Blood Concentrations of Hydroxychloroquine and Its Desethyl Derivative Correlate Negatively with the Percentage of CD45RO⁺ Cells among CD4⁺ Lymphocytes in Hydroxychloroquine-Treated Lupus Patients

Authors: SAILLER, LAURENT; PUISSANT, BÉNÉDICTE¹; MÉLIANI, PASCAL²; CASTEX, JEAN OLIVIER³; SAIVIN, SYLVIE³; ADOUE, D⁴; FOURNIE, B⁵; ARLET, PHILIPPE²; MONTASTRUC, JEAN-LOUIS⁶; LAPEYRE-MESTRE, MARYSE⁶; POURRAT, JACQUES⁷; BLANCHER, ANTOINE¹

Source: Annals of the New York Academy of Sciences, Volume 1108, Number 1, June 2007 , pp. 41-50(10)

Publisher: Blackwell Publishing

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Abstract:

The objective of the study was to investigate the influence of the blood concentrations of hydroxychloroquine ([HCQ]) and its derivative desethylhydroxychloroquine ([DHCQ]) on lymphocyte activation or differentiation in HCQ-treated lupus patients. We studied the correlations between [HCQ], [DHCQ], and the frequency of various lymphocyte subsets in 58 HCQ-treated lupus patients (mean HCQ dose: 4.93 ± 1.58 mg/kg/day; mean duration of the disease: 122 ± 64 months). [HCQ] and [DHCQ] were determined by high-performance liquid chromatography (HPLC). Lymphocyte markers were studied by flow cytometry using monoclonal anti-CD3, -CD4, -CD8, -CD25, -DR, -CD45RA,-CD45RO, -CD19, -CD38, and -CD86 antibodies. sIL2-R serum concentrations were measured by enzyme-linked immunosorbent assay (ELISA). [HCQ] and [DHCQ] were 599.9 ng/mL (median: 529.5; range: 55-1935) and 353.43 (median: 286 ng/mL; range: 118-1090). In a multiple regression analysis, [HCQ] and [DHCQ] were associated with the HCQ prescribed dose in mg/kg/day (P= 0.0002 and P= 0.03) and with compliance to the treatment (P= 0.004 and P= 0.03). We found a negative correlation between [HCQ], [DHCQ], and the CD45RO⁺ cell frequency among CD3⁺CD4⁺ cells (P= 0.03 and P= 0.007, respectively). Other lymphocyte subset markers (LSMs) and sIL2-R concentrations were not significantly associated with [HCQ] or [DHCQ]. In the multiple regression analysis, CD45RO⁺ expression was negatively influenced by [HCQ] (P= 0.005), and positively influenced by smoking habits (P= 0.005) and age (P= 0.005). Similar results were found in the multivariate model including [DHCQ]. Disease activity and taking more than 10 mg/day of corticosteroids or an immunosuppressive drug did not influence CD45RO⁺ expression. Lupus patients had less CD3⁺CD4⁺CD45RO⁺ cells than controls (P= 0.03). In lupus patients, HCQ and DHCQ may alter the generation or the blood circulation of CD4⁺CD45RO⁺ lymphocytes in a concentration-dependent pattern.

Keywords: hydroxychloroquine; desethylhydroxychloroquine; systemic lupus erythematosus; lymphocytes; smoking

Document Type: Research article

DOI: 10.1196/annals.1422.005

Affiliations: 1: Laboratoire d'Immunologie, Hôpital de Rangueil, 31059 Toulouse Cédex, France 2: Service de Médecine Interne, Salle Le Tallec Hôpital Purpan, 31059 Toulouse Cédex, France 3: Service de Pharmacologie Clinique, Laboratoire de Pharmacocinétique Clinique et Toxicologie, Hôpital Purpan, 31059 Toulouse Cédex, France 4: Service de Médecine interne, Pavillon des Médecines, Hôpital Purpan, 31059 Toulouse Cédex, France 5: Service de Rhumatologie et Réadaptation Fonctionnelle, CHU Purpan, 31059 Toulouse Cédex, France 6: Service de Pharmacologie Clinique, Unité de Pharmacoépidémiologie EA3696, INSERM IFR 126,Faculté de Médecine, Université Paul Sabatier, 31000 Toulouse, France 7: Service de Néphrologie et Immunologie Clinique, Hôpital de Ranguei, 31059 Toulouse Cédex, France

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