renal toxicity is less common with PSIs, there is interest in increased early use of the latter agents. However, increased use in stem cell transplantation regimens as GVH disease prophylaxis, particularly when combined with tacrolimus, has revealed an increased incidence of hemolytic-uremic syndrome.
Tofacitinib (Xeljanz) inhibits JAK enzymes that stimulate hematopoiesis and immune cell function in response to cytokine or growth factor signaling. Tofacitinib reduces circulating NK cells, serum immunoglobulins, and C-reactive protein. It is approved for adults with moderate to severe RA. It has a black box warning for serious infections and malignancies, similar to anti–TNF-α Mabs (see below).
Mycophenolate mofetil (MMF) is a semisynthetic derivative of mycophenolic acid, isolated from the mold Penicillium glaucus. In vitro, it inhibits Tand B-lymphocyte responses, including mitogen and mixed lymphocyte responses, probably by inhibition of de novo synthesis of purines. Mycophenolate mofetil is hydrolyzed to mycophenolic acid, the active immunosuppressive moiety; it is synthesized and administered as MMF to enhance bioavailability.
Mycophenolate mofetil is available in both oral and intravenous forms. The oral form is rapidly metabolized to mycophenolic acid. Although the cytochrome P450 3A system is not involved, some drug interactions still occur. Plasma drug levels should be monitored frequently.
Mycophenolate mofetil is used in solid organ transplant patients for refractory rejection and, in combination with prednisone, as an alternative to cyclosporine or tacrolimus in patients who do not tolerate those drugs. Its antiproliferative properties make it the first-line drug for preventing or reducing chronic allograft vasculopathy in cardiac transplant recipients. Mycophenolate mofetil is used as prophylaxis for and treatment of both acute and chronic GVH disease in hematopoietic stem cell transplant patients. Newer immunosuppressant applications for MMF include lupus nephritis, rheumatoid arthritis, inflammatory bowel disease, and some dermatologic disorders.
Toxicities include gastrointestinal disturbances (nausea and vomiting, diarrhea, abdominal pain) headache, hypertension, and reversible myelosuppression (primarily neutropenia).
Thalidomide is an oral sedative drug that was withdrawn from the market in the 1960s because of disastrous teratogenic effects when used during pregnancy. Nevertheless, it has significant immunomodulatory actions and is currently in active use or in clinical trials for more than 40 different illnesses. Thalidomide inhibits angiogenesis and has anti-inflammatory and immunomodulatory effects. It inhibits tumor necrosis factor-alpha (TNF-α), reduces phagocytosis by neutrophils, increases production of IL-10, alters adhesion molecule expression, and enhances cell-mediated immunity via interactions with T cells. The complex actions of thalidomide continue to be studied as its clinical use evolves.