Increase of peripheral T regulatory cells during remission induction with cyclophosphamide in active systemic lupus erythematosus

Background: Cyclophosphamide efficacy in lupus nephritis (LN) and neuropsychiatric systemic lupus erythematosus (NPSLE) is probably mediated by a non-specific ablation of reactive lymphocytes. However, little is known in regard to its effect on T regulatory cells (Tregs) in such patients, which was the aim of this study. Patients and Methods: Ten Caucasian lupus patients were included, six with LN classes IV-V (mean age 33.8 +/- 8.8 years) and four with NPSLE (mean age 35.5 +/- 8.8 years, clinical manifestations: 1/4 acute confusional state, 1/4 psychosis, 2/4 refractory seizures). Cyclophosphamide was administered at monthly pulses (500 mg/m(2)/month for 6 months); doses of other administered drugs, including steroids, remained stable or lower. CD4(+)CD25(high)FOXP3(+) Tregs were assessed by flow-cytometry at baseline and before every subsequent pulse and 3-6 months after the final pulse. Disease activity was assessed by SLE Disease Activity Index (SLEDAI). Results: In LN patients, Tregs were significantly increased even after the fourth pulse (0.54 +/- 0.20% vs. 1.24 +/- 0.29%, P < 0.001). Likewise, in NPSLE, Tregs were significantly expanded after the fourth pulse (0.57 +/- 0.23% vs. 1.41 +/- 0.28%, P < 0.001). SLEDAI was significantly reduced in all patients. Conclusions: Cyclophosphamide pulse therapy was associated with a significant increase of the CD4(+)CD25(high)FOXP3(+) Tregs in patients with active LN and NPSLE. This effect is probably indirect and may partially explain the beneficial role of cyclophosphamide in such cases.