Around 25% of patients with systemic lupus erythematosus (SLE) could be refractory to conventional therapies. P-glycoprotein expression on cell surface has been implied on drug resistance, however, to date, it is unknown if P-gp serum levels are associated with SLE disease activity. Evaluate the association of serum P-gp levels and SLE with disease activity despite treatment. A cross-sectional study was conducted on 93 female SLE patients, all receiving glucocorticoids at stable doses for the previous 6 months before to baseline. SLE patients were classified into two groups: (a) patients with active disease [SLE disease activity index (SLEDAI) ≥ 3] despite treatment, and (b) patients with inactive disease (SLEDAI < 3) after treatment. Forty-three healthy females comprised the control group. Serum P-gp, anti-DNA, and both anti-nucleosome antibody levels were measured using ELISA. Active-SLE patients despite treatment had higher P-gp levels compared with inactive-SLE after treatment (78.02 ng/mL ± 114.11 vs. 33.75 ng/mL ± 41.11; p = 0.018) or versus reference group subjects (30.56 ng/mL ± 28.92; p = 0.011). P-gp levels correlated with the scores of SLEDAI (r = 0.26; p = 0.01), Mexican-SLEDAI (MEX-SLEDAI) (r = 0.32; p = 0.002), SLICC/ACR damage index (r = 0.47; p < 0.001), and with prednisone doses (r = 0.33; p = 0.001). In the multivariate model, the high P-gp levels were associated with SLICC/ACR score (p = 0.001), and SLEDAI score (p = 0.014). Our findings support a relationship between serum P-gp levels and SLE with disease activity despite treatment, but it requires further validation in longitudinal studies.
Drug resistance P-glycoprotein Glucocorticoids Systemic lupus erythematosus Disease activity
This is a preview of subscription content, log in to check access.
The authors wish thank to IMSS Foundation (Fundacion IMSS, A.C.) for the support for the research. Also, the authors thank M.B., M.A., for her style correction of the manuscript
This project was financed by a Grant from the “Fondo en Investigación en Salud” del Instituto Mexicano del Seguro Social. Grant: FIS/IMSS/PROT/G14/1296. Dr Gonzalez-Lopez holds Fundacion IMSS, A.C research scholarship (Beca de Excelencia en Investigación 2016 por la Fundación IMSS, A. C.)
Compliance with ethical standards
Authors declare that they have no conflict of interest.
This study was conducted according to the recommendations described by the 64th Declaration of Helsinki and was in accordance with the ethical standards of the Ethics and Research Board of UMAE Centro Medico Nacional de Occidente del Instituto Mexicano del Seguro Social (13-01 with approval code: R-2014-1301-77).
Informed consent was obtained from all individual participants included in the study.
Ruiz E, Ramalle-Gomara E, Elena A, Quinones C, Alonso V, Posada M. Trends in systemic lupus erythematosus mortality in Spain from 1981 to 2010. Lupus. 2014;23:431–5.CrossRefPubMedGoogle Scholar
Cervera R, Khamashta MA, Font J, et al. Morbidity and mortality in systemic lupus erythematosus during a 10-year period: a comparison of early and late manifestations in a cohort of 1,000 patients. Medicine (Baltimore). 2003;82:299–308.CrossRefGoogle Scholar
Mak A, Cheung MWL, Chiew HJ, Liu Y, Ho RC. Global trend of survival and damage of systemic lupus erythematosus: meta-analysis and meta-regression of observational studies from the 1950s to 2000s. Semin Arthritis Rheum. 2012;41:830–9.CrossRefPubMedGoogle Scholar
Pego-Reigosa JM, Rua-Figueroa I, Lopez-Longo FJ, et al. Analysis of disease activity and response to treatment in a large Spanish cohort of patients with systemic lupus erythematosus. Lupus. 2014;24:720–9.CrossRefPubMedGoogle Scholar
García-Carrasco M, Mendoza-Pinto C, Macias Díaz S, et al. P-glycoprotein in autoimmune rheumatic diseases. Autoimmun Rev. 2015;14:594–600.CrossRefPubMedGoogle Scholar
Gottesman MM, Fojo T, Bates SE. Multidrug resistance in cancer: role of ATP-dependent transporters. Nat Rev Cancer. 2002;2:48–58.CrossRefPubMedGoogle Scholar
Zhang C, Zuo Z, Kwan P, Baum L. In vitro transport profile of carbamazepine, oxcarbazepine, eslicarbazepine acetate, and their active metabolites by human P-glycoprotein. Epilepsia. 2011;52:1894–904.CrossRefPubMedGoogle Scholar
Huisman MT, Smit JW, Schinkel AH. Significance of P-glycoprotein for the pharmacology and clinical use of HIV protease inhibitors. AIDS. 2000;14:237–42.CrossRefPubMedGoogle Scholar
Chu TM, Lin TH, Kawinski E. Detection of soluble P-glycoprotein in culture media and extracellular fluids. Biochem Biophys Res Commun. 1994;203:506–12.CrossRefPubMedGoogle Scholar
Chiampanichayakul S, Anuchapreeda S, Chruewkamlow N, Mahasongkram K, Thanaratanakorn P, Kasinrerk W. Production of monoclonal antibodies to P-glycoprotein: its application in detection of soluble and surface P-glycoprotein of leukemia patients. Int J Hematol. 2010;92:326–33.CrossRefPubMedGoogle Scholar
Lum BL, Gosland MP. MDR expression in normal tissues. Pharmacologic implications for the clinical use of P-glycoprotein inhibitors. Hematol Oncol Clin North Am. 1995;9:319–36.PubMedGoogle Scholar
Picchianti-Diamanti A, Rosado MM, Scarsella M, Laganà B, D’Amelio R. P-glycoprotein and drug resistance in systemic autoimmune diseases. Int J Mol Sci. 2014;15:4965–76.CrossRefPubMedPubMedCentralGoogle Scholar
Henmi K, Yoshida M, Yoshikawa N, Hirano T. P-glycoprotein functions in peripheral-blood CD4+ cells of patients with systemic lupus erythematosus. Biol Pharm Bull. 2008;31:873–8.CrossRefPubMedGoogle Scholar
Klimecki WT, Futscher BW, Grogan TM, Dalton WS. P-glycoprotein expression and function in circulating blood cells from normal volunteers. Blood. 1994;83:2451–8.PubMedGoogle Scholar
Richaud-Patin Y, Soto-Vega E, Jakez-Ocampo J, Llorente L. P-glycoprotein in autoimmune diseases. Autoimmun Rev. 2004;3:188–92.CrossRefPubMedGoogle Scholar
Norris MD, De Graaf D, Haber M, et al. Involvement of MDR1 P-glycoprotein in multifactorial resistance to methotrexate. Int J Cancer. 1996;65:613–9.CrossRefPubMedGoogle Scholar
Tsujimura S, Saito K, Nakayamada S, Tanaka Y. Relevance of multidrug resistance 1 and P-glycoprotein to drug resistance in patients with systemic lupus erythematosus. Histol Histopathol. 2007;22:465–8.PubMedGoogle Scholar
Kansal A, Tripathi D, Rai MK, Agarwal V. Persistent expression and function of P-glycoprotein on peripheral blood lymphocytes identifies corticosteroid resistance in patients with systemic lupus erythematosus. Clin Rheumatol. 2015;35:341–9.CrossRefPubMedGoogle Scholar
Tsujimura S, Saito K, Nakayamada S, Nakano K, Tanaka Y. Clinical relevance of the expression of P-glycoprotein on peripheral blood lymphocytes to steroid resistance in patients with systemic lupus erythematosus. Arthritis Rheum. 2005;52:1676–83.CrossRefPubMedGoogle Scholar
Gladman D, Ginzler E, Goldsmith C, et al. The development and initial validation of the Systemic Lupus International Collaborating Clinics/American College of Rheumatology damage index for systemic lupus erythematosus. Arthritis Rheum. 1996;39:363–9.CrossRefPubMedGoogle Scholar
Guzman J, Cardiel MH, Arce-Salinas A, Sanchez-Guerrero J, Alarcon-Segovia D. Measurement of disease activity in systemic lupus erythematosus. Prospective validation of 3 clinical indices. J Rheumatol. 1992;19:1551–8.PubMedGoogle Scholar
Bombardier C, Gladman DD, Urowitz MB, et al. Derivation of the sledai. A disease activity index for lupus patients. Arthritis Rheum. 1992;35:630–40.CrossRefPubMedGoogle Scholar
Tsujimura S, Saito K, Nakayamada S, et al. Transcriptional regulation of multidrug resistance-1 gene by interleukin-2 in lymphocytes. Genes Cells. 2004;9:1265–73.CrossRefPubMedGoogle Scholar
Tsujimura S, Tanaka Y. Treatment strategy based on targeting P-glycoprotein on peripheral lymphocytes in patients with systemic autoimmune disease. Clin Exp Nephrol. 2012;16:102–8.CrossRefPubMedGoogle Scholar
Ramesh R, Kozhaya L, McKevitt K, et al. Pro-inflammatory human Th17 cells selectively express P-glycoprotein and are refractory to glucocorticoids. J Exp Med. 2014;211:89–104.CrossRefPubMedPubMedCentralGoogle Scholar
Prasad N, Jaiswal AK, Agarwal V, et al. Differential alteration in peripheral T-regulatory and T-effector cells with change in P-glycoprotein expression in Childhood Nephrotic Syndrome: A longitudinal study. Cytokine. 2015;72:190–6.CrossRefPubMedGoogle Scholar
Pawlik A, Baskiewicz-Masiuk M, Machalinski B, Safranow K, Gawronska-Szklarz B. Involvement of P-glycoprotein in the release of cytokines from peripheral blood mononuclear cells treated with methotrexate and dexamethasone. J Pharm Pharmacol. 2005;57:1421–5.CrossRefPubMedGoogle Scholar
Drach J, Gsur A, Hamilton G, et al. Involvement of P-glycoprotein in the transmembrane transport of interleukin-2 (IL-2), IL-4, and interferon-gamma in normal human T lymphocytes. Blood. 1996;88:1747–54.PubMedGoogle Scholar