Tacrolimus Versus Cyclophosphamide as Treatment for Diffuse Proliferative or Membranous Lupus Nephritis: Prospective Cohort Study

Systemic lupus erythematosus (SLE) is a multisystem autoimmune disease. About 60% of SLE patients have renal disease, and patients with rapidly progressive destruction of renal parenchyma have significantly poorer prognosis. Drug therapies that employ corticosteroids, cyclophosphamide, and/or mycophenolate mofetil have improved patient outcomes, but a significant number of patients have refractory disease or cannot tolerate these drugs. Moreover, SLE patients who are partially responsive or resistant to treatment have significant morbidity，mortality, and exacerbations of renal function. Thus, in patients with lupus nephritis (LN), the two main causes of morbidity and mortality are treatment-related or patient-related. It has been suggested that new therapies be developed for SLE that more specifically target the relevant immunopathogenetic pathways, so as to achieve greater efficacy and reduce therapy-related toxicities ，and to save or protect renal function.

Tacrolimus (TAC) is an immunosuppressive macrolide of the calcineurin inhibitor (CNI) group that is widely administered following organ transplantation. In 1989, Takabayashi K. et al. studied the effect of TAC on a murine model of SLE, and showed that it prolonged lifespan, reduced proteinuria, and prevented the progression of nephropathy, although it had no appreciable effect on the levels of anti-dsDNA antibodies. More recent small-scale studies have shown that TAC may be an effective treatment for nephritic syndrome and LN8-11. However, there is little clinical experience in the use of TAC for treatment of LN, especially for LN with severe renal disease, and limited knowledge of the comparative efficacy of TAC and other therapies.

In this comparative open-label cohort study, we compared the efficacy and safety of TAC and CYC in the treatment of diffuse proliferative and membranous lupus nephritis with severe renal disease.

LN is characterized by autoantibody-mediated vasculitis that may lead to rapid progression of multi-system and organ damage. The kidneys are often involved due to excretion of excessive urinary protein and/or rapidly progressive kidney injury, and end-stage renal disease may result. Treatment-related differences in the rates of renal failure may not be discernible early in the course of treatment, but there are definite advantages of rapid remission, effective prophylaxis against relapse, and prevention of renal failure.

An intravenous pulse CYC regime has been the "gold standard" immunosuppressive regime for the treatment of LN. The activation of lymphocytes, production of autoantibody, and high expression of IFN-γ in the circulation and renal tissue are important indicators of renal injury in SLE. Previous clinical and animal studies have shown that TAC therapy inhibits T-lymphocyte activation, suppresses cytokine production in lymphocytes, suppresses antigen-induced monokine (TNF-α) production in macrophages, reduces interleukin-2 mRNA expression, decreases serum levels of IFN-γ and IFN-γ mRNA expression in the kidney and spleen, and decreases serum levels of IgG-class anti-DNA antibodies. A recent study also showed that TAC treatment affects B-cell antibody responses indirectly by interfering with T-helper cells.