Mycophenolate mofetil combined with a cyclooxygenase-2 inhibitor ameliorates murine lupus nephritis

Background. Approaches to the treatment of lupus nephritis include immunosu ppressants associated with anti-inflammatory drugs, mainly steroids, which, however, cause major side effects. Mycophenolate mofetil (MMF) has been de scribed as being less toxic than conventional immunosuppressants. and it wa s effective in preventing progressive nephritis in lupus mice. Our study ev aluated the therapeutic effect of MMF in NZB/W F1 hybrid mice with establis hed disease. We also examined the combination of MMF with a selective cyclo oxygenase-2 (COX-2) inhibitor, DFU, based on previous findings of excessive renal production of COX-2-derived thromboxane A(2) (TXA(2)) in lupus nephr itis. Methods. Four groups of NZB/W mice (N = 30 each group). starting at five mo nths of age, were given daily by gavage the following: vehicle. MMF 60 mg/k g, DFU 3 mg/kg, or MMF + DFU. Fifteen mice for each group were used for the survival studies, and the remaining mice were sacrificed at nine months. Results. MMF or DFU alone partially delayed the onset of proteinuria compar ed with vehicle. Combined therapy was significantly (P < 0.05) more effecti ve than single drugs. Animal survival was partially ameliorated by MMF and significantly improved by the drug combination in comparison with the: vehi cle (P = 0.005) and DFU alone (P < 0.03). At nine months, serum blood urea nitrogen (BUN) levels were lower in all of the treated groups than in the v ehicle group. Renal damage was also limited, but to a greater extent in mic e given the combined therapy. In untreated mice, renal COX-2 mRNA expressio n was up-regulated, and generation of TXB2, the stable breakdown product of TXA(2), increased. DFU prevented the abnormal renal TXB2 production, confi rming the COX-2 origin of this eicosanoid, whereas renal 6-keto-PGF(1 alpha ) and prostaglandin E-2 (PGE(2)) were not affected substantially. Conclusions. These results offer a strong case for exploring the possibilit y that in humans MMF combined with COX-2 inhibitors has a role in the treat ment options for lupus nephritis. This combined drug therapy may be at leas t as effective as steroids but without the obvious nephrotoxicity of the la tter.