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      Hydroxychloroquine levels in patients with systemic lupus erythematosus: whole blood is preferable but serum levels also detect non-adherence

      research-article
      1 , 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 11 , 20 , 7 , 8 , 21 , 22 , 23 , 24 , 4 , 5 , 4 , 5 , 25 , 26 , 11 , 27 , 11 , 27 , 28 , 29 , 30 , 31 , 32 , 11 , 20 , 1 , 2 , 11 , 27 , on behalf of the PLUS Group, 33 , 13 , 34 , 35 ,
      Arthritis Research & Therapy
      BioMed Central
      Hydroxychloroquine, Systemic lupus erythematosus, Serum, Drug monitoring, Adherence

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          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.

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          Most cited references18

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          Clinical efficacy and side effects of antimalarials in systemic lupus erythematosus: a systematic review.

          Antimalarial drugs (AMs), chloroquine (CQ) and hydroxychloroquine (HCQ), are frequently withdrawn in patients with lupus with either severe or remitting disease. However, additional effects beyond immunomodulation have been recently described. The aim of the present work was to analyse all the published evidence of the beneficial and adverse effects of AM therapy in systemic lupus erythematosus (SLE). A systematic review of the English literature between 1982 and 2007 was conducted using the MEDLINE and EMBASE databases. Randomised controlled trials (RCTs) and observational studies were selected. Case reports were excluded except for toxicity reports. The GRADE system was used to analyse the quality of the evidence. A total of 95 articles were included in the systematic review. High levels of evidence were found that AMs prevent lupus flares and increase long-term survival of patients with SLE; moderate evidence of protection against irreversible organ damage, thrombosis and bone mass loss. Toxicity related to AMs is infrequent, mild and usually reversible, with HCQ having a safer profile. In pregnant women, high levels of evidence were found that AMs, particularly HCQ, decrease lupus activity without harming the baby. By contrast, evidence supporting an effect on severe lupus activity, lipid levels and subclinical atherosclerosis was weak. Individual papers suggest effects in preventing the evolution from SLE-like to full-blown SLE, influencing vitamin D levels and protecting patients with lupus against cancer. Given the broad spectrum of beneficial effects and the safety profile, HCQ should be given to most patients with SLE during the whole course of the disease, irrespective of its severity, and be continued during pregnancy.
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            The risk of toxic retinopathy in patients on long-term hydroxychloroquine therapy.

            Hydroxychloroquine sulfate is widely used for the long-term treatment of autoimmune conditions but can cause irreversible toxic retinopathy. Prior estimations of risk were low but were based largely on short-term users or severe retinal toxicity (bull's eye maculopathy). The risk may be much higher because retinopathy can be detected earlier when using more sensitive screening techniques.
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              • Article: not found

              A randomized study of the effect of withdrawing hydroxychloroquine sulfate in systemic lupus erythematosus. The Canadian Hydroxychloroquine Study Group.

              The antimalarial drug hydroxychloroquine is thought to be effective in controlling some of the manifestations of systemic lupus erythematosus, but its effectiveness has not been demonstrated conclusively. We conducted a six-month, randomized, double-blind, placebo-controlled study of the effect of discontinuing hydroxychloroquine sulfate treatment in 47 patients with clinically stable systemic lupus erythematosus. The patients were randomly assigned to continue their same dose of hydroxychloroquine (n = 25) or to receive placebo (n = 22) for 24 weeks. Ten patients in each group were also taking prednisone. The relative risk of a clinical flare-up, defined as the development of specific clinical manifestations of systemic lupus erythematosus or an increase in their severity, was 2.5 times higher (95 percent confidence interval, 1.08 to 5.58) in the patients taking placebo than in those continuing to take hydroxychloroquine (16 of 22 patients vs. 9 of 25 had flare-ups), and the time to a flare-up was shorter (P = 0.02). The relative risk of a severe exacerbation of disease that required withdrawal from the study was 6.1 times higher (95 percent confidence interval, 0.72 to 52.44) for the patients taking placebo (5 of 22 patients vs. 1 of 25 had severe exacerbations of disease). Changes in the dose of prednisone were not different in the two groups. Patients with quiescent systemic lupus erythematosus who are taking hydroxychloroquine are less likely to have a clinical flare-up if they are maintained on the drug.
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                Author and article information

                Contributors
                nathalie.costedoat@gmail.com
                Journal
                Arthritis Res Ther
                Arthritis Res. Ther
                Arthritis Research & Therapy
                BioMed Central (London )
                1478-6354
                1478-6362
                25 September 2020
                25 September 2020
                2020
                : 22
                : 223
                Affiliations
                [1 ]GRID grid.411784.f, ISNI 0000 0001 0274 3893, AP-HP, Hôpital Cochin, Biologie du médicament – Toxicologie, ; 27 rue du Faubourg Saint-Jacques, 75014 Paris, France
                [2 ]GRID grid.10992.33, ISNI 0000 0001 2188 0914, UMR8038 CNRS, U1268 INSERM, Faculty of Pharmacy, , University Paris Descartes, PRES Sorbonne Paris Cité, ; Paris, France
                [3 ]GRID grid.413980.7, Service de Médecine interne, Hôpital Hédi Chaker, ; Sfax, Tunisie
                [4 ]GRID grid.7452.4, ISNI 0000 0001 2217 0017, Université Paris-Diderot, Sorbonne Paris-Cité, ; F-75205 Paris, France
                [5 ]AP-HP, Hôpital Bichat Claude-Bernard, service de médecine interne, 46 rue Henri-Huchard, 75018 Paris, France
                [6 ]GRID grid.411439.a, ISNI 0000 0001 2150 9058, AP-HP, Hôpital Pitié-Salpêtrière, Département d’immunologie, ; 47-83 Boulevard de l’Hôpital, 75651 Paris Cedex 13, France
                [7 ]GRID grid.7452.4, ISNI 0000 0001 2217 0017, Université Paris Diderot, Sorbonne Paris Cité, ; Paris, France
                [8 ]GRID grid.413328.f, ISNI 0000 0001 2300 6614, AP-HP, Hôpital Saint Louis, service d’immunologie clinique, ; 1 avenue Claude Vellefaux, 75010 Paris, France
                [9 ]GRID grid.494717.8, ISNI 0000000115480420, Université de Clermont-Ferrand, ; 63003 Clermont-Ferrand, France
                [10 ]GRID grid.411163.0, ISNI 0000 0004 0639 4151, CHU Clermont-Ferrand, Hôpital Gabriel Montpied, service de médecine interne, ; 58 rue Montalembert, 63003 Clermont-Ferrand cedex1, France
                [11 ]GRID grid.462844.8, ISNI 0000 0001 2308 1657, UPMC, Université Paris 6, ; Paris, France
                [12 ]AP-HP, Hôpital Tenon, service de dermatologie allergologie, 4 rue de la Chine, 75020 Paris, France
                [13 ]GRID grid.411784.f, ISNI 0000 0001 0274 3893, AP-HP, Hôpital Cochin, Centre de référence maladies auto-immunes et systémiques rares, service de médecine interne, ; 27 rue du Faubourg Saint-Jacques, 75014 Paris, France
                [14 ]GRID grid.5842.b, ISNI 0000 0001 2171 2558, Université de Paris, ; F-75205 Paris, France
                [15 ]GRID grid.411296.9, ISNI 0000 0000 9725 279X, AP-HP, Hôpital Lariboisière, service de rhumatologie, DMU Locomotion, ; 2 rue Ambroise Paré, 75010 Paris, France
                [16 ]GRID grid.134996.0, ISNI 0000 0004 0593 702X, CHU Amiens, Hôpital Nord, service de médecine interne, ; Place Victor Pauchet, 80000 Amiens, France
                [17 ]GRID grid.412116.1, ISNI 0000 0001 2292 1474, AP-HP, Hôpital Henri Mondor, service de médecine interne, ; 51 avenue du Maréchal de Tassigny, 94000 Créteil, France
                [18 ]GRID grid.489921.f, Centre Hospitalier Saint Joseph Saint Luc, service de médecine interne, ; 20 quai Claude Bernard, 69007 Lyon, France
                [19 ]GRID grid.413852.9, ISNI 0000 0001 2163 3825, Hospices Civils de Lyon, Groupement Hospitalier Edouard Herriot, service de médecine interne, ; 5 place d’Arsonval, 69003 Lyon, France
                [20 ]GRID grid.411439.a, ISNI 0000 0001 2150 9058, AP-HP, Hôpital Pitié-Salpêtrière, Centre de référence pour le Lupus Systémique et le syndrome des Antiphospholipides, service de médecine interne, ; 47-83 Boulevard de l’Hôpital, 75651 Paris Cedex 13, France
                [21 ]GRID grid.413756.2, ISNI 0000 0000 9982 5352, Servie de Médecine Interne, , Hôpital Ambroise Paré, Université Paris Saclay, ; 9 Avenue Charles de Gaulle, 92104 Boulogne-Billancourt, France
                [22 ]GRID grid.15781.3a, ISNI 0000 0001 0723 035X, Université Paul-Sabatier, ; Toulouse, France
                [23 ]GRID grid.414282.9, ISNI 0000 0004 0639 4960, CHU Toulouse, Hôpital Purpan, Service de Médecine Interne, ; Place Dr Baylac, F-31059 Toulouse, France
                [24 ]GRID grid.414106.6, ISNI 0000 0000 8642 9959, Hôpital Foch, Service de médecine interne, ; 92150 Suresnes, France
                [25 ]Sorbonne Université, Hôpital Saint Antoine, APHP, service de médecine interne, F 75012 Paris, France
                [26 ]GRID grid.150338.c, ISNI 0000 0001 0721 9812, Hôpitaux Universitaires de Genève, Service de Médecine interne Générale, ; Avenue Gabrielle Perret Gentil 4, CH-1211 Geneva, Switzerland
                [27 ]GRID grid.411439.a, ISNI 0000 0001 2150 9058, AP-HP, Hôpital Pitié-Salpêtrière, Centre de référence maladies auto-immunes et systémiques rares, service de médecine interne 2, ; 47-83 Boulevard de l’Hôpital, 75651 Paris Cedex 13, France
                [28 ]GRID grid.411439.a, ISNI 0000 0001 2150 9058, AP-HP, Hôpital Pitié-Salpêtrière, service de gériatrie, ; 47-83 Boulevard de l’Hôpital, 75651 Paris Cedex 13, France
                [29 ]GRID grid.412370.3, ISNI 0000 0004 1937 1100, AP-HP, Hôpital Saint Antoine, Service de Rhumatologie, ; 184 Rue du Faubourg Saint-Antoine, 75012 Paris, France
                [30 ]GRID grid.50550.35, ISNI 0000 0001 2175 4109, Service de Rhumatologie, Hôpitaux Universitaires Paris-Sud, AP-HP, Université Paris-Sud, INSERM UMR 1184, ; Paris, France
                [31 ]GRID grid.411784.f, ISNI 0000 0001 0274 3893, AP-HP, Hôpital Cochin, service d’immunologie biologique, ; 27 rue du Faubourg Saint-Jacques, 75014 Paris, France
                [32 ]GRID grid.462416.3, ISNI 0000 0004 0495 1460, INSERM, UMRS 970, Paris Cardiovascular Research Center, ; Paris, France
                [33 ]GRID grid.5399.6, ISNI 0000 0001 2176 4817, Aix-Marseille Univ, C2VN, INSERM 1263, INRA 1260 ; AP-HM, Centre de Néphrologie et Transplantation Rénale, ; Marseille, France
                [34 ]GRID grid.10992.33, ISNI 0000 0001 2188 0914, Université Paris-Descartes, ; Paris, France
                [35 ]GRID grid.469994.f, ISNI 0000 0004 1788 6194, INSERM U 1153, Center for Epidemiology and Statistics Sorbonne Paris Cité (CRESS), ; Paris, France
                Author information
                http://orcid.org/0000-0002-1555-9021
                Article
                2291
                10.1186/s13075-020-02291-z
                7517694
                32977856
                ece03d8f-7c27-426e-98d1-b8d9ee5d586e
                © The Author(s) 2020

                Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

                History
                : 13 February 2020
                : 7 August 2020
                Funding
                Funded by: FundRef http://dx.doi.org/10.13039/100006695, Ministère de la santé "French PHRC 2005";
                Categories
                Research Article
                Custom metadata
                © The Author(s) 2020

                Orthopedics
                hydroxychloroquine,systemic lupus erythematosus,serum,drug monitoring,adherence
                Orthopedics
                hydroxychloroquine, systemic lupus erythematosus, serum, drug monitoring, adherence

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