Treatment of Pediatric-Onset Lupus Nephritis: A New Option of Less Cytotoxic Immunosuppressive Therapy

Abstract

Optimal treatment for lupus nephritis in adolescents is still a great challenge. Systemic lupus erythematosus (SLE) is a chronic disease characterized by frequent disease flares for which effective and safe maintenance therapy is required (Chan et al., 2005; Lai et al., 2005). Since diffuse proliferative lupus nephritis (DPLN) is a major concern regarding treatment of young patients with SLE, the optimal immunosuppressive therapy for controlling the activity of DPLN in this population remains controversial (Niaudet, 2000; Tanaka et al., 2004, 2009). Intermittent monthly pulses of intravenous cyclophosphamide (CPA) have been reported to be effective even for patients with pediatric-onset SLE (Lehman & Onel, 2000); however, CPA is a potent immunosuppressive agent associated with myelotoxicity, gonadal toxicity, and an increased risk of secondary malignancy (Chan et al., 2000; Lai et al., 2005). Since therapy related-adverse events are a major therapeutic risk of the immunosuppressive treatment in patients with SLE, selecting a safe and effective treatment protocol poses a big dilemma for physicians treating young patients. Thus, optimal maintenance treatment for controlling the clinical activity of SLE, particularly in young patients with pediatric-onset SLE, remains to be established (Yang et al., 1994; Niaudet, 2000; Tanaka et al., 2001). Mycofenolate mofetil (MMF) has recently been reported to be as effective as and less toxic than oral CPA or monthly intermittent pulse therapy with intravenous CPA (iv-CPA) for SLE patients (Chan et al., 2000; Lai et al., 2005; Sinclair et al., 2007). However, clinical use of MMF, in patients other than those undergoing solid organ transplantation, has not been approved by the Japanese Ministry of Health and Welfare yet. On the other hand, mizoribine (MZR), a selective inhibitor of inosine monophosphate dehydrogenase in the de novo pathway of purine nucleotides, which acts very similar to MMF (Burkhardt & Kalden, 1997; Yokota, 2002), has been successfully used without any serious adverse effects for the long-term treatment of young patients with lupus nephritis (Tanaka et al., 2004; Yumura et al., 2005). We hypothesized that calcineurin inhibitors, other than MZR, might be a feasible alternative treatment for patients with pediatric-onset lupus nephritis (Tanaka et al., 2007a, 2009). Tacrolimus (Tac) is a T-cell-specific calcineurin inhibitor that prevents the activation of helper T cells, thereby inhibiting the transcription of the early activation genes of interleukin (IL)-2