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Rapamycin reduces disease activity and normalizes T cell activation-induced calcium fluxing in patients with systemic lupus erythematosus.
Arthritis Rheum 2006; 54(9):2983-8AR

Abstract

OBJECTIVE

Systemic lupus erythematosus (SLE) is an autoimmune disease of unknown origin. Current treatment options are often ineffective or poorly tolerated. Recent observations have revealed mitochondrial hyperpolarization and enhanced Ca2+ fluxing in T cells from SLE patients. Rapamycin, a lipophilic macrolide antibiotic that regulates mitochondrial transmembrane potential and Ca2+ fluxing, has been used safely and effectively to treat renal transplant rejection since 1999. In addition, rapamycin has been shown to ameliorate T cell function and to prolong survival in lupus-prone MRL/lpr mice. We therefore undertook the present study to investigate whether rapamycin is beneficial in patients with SLE.

METHODS

Nine patients with clinically active SLE that had been treated unsuccessfully with other immunosuppressive medications began therapy with rapamycin, 2 mg/day orally. Disease activity was assessed with the British Isles Lupus Assessment Group (BILAG) score, SLE Disease Activity Index (SLEDAI), and requirement for prednisone therapy. Mitochondrial transmembrane potential and Ca2+ fluxing were assessed by flow cytometry.

RESULTS

In patients treated with rapamycin, the BILAG score was reduced by a mean +/- SEM of 1.93 +/- 0.9 (P = 0.0218), the SLEDAI by 5.3 +/- 0.8 (P = 0.00002), and concurrent prednisone use by 26.4 +/- 6.7 mg/day (P = 0.0062) compared with pre-rapamycin treatment. While mitochondrial hyperpolarization persisted, pretreatment cytosolic and mitochondrial Ca2+ levels and T cell activation-induced rapid Ca2+ fluxing were normalized in rapamycin-treated patients.

CONCLUSION

Rapamycin appears to be a safe and effective therapy for SLE that has been refractory to traditional medications. Mitochondrial dysfunction and Ca2+ fluxing could serve as biomarkers to guide decisions regarding future therapeutic interventions in SLE.

Authors+Show Affiliations

State University of New York, Syracuse, NY 13210, USA.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural

Language

eng

PubMed ID

16947529

Citation

Fernandez, David, et al. "Rapamycin Reduces Disease Activity and Normalizes T Cell Activation-induced Calcium Fluxing in Patients With Systemic Lupus Erythematosus." Arthritis and Rheumatism, vol. 54, no. 9, 2006, pp. 2983-8.
Fernandez D, Bonilla E, Mirza N, et al. Rapamycin reduces disease activity and normalizes T cell activation-induced calcium fluxing in patients with systemic lupus erythematosus. Arthritis Rheum. 2006;54(9):2983-8.
Fernandez, D., Bonilla, E., Mirza, N., Niland, B., & Perl, A. (2006). Rapamycin reduces disease activity and normalizes T cell activation-induced calcium fluxing in patients with systemic lupus erythematosus. Arthritis and Rheumatism, 54(9), pp. 2983-8.
Fernandez D, et al. Rapamycin Reduces Disease Activity and Normalizes T Cell Activation-induced Calcium Fluxing in Patients With Systemic Lupus Erythematosus. Arthritis Rheum. 2006;54(9):2983-8. PubMed PMID: 16947529.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Rapamycin reduces disease activity and normalizes T cell activation-induced calcium fluxing in patients with systemic lupus erythematosus. AU - Fernandez,David, AU - Bonilla,Eduardo, AU - Mirza,Naureen, AU - Niland,Brian, AU - Perl,Andras, PY - 2006/9/2/pubmed PY - 2006/11/10/medline PY - 2006/9/2/entrez SP - 2983 EP - 8 JF - Arthritis and rheumatism JO - Arthritis Rheum. VL - 54 IS - 9 N2 - OBJECTIVE: Systemic lupus erythematosus (SLE) is an autoimmune disease of unknown origin. Current treatment options are often ineffective or poorly tolerated. Recent observations have revealed mitochondrial hyperpolarization and enhanced Ca2+ fluxing in T cells from SLE patients. Rapamycin, a lipophilic macrolide antibiotic that regulates mitochondrial transmembrane potential and Ca2+ fluxing, has been used safely and effectively to treat renal transplant rejection since 1999. In addition, rapamycin has been shown to ameliorate T cell function and to prolong survival in lupus-prone MRL/lpr mice. We therefore undertook the present study to investigate whether rapamycin is beneficial in patients with SLE. METHODS: Nine patients with clinically active SLE that had been treated unsuccessfully with other immunosuppressive medications began therapy with rapamycin, 2 mg/day orally. Disease activity was assessed with the British Isles Lupus Assessment Group (BILAG) score, SLE Disease Activity Index (SLEDAI), and requirement for prednisone therapy. Mitochondrial transmembrane potential and Ca2+ fluxing were assessed by flow cytometry. RESULTS: In patients treated with rapamycin, the BILAG score was reduced by a mean +/- SEM of 1.93 +/- 0.9 (P = 0.0218), the SLEDAI by 5.3 +/- 0.8 (P = 0.00002), and concurrent prednisone use by 26.4 +/- 6.7 mg/day (P = 0.0062) compared with pre-rapamycin treatment. While mitochondrial hyperpolarization persisted, pretreatment cytosolic and mitochondrial Ca2+ levels and T cell activation-induced rapid Ca2+ fluxing were normalized in rapamycin-treated patients. CONCLUSION: Rapamycin appears to be a safe and effective therapy for SLE that has been refractory to traditional medications. Mitochondrial dysfunction and Ca2+ fluxing could serve as biomarkers to guide decisions regarding future therapeutic interventions in SLE. SN - 0004-3591 UR - https://www.unboundmedicine.com/medline/citation/16947529/Rapamycin_reduces_disease_activity_and_normalizes_T_cell_activation_induced_calcium_fluxing_in_patients_with_systemic_lupus_erythematosus_ L2 - https://doi.org/10.1002/art.22085 DB - PRIME DP - Unbound Medicine ER -