Effective treatment of young patients with pediatric-onset, long-standing lupus nephritis with tacrolimus given as a single daily dose: an open-label pilot study

Abstract

The objective of the current work is to report the preliminary experience with tacrolimus (TL) administered as a single-dose daily for maintenance therapy of young patients with pediatric-onset, long-standing systemic lupus erythematosus (SLE). Six consecutive patients with long-standing SLE were recruited for a 6-month open-label trial of single-dose-daily administration of tacrolimus (3 mg/day) without dose up of concomitantly administered prednisolone (PDN). TL treatment was started at the time of the most recent flares. Data on the clinical and serologic lupus activity were collected prospectively. The baseline characteristics of the patients were: mean age, 20 years; urinary protein/creatinine ratio, 1.22 +/- 1.94; serum C3 level, 70.8 +/- 21.2 (normal, 79-152 mg/dL); serum complement hemolytic activity (CH50), 22.2 +/- 10.3 (normal, 23-46 U/mL); serum anti-dsDNA antibody titer, 60.4 +/- 71.7 IU/mL (normal, < 12.0 IU/mL); serum creatinine, 0.55 +/- 0.11 mg/dL; European Consensus Lupus Activity Measurement (ECLAM) index, 5.2 +/- 2.6. Despite the gradual tapering of the PDN dose, marked improvement as compared with the baseline values was observed in the ECLAM index examined at one and three months and serological parameters examined at three months after the start of treatment. After a 6-months' therapy, complete response was achieved in all of the patients (serum CH50 value, 27.7 +/- 8.3 U/mL; serum anti-dsDNA antibody titer, 28.4 +/- 27.9 U/mL and the ECLAM index, 1.2 +/- 1.2 (P < 0.05), respectively), except in one patient who showed WHO class V lupus nephritis. No serious adverse effects were observed. These data suggest that TL, even when administered as a single-daily dose, is effective and safe for selected young patients with pediatric-onset, long-standing SLE. However, further studies on a larger number of patients are needed to confirm these results.

Pharmacokinetics of Orally Administered Tacrolimus in Lupus Nephritis Patients

“…The therapeutic range of blood concentration relating to the e‹cacy of tacrolimus in lupus nephritis is still unknown. 19) As the limitations of this study were the small number of patients, veriˆcation of these observations will require further studies with an increased patient sample size. Because AUC is generally thought to be correlated with trough concentration (C 12 h ) in transplant patients who are treated with tacrolimus twice a day, blood tacrolimus concentrations are monitored by C 12 h .…”

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

“…Recently, Tac combined with PDN has been successfully administered without serious adverse effects, as induction and maintenance treatment for patients with proliferative and membranous lupus nephritis (Politt et al, 2004;Maruyama et al, 2005;Mok et al, 2005;Tse et al, 2007;Szeto et al, 2008). However, there is little information regarding the efficacy and safety of Tac in young patients with lupus nephritis (Tanaka et al, 2007a(Tanaka et al, , 2009). The safety of Tac treatment is important because of its potent nephrotoxicity.…”

“…Although these patients did not necessarily have permanently high blood levels of Tac (Duddridge & Powell, 1997;Tse et al, 2007), the development of an optimal Tac treatment strategy for lupus nephritis, with a dose as low as possible, is sought to minimize treatment toxicity while maintaining treatment efficacy. In this context, in Japan, Tac is usually administered once daily for patients with rheumatoid arthritis (RA) or lupus nephritis since once-daily administration of Tac is the governmental approved protocol (Kawai & Yamamoto, 2006;Tanaka et al, 2007aTanaka et al, , 2009Asamiya et al, 2009). Kawai and Yamamoto (2006) reported the safety of Tac administered at a dose of 1.5-3.0 mg once daily for the treatment of RA even in the elderly.…”

“…Interestingly, Tac has been reported to stimulate glucocorticoid receptor (GR) transactivity through its ligands (Davies et al, 2005), which may explain the tendency to exacerbate glucose intolerance in selected patients . However, some patients who had experienced new flares of SLE while receiving CsA were successfully treated with Tac (Tanaka et al, 2007a(Tanaka et al, , 2009. Differential control of the GR hormone-binding function by immunosuppressive ligands, such as Tac, reportedly stimulates GR transactivity beyond the effect of the ligand on hormone retention although this is not the case with CsA (Davies et al, 2005).…”

Long-Term Tacrolimus-Based Immunosuppressive Treatment for Young Patients with Lupus Nephritis: A Prospective Study in Daily Clinical Practice

“…Cyclosporine A (CsA) and tacrolimus (Tac) are T cell-specific calcineurin inhibitors that prevent activation of helper T cells, thereby inhibiting the transcription of interleukin (IL)-2 and proinflammatory cytokines such as tumor necrosis factor-α, IL-1β, and IL-6 [7,8]. Recently, CsA and Tac combined with prednisolone (PDN) have been observed to be useful to treat difficult cases of LN, including pediatric-onset cases [7,9,10,11,12,13,14,15,16,17,18,19,20]. These studies found that both CsA and Tac ameliorated the clinical activity of lupus and exerted an anti-proteinuric effect in LN.…”