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AB0518 Clinical Relevance of the Activity of P-Glycoprotein on Peripheral Blood Mononuclear Cells and Polymorphonuclear Neutrophils to Methotrexate in Patients with Systemic Lupus Erythematosus
  1. C. Mendoza-Pinto1,2,
  2. M. García Carrasco1,2,
  3. S. Macías Díaz3,
  4. S. Méndez Martínez3,
  5. P. Soto Santillán1,
  6. B. Pérez Romano4,
  7. E.O. Guzmán Ruiz4,
  8. A. Ruiz Arguelles4,5
  1. 1Department of Rheumatology and Immunology, Benemérita Universidad Autόnoma de Puebla
  2. 2Systemic Autoimmune Diseases Research Unit, HGR 36-CIBIOR, Instituto Mexicano del Seguro Social
  3. 3Systemic Autoimmune Diseases Research Unit, HGR 36-CIBIOR, HGR 36, Instituto Mexicano del Seguro Social
  4. 4Department of Immunology, Laboratorios Clínicos de Puebla
  5. 5Department of Chemistry and Biology, School of Sciences, Universidad de las Américas Puebla, Puebla, Mexico

Abstract

Background Previous studies have reported that methotrexate is effluxed from cells by several transmembrane proteins, including P glycoprotein (P-gp). Moreover, various studies have examined the relationship between disease activity and P-gp expression levels/function in systemic lupus erythematosus (SLE) patients. Nonetheless, the role of P-gp activity in SLE patients receiving methotrexate has not previously been evaluated.

Objectives To investigate the relationship between P-gp activity on peripheral blood leukocytes from SLE patients with lupus arthritis and clinical response to methotrexate.

Methods Mononuclear cells (MNC) and polymorphonuclear neutrophils (PMN) were isolated from SLE patients (≥4 of the ACR classification criteria) with joint manifestations who had received methotrexate and corticosteroids (≥15 mg). Methotrexate responders and non-responders were compared according to the Clinical Disease Activity Index (CDAI) score. A flow cytometric daunorrubicin- efflux assay was made in peripheral blood leukocytes to determine the P-gp activity.

Results Thirty-two patients were included: 34.4% had responded to methotrexate and 65.6% had not. The mean relative fluorescence unit (RFU) of both MNC and PMN were significantly lower in patients with a good response compared with those without good response (7.0±4.3 vs. 9.6±3.8; p=0.4 and 4.2±3.5 vs. 7.6±4.0; p=0.004. The prevalence of low fluorescence levels (<5 RFU), which signifies higher P-gp activity of both MNC and PMNC was higher in methotrexate responders compared to non-responders, 27.3% vs. 4.8% (p=0.10) and 81.8% vs. 23.8% (p=0.003), respectively.

Conclusions In patients with SLE, P-gp activity with clinical response to oral methotrexate treatment led to down P-gp activity. Further studies are required to determine the mechanisms behind this finding and whether P-gp activity mediates alterations in the efficacy of methotrexate.

References

  1. Carneiro JR, Sato EI. Double blind, randomized, placebo controlled clinical trial of methotrexate in systemic lupus erythematosus. J Rheumatol. 1999; 26: 1275–9.

  2. Tsujimura S, Saito K, Nakayamada S, et al. Clinical relevance of the expression of P-glycoprotein on peripheral blood lymphocytes to steroid resistance in patients with systemic lupus erythematosus. Arthritis Rheumatol. 2005; 52: 1676–1683.

  3. Lu MC, Lai NS, Li KJ, et al. Increased multidrug resistance-associated protein activity in mononuclear cells of patients with systemic lupus erythematosus. Clin Exp Rheumatol. 2008; 26: 638-645.

Acknowledgements We would like to thank David Buss for his valuable guidance and advice during this project.

Disclosure of Interest None declared

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