Hydroxychloroquine levels in patients with systemic lupus erythematosus: whole blood is preferable but serum levels also detect non-adherence
Authors: Blanchet Benoit , Jallouli Moez , Allard Marie , Ghillani-Dalbin Pascale , Galicier Lionel , Aumaître Olivier , Chasset François , Le Guern Véronique , Lioté Frédéric , Smail Amar , Limal Nicolas , Perard Laurent , Desmurs-Clavel Hélène , Le Thi Huong Du , Asli Bouchra , Kahn Jean-Emmanuel , Sailler Laurent , Ackermann Félix , Papo Thomas , Sacré Karim , Fain Olivier , Stirnemann Jérôme , Cacoub Patrice , Leroux Gaelle , Cohen-Bittan Judith , Sellam Jérémie , Mariette Xavier , Goulvestre Claire , Hulot Jean Sébastien , Amoura Zahir , Vidal Michel , Piette Jean-Charles ,   on behalf of the PLUS Group, Astudillo Leonardo , Belizna Cristina , Belmatoug Nadia , Benveniste Olivier , Benyamine Audrey , Bezanahary Holly , Blanco Patrick , Bodaghi Bahram , Bourgeois Pierre , Brihaye Benoît , Chatelus Emmanuel , Damade Richard , Daugas Eric , De Gennes Christian , Delfraissy Jean-François , Delluc Céline , Delluc Aurélien , Duhaut Pierre , Dupuy Alain , Durieu Isabelle , Ea Hang Korng , Farge Dominique , Funck-Brentano Christian , Gandjbakhch Frédérique , Gellen-Dautremer Justine , Godeau Bertrand , Goujard Cécile , Grandpeix Catherine , Grange Claire , Grimaldi Lamiae , Guettrot-Imbert Gaëlle , Guillevin Loïc , Hachulla Eric , Harle Jean-Robert , Haroche Julien , Hausfater Pierre , Jouquan Jean , Kaplanski Gilles , Keshtmand Homa , Khellaf Mehdi , Lambotte Olivier , Launay David , Lechat Philippe , Levesque Hervé , Lidove Olivier , Liozon Eric , Ly Kim , Mahevas Matthieu , Mariampillai Kubéraka , Mathian Alexis , Mazodier Karin , Michel Marc , Morel Nathalie , Mouthon Luc , Musset Lucile , Ngack Rokiya , Ninet Jacques , Oksenhendler Eric , Pellegrin Jean-Luc , Peyr Olivier , Piette Anne-Marie , Poindron Vincent , Pourrat Jacques , Roux Fabienne , Saadoun David , Sahali Sabrinel , Saint-Marcoux Bernadette , Sarrot-Reynauld Françoise , Schoindre Yoland , Sene Damien , Serratrice Jacques , Seve Pascal , Sibilia Jean , Simon Claude , Sordet Christelle , Terrier Benjamin , Trad Salim , Viallard Jean-François , Vidal Elisabeth , Wechsler Bertrand , Weiller Pierre-Jean , Jourde-Chiche Noémie , Costedoat-Chalumeau Nathalie 
Published: September 2020

Abstract
Background
Hydroxychloroquine (HCQ) levels can be measured in both serum and whole blood. No cut-off point for non-adherence has been established in serum nor have these methods ever been compared. The aims of this study were to compare these two approaches and determine if serum HCQ cut-off points can be established to identify non-adherent patients.

Methods
HCQ levels were measured in serum and whole blood from 573 patients with systemic lupus erythematosus (SLE). The risk factors for active SLE (SLEDAI score > 4) were identified by multiple logistic regression. Serum HCQ levels were measured in 68 additional patients known to be non-adherent, i.e. with whole-blood HCQ < 200 ng/mL.

Results
The mean (± SD) HCQ levels were 469 ± 223 ng/mL in serum and 916 ± 449 ng/mL in whole blood. The mean ratio of serum/whole-blood HCQ levels was 0.53 ± 0.15. In the multivariate analysis, low whole-blood HCQ levels (P = 0.023), but not serum HCQ levels, were independently associated with active SLE.
From the mean serum/whole-blood level ratio, a serum HCQ level of 106 ng/mL was extrapolated as the corresponding cut-off to identify non-adherent patients with a sensitivity of 0.87 (95% CI 0.76–0.94) and specificity of 0.89 (95% CI 0.72–0.98).
All serum HCQ levels of patients with whole-blood HCQ below the detectable level (< 20 ng/mL) were also undetectable (< 20 ng/mL).

Conclusions
These data suggest that whole blood is better than serum for assessing the pharmacokinetic/pharmacodynamic relation of HCQ. Our results support the use of serum HCQ levels to assess non-adherence when whole blood is unavailable.