Role of Mycophenolate Mofetil in the Treatment of Lupus Nephritis

Abstract

In patients with systemic lupus erythematosus (SLE), lupus, nephritis is present in approximately 25% of patients at the time of diagnosis and eventually develops in up to 60% of adults and 80% of children (1). Selected observational studies have reported that patients with proliferative glomerulonephritis (class III, IV, and V with intracapillary proliferation) have an average absolute risk for the development of chronic kidney disease (CKD) and all-cause mortality of approximately 25 and 13%, respectively (2–5). Treatment of patients with SLE and proliferative lupus nephritis includes the use of immunosuppressive agents in combination with corticosteroids aiming to reduce the risk for the development of CKD and death. Optimal management of proliferative lupus nephritis with immunosuppressive agents remains a challenge because of the need to balance the efficacy and safety of the therapeutic agents. In the last 30 yr of the last century, randomized clinical trials performed primarily at the National Institutes of Health demonstrated that regimens using cyclophosphamide with corticosteroids were superior to corticosteroids alone for the treatment of proliferative lupus nephritis (6–10). The incidence of CKD was significantly lower on average of 15% in patients who received long-term cyclophosphamide compared with 45% in patients who received corticosteroids alone. Two published meta-analyses indicated that regimens of cyclophosphamide were more efficacious than regimens of corticosteroids alone, reducing the risk for the development of CKD (11,12) and all-cause mortality (11). However, the success of cyclophosphamide regimens comes with the burden of adverse events. The incidence of amenorrhea is significantly increased, ranging from 45 to 71% in patients who receive cyclophosphamide for 6 mo. In addition, the incidence of herpes zoster infection is significantly increased, ranging from 25 to 33% with the use of cyclophosphamide. Hemorrhagic cystitis is seen primarily with the long-term use of oral cyclophosphamide with an incidence ranging from 14 to 17% (6–10). The safety concerns of cyclophosphamide regimens has led to the use of azathioprine (a nonselective inhibitor of purine synthesis) with corticosteroids, which reduces the risk for all-cause mortality (12). However, azathioprine does not have a clear beneficial effect on the risk for important renal events (12,13) unless it is used after an induction regimen of cyclophosphamide (14,15). In the past decade, the immunosuppressive agent mycophenolate mofetil (MMF) has been used in the treatment of lupus nephritis. The development of MMF, which is an ester prodrug of mycophenolic acid (MPA) with superior bioavailability (16), was based on the observations that patients with adenosine deaminase deficiency, a deficiency of the de novo pathway for purine synthesis, have a combined B and T cell immunodeficiency, whereas patients with hypoxanthine-guanine-phosphoribosyl transferase deficiency, a defect of the salvage pathway for purine synthesis, develop neurologic abnormalities and gout yet have essentially normal immune functions (17,18). Lymphocytes use preferentially the de novo pathway for synthesis of guanosine monophosphate. Therefore, inhibition of the de novo purine synthesis seemed to be an attractive option to modulate immune responses while limiting adverse effects of nonselective immunosuppressive agents. MPA, a fermentation product of Penicillium brevicompactum and related fungi, is an inhibitor of inosine monophosphate dehydrogenase, a key enzyme in the de novo pathway of purine synthesis. As expected, MPA in vitro and in vivo inhibits lymphocytes proliferation, modulates apoptosis in activated T lymphocytes, and attenuates the autoantibody production by B cells and the production of oxygen radicals and adhesion molecules, all essential mechanisms that propagate the autoimmune and inflammatory responses in SLE (19–21). The efficacy of MMF was demonstrated in rodent models of lupus nephritis (22,23). The biologic plausibility for the use of MMF in the treatment of proliferative lupus nephritis has lead to the study of this agent in five induction trials, aiming to achieve remission, and one maintenance trial, aiming to prevent relapse conducive to CKD.