Recent findings about antimalarials in cutaneous lupus erythematosus: What dermatologists should know.

Publisher: Wiley-Blackwell Country of Publication: England NLM ID: 7600545 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1346-8138 (Electronic) Linking ISSN: 03852407 NLM ISO Abbreviation: J Dermatol Subsets: MEDLINE

Publication: London : Wiley-Blackwell
Original Publication: Tokyo, Japanese Dermatological Association, <-2005>

Antimalarials*/adverse effects ; Antimalarials*/administration & dosage ; Antimalarials*/therapeutic use ; Lupus Erythematosus, Cutaneous*/chemically induced ; Lupus Erythematosus, Cutaneous*/drug therapy ; Lupus Erythematosus, Cutaneous*/diagnosis ; Lupus Erythematosus, Cutaneous*/blood ; Hydroxychloroquine*/adverse effects ; Hydroxychloroquine*/therapeutic use ; Hydroxychloroquine*/administration & dosage; Humans ; Chloroquine/adverse effects ; Chloroquine/administration & dosage ; Chloroquine/therapeutic use ; Quinacrine/administration & dosage ; Quinacrine/therapeutic use ; Quinacrine/adverse effects ; Lupus Erythematosus, Systemic/drug therapy ; Lupus Erythematosus, Systemic/blood

Antimalarials (AMs), particularly hydroxychloroquine (HCQ) and chloroquine (CQ), are the cornerstone of the treatment for both systemic lupus erythematosus (SLE) and cutaneous lupus erythematosus (CLE). HCQ and CQ are recommended as first-line oral agents in all CLE guidelines. Initially thought to have potential therapeutic effects against COVID-19, HCQ has drawn significant attention in recent years, highlighting concerns over its potential toxicity among patients and physicians. This review aims to consolidate current evidence on the efficacy of AMs in CLE. Our focus will be on optimizing therapeutic strategies, such as switching from HCQ to CQ, adding quinacrine to either HCQ or CQ, or adjusting HCQ dose based on blood concentration. Additionally, we will explore the potential for HCQ dose reduction or discontinuation in cases of CLE or SLE remission. Our review will focus on the existing evidence regarding adverse events linked to AM usage, with a specific emphasis on severe events and those of particular interest to dermatologists. Last, we will discuss the optimal HCQ dose and the balance between preventing CLE or SLE flares and minimizing toxicity.
(© 2024 Japanese Dermatological Association.)

The Canadian Hydroxychloroquine Study Group. A randomized study of the effect of withdrawing hydroxychloroquine sulfate in systemic lupus erythematosus. N Engl J Med. 1991;324:150–154.
Tsakonas E, Joseph L, Esdaile JM, Choquette D, Senécal JL, Cividino A, et al. A long‐term study of hydroxychloroquine withdrawal on exacerbations in systemic lupus erythematosus. Lupus. 1998;7:80–85.
Levy RA, Vilela VS, Cataldo MJ, Ramos RC, Duarte JLMB, Tura BR, et al. Hydroxychloroquine (HCQ) in lupus pregnancy: double‐blind and placebo‐controlled study. Lupus. 2001;10:401–404.
Williams HJ, Egger MJ, Singer JZ, Willkens RF, Kalunian KC, Clegg DO, et al. Comparison of hydroxychloroquine and placebo in the treatment of the arthropathy of mild systemic lupus erythematosus. J Rheumatol. 1994;21:1457–1462.
Quatraro A, Consoli G, Magno M, Caretta F, Nardozza A, Ceriello A, et al. Hydroxychloroquine in decompensated, treatment‐refractory noninsulin‐dependent diabetes mellitus. A new job for an old drug? Ann Intern Med. 1990;112:678–681.
Cairoli E, Rebella M, Danese N, Garra V, Borba EF. Hydroxychloroquine reduces low‐density lipoprotein cholesterol levels in systemic lupus erythematosus: a longitudinal evaluation of the lipid‐lowering effect. Lupus. 2012;21:1178–1182.
Alarcón GS, McGwin G, Bertoli AM, Fessler BJ, Calvo‐Alén J, Bastian HM, et al. Effect of hydroxychloroquine on the survival of patients with systemic lupus erythematosus: data from LUMINA, a multiethnic US cohort (LUMINA L). Ann Rheum Dis. 2007;66:1168–1172.
Akhavan PS, Su J, Lou W, Gladman DD, Urowitz MB, Fortin PR. The early protective effect of hydroxychloroquine on the risk of cumulative damage in patients with systemic lupus erythematosus. J Rheumatol. 2013;40:831–841.
Pons‐Estel GJ, Alarcón GS, McGwin G, Danila MI, Zhang J, Bastian HM, et al. Protective effect of hydroxychloroquine on renal damage in patients with lupus nephritis: LXV, data from a multiethnic US cohort. Arthritis Rheum. 2009;61:830–839.
James JA, Kim‐Howard XR, Bruner BF, Jonsson MK, McClain M, Arbuckle MR, et al. Hydroxychloroquine sulfate treatment is associated with later onset of systemic lupus erythematosus. Lupus. 2007;16:401–409.
Pons‐Estel GJ, Alarcón GS, Hachuel L, Boggio G, Wojdyla D, Pascual‐Ramos V, et al. Anti‐malarials exert a protective effect while Mestizo patients are at increased risk of developing SLE renal disease: data from a Latin‐American cohort. Rheumatology (Oxford). 2012;51:1293–1298.
Maisonnasse P, Guedj J, Contreras V, Behillil S, Solas C, Marlin R, et al. Hydroxychloroquine use against SARS‐CoV‐2 infection in non‐human primates. Nature. 2020;585:584–587.
Hong H, Friedland A, Hu M, Anstrom KJ, Halabi S, McKinnon JE, et al. Safety and efficacy of hydroxychloroquine as prophylactic against COVID‐19 in healthcare workers: a meta‐analysis of randomised clinical trials. BMJ Open. 2023;13:e065305.
Melles RB, Marmor MF. The risk of toxic retinopathy in patients on long‐term hydroxychloroquine therapy. JAMA Ophthalmol. 2014;132:1453–1460.
Lenfant T, Costedoat‐Chalumeau N. Hydroxychloroquine dose: balancing toxicity and SLE flare risk. Nat Rev Rheumatol. 2023;19:6–7.
Felten R, Lipsker D, Sibilia J, Chasset F, Arnaud L. The history of lupus throughout the ages. J Am Acad Dermatol. 2022;87:1361–1369.
Wallace DJ. The history of antimalarials. Lupus. 1996;5(Suppl 1):S2–S3.
Page F. Treatment of lupus erythematosus with mepacrine. Lancet. 1951;2:755–758.
Lewis HM, Frumess GM. Plaquenil in the treatment of discoid lupus erythematosus; a preliminary report. AMA Arch Dermatol. 1956;73:576–581.
Christiansen JV. Treatment of lupus erythematosus with chloroquine; therapeutic results and a comparison of the value of chloroquine and mepacrine. Br J Dermatol. 1957;69:157–168.
Kraak JH, Van Ketel W, Prakken JR, Van Zwet W. The value of hydroxychloroquine (PLAQUENIL) for the treatment of chronic discoid lupus erythematosus; a double blind trial. Dermatologica. 1965;130:293–305.
Ruzicka T, Sommerburg C, Goerz G, Kind P, Mensing H. Treatment of cutaneous lupus erythematosus with acitretin and hydroxychloroquine. Br J Dermatol. 1992;127:513–518.
Islam MN, Hossain M, Haq SA, Alam MN, Ten Klooster PM, Rasker JJ. Efficacy and safety of methotrexate in articular and cutaneous manifestations of systemic lupus erythematosus. Int J Rheum Dis. 2012;15:62–68.
Bezerra ELM, Vilar MJP, da Trindade Neto PB, Sato EI. Double‐blind, randomized, controlled clinical trial of clofazimine compared with chloroquine in patients with systemic lupus erythematosus. Arthritis Rheum. 2005;52:3073–3078.
Yokogawa N, Tanikawa A, Amagai M, Kato Y, Momose Y, Arai S, et al. Response to hydroxychloroquine in Japanese patients with lupus‐related skin disease using the cutaneous lupus erythematosus disease area and severity index (CLASI). Mod Rheumatol. 2013;23:318–322.
Chasset F, Bouaziz JD, Costedoat‐Chalumeau N, Francès C, Arnaud L. Efficacy and comparison of antimalarials in cutaneous lupus erythematosus subtypes: a systematic review and meta‐analysis. Br J Dermatol. 2017;177:188–196.
Ruiz‐Irastorza G, Ramos‐Casals M, Brito‐Zeron P, Khamashta MA. Clinical efficacy and side effects of antimalarials in systemic lupus erythematosus: a systematic review. Ann Rheum Dis. 2010;69:20–28.
Mittal L, Zhang L, Feng R, Werth VP. Antimalarial drug toxicities in patients with cutaneous lupus and dermatomyositis: a retrospective cohort study. J Am Acad Dermatol. 2018;78:100–106.e1.
Wahie S, Meggitt SJ. Long‐term response to hydroxychloroquine in patients with discoid lupus erythematosus. Br J Dermatol. 2013;169:653–659.
Kuhn A, Aberer E, Bata‐Csörgő Z, Caproni M, Dreher A, Frances C, et al. S2k guideline for treatment of cutaneous lupus erythematosus – guided by the European dermatology forum (EDF) in cooperation with the European academy of dermatology and venereology (EADV). J Eur Acad Dermatol Venereol. 2017;31:389–404.
Costedoat‐Chalumeau N, Amoura Z, Hulot JS, Aymard G, Leroux G, Marra D, et al. Very low blood hydroxychloroquine concentration as an objective marker of poor adherence to treatment of systemic lupus erythematosus. Ann Rheum Dis. 2007;66:821–824.
Francès C, Cosnes A, Duhaut P, Zahr N, Soutou B, Ingen‐Housz‐Oro S, et al. Low blood concentration of hydroxychloroquine in patients with refractory cutaneous lupus erythematosus: a French multicenter prospective study. Arch Dermatol. 2012;148:479–484.
Feldman CH, Collins J, Zhang Z, Subramanian SV, Solomon DH, Kawachi I, et al. Dynamic patterns and predictors of hydroxychloroquine nonadherence among Medicaid beneficiaries with systemic lupus erythematosus. Semin Arthritis Rheum. 2018;48:205–213.
Nguyen Y, Blanchet B, Urowitz MB, Hanly JG, Gordon C, Bae SC, et al. Association between severe nonadherence to hydroxychloroquine and systemic lupus erythematosus flares, damage, and mortality in 660 patients from the SLICC inception cohort. Arthritis Rheumatol. 2023;75:2195–2206.
Costedoat‐Chalumeau N, Amoura Z, Hulot JS, Hammoud HA, Aymard G, Cacoub P, et al. Low blood concentration of hydroxychloroquine is a marker for and predictor of disease exacerbations in patients with systemic lupus erythematosus. Arthritis Rheum. 2006;54:3284–3290.
Costedoat‐Chalumeau N, Galicier L, Aumaître O, Francès C, le Guern V, Lioté F, et al. Hydroxychloroquine in systemic lupus erythematosus: results of a French multicentre controlled trial (PLUS study). Ann Rheum Dis. 2013;72:1786–1792.
Chasset F, Arnaud L, Costedoat‐Chalumeau N, Zahr N, Bessis D, Francès C. The effect of increasing the dose of hydroxychloroquine (HCQ) in patients with refractory cutaneous lupus erythematosus (CLE): an open‐label prospective pilot study. J Am Acad Dermatol. 2016;74:693–699.e3.
Petri M, Elkhalifa M, Li J, Magder LS, Goldman DW. Hydroxychloroquine blood levels predict hydroxychloroquine retinopathy. Arthritis Rheumatol. 2020;72:448–453.
Lenfant T, Salah S, Leroux G, Bousquet E, le Guern V, Chasset F, et al. Risk factors for hydroxychloroquine retinopathy in systemic lupus erythematosus: a case‐control study with hydroxychloroquine blood‐level analysis. Rheumatology (Oxford). 2020;59:3807–3816.
Chasset F, Arnaud L, Jachiet M, Monfort JB, Bouaziz JD, Cordoliani F, et al. Changing antimalarial agents after inefficacy or intolerance in patients with cutaneous lupus erythematosus: a multicenter observational study. J Am Acad Dermatol. 2018;78:107–114.e1.
Zeidi M, Kim HJ, Werth VP. Increased myeloid dendritic cells and TNF‐α expression predicts poor response to hydroxychloroquine in cutaneous lupus erythematosus. J Invest Dermatol. 2019;139:324–332.
Almeida‐Brasil CC, Hanly JG, Urowitz M, Clarke AE, Ruiz‐Irastorza G, Gordon C, et al. Flares after hydroxychloroquine reduction or discontinuation: results from the systemic lupus international collaborating clinics (SLICC) inception cohort. Ann Rheum Dis. 2022;81:370–378.
Fernandez‐Ruiz R, Bornkamp N, Kim MY, Askanase A, Zezon A, Tseng CE, et al. Discontinuation of hydroxychloroquine in older patients with systemic lupus erythematosus: a multicenter retrospective study. Arthritis Res Ther. 2020;22:191.
Sonigo G, Jachiet M, Bessis D, Cordel N, Faucon C, Petit A, et al. Hydroxychloroquine dose tapering or discontinuation in cutaneous lupus erythematosus after remission: a retrospective multicenter cohort study of 56 patients. J Am Acad Dermatol. 2022;87:203–206.
Fayard D, Francès C, Amoura Z, Breillat P, Mathian A, Senet P, et al. Prevalence and factors associated with long‐term remission in cutaneous lupus: a longitudinal cohort study of 141 cases. J Am Acad Dermatol. 2022;87:323–332.
Jorge AM, Mancini C, Zhou B, Ho G, Zhang Y, Costenbader K, et al. Hydroxychloroquine dose per ophthalmology guidelines and the risk of systemic lupus erythematosus flares. JAMA. 2022;328:1458–1460.
Vázquez‐Otero I, Medina‐Cintrón N, Arroyo‐Ávila M, González‐Sepúlveda L, Vilá LM. Clinical impact of hydroxychloroquine dose adjustment according to the American Academy of ophthalmology guidelines in systemic lupus erythematosus. Lupus Sci Med. 2020;7:e000395.
Almeida‐Brasil CC, Pineau CA, Vinet E, Hanly JG, Peschken CA, Clarke AE, et al. Predictors of unsuccessful hydroxychloroquine tapering and discontinuation: can we personalize decision‐making in systemic lupus treatment? Arthritis Care Res (Hoboken). 2022;74:1070–1078.
Aouhab Z, Hong H, Felicelli C, Tarplin S, Ostrowski RA. Outcomes of systemic lupus erythematosus in patients who discontinue hydroxychloroquine. ACR Open Rheumatol. 2019;1:593–599.
Papachristos DA, Gladman DD, Su J, Urowitz MB. Outcomes following antimalarial withdrawal in patients with quiescent systemic lupus erythematosus. Semin Arthritis Rheum. 2022;55:152046.
Jin Z, Wang F, Pan W, Liu L, Wu M, Hu H, et al. Association of antimalarial drugs with decreased overall and cause specific mortality in systemic lupus erythematosus. Rheumatology (Oxford). 2021;60:1774–1783.
Dima A, Jurcut C, Chasset F, Felten R, Arnaud L. Hydroxychloroquine in systemic lupus erythematosus: overview of current knowledge. Ther Adv Musculoskelet Dis. 2022;14:1759720X211073001.
Frederick W, Marmor MF. Rates and predictors of hydroxychloroquine retinal toxicity in patients with rheumatoid arthritis and systemic lupus erythematosus. Arthritis Care Res. 2010;62:775–784.
Almeida‐Brasil CC, Hanly JG, Urowitz M, Clarke AE, Ruiz‐Irastorza G, Gordon C, et al. Retinal toxicity in a multinational inception cohort of patients with systemic lupus on hydroxychloroquine. Lupus Sci Med. 2022;9:e000789.
Fanouriakis A, Kostopoulou M, Cheema K, Anders HJ, Aringer M, Bajema I, et al. Update of the Joint European League against Rheumatism and European Renal Association‐European Dialysis and Transplant Association (EULAR/ERA‐EDTA) recommendations for the management of lupus nephritis. Ann Rheum Dis. 2019;2020:713–723.
Fanouriakis A, Kostopoulou M, Alunno A, Aringer M, Bajema I, Boletis JN, et al. 2019 Update of the EULAR recommendations for the management of systemic lupus erythematosus. Ann Rheum Dis. 2019;78:736–745.
Marmor MF, Kellner U, Lai TYY, Melles RB, Mieler WF, Lum F. Recommendations on screening for chloroquine and hydroxychloroquine retinopathy (2016 revision). Ophthalmology. 2016;123:1386–1394.
Rosenbaum JT, Costenbader KH, Desmarais J, Ginzler EM, Fett N, Goodman SM, et al. ACR, AAD, RDS, and AAO 2020 joint statement on hydroxychloroquine use with respect to retinal toxicity. Arthritis Rheumatol. 2021;73:908–911.
Melles RB, Jorge AM, Marmor MF, Zhou B, Conell C, Niu J, et al. Hydroxychloroquine dose and risk for incident retinopathy: a cohort study. Ann Intern Med. 2023;176:166–173.
Fanouriakis A, Kostopoulou M, Andersen J, Aringer M, Arnaud L, Bae SC, et al. EULAR recommendations for the management of systemic lupus erythematosus: 2023 update. Ann Rheum Dis. 2024;83:15–29.
Costedoat‐Chalumeau N, Isenberg D, Petri M. Comment on the 2019 update of the EULAR recommendations for the management of systemic lupus erythematosus by Fanouriakis et al. Ann Rheum Dis. 2020;79:e90.
Goldman A, Bomze D, Dankner R, Hod H, Meirson T, Boursi B, et al. Cardiovascular adverse events associated with hydroxychloroquine and chloroquine: a comprehensive pharmacovigilance analysis of pre‐COVID‐19 reports. Br J Clin Pharmacol. 2021;87:1432–1442.
Costedoat‐Chalumeau N, Hulot JS, Amoura Z, Leroux G, Lechat P, Funck‐Brentano C, et al. Heart conduction disorders related to antimalarials toxicity: an analysis of electrocardiograms in 85 patients treated with hydroxychloroquine for connective tissue diseases. Rheumatology (Oxford). 2007;46:808–810.
Belmont HM, Haj‐Ali M. Whole blood drug levels do not correlate with QTc intervals in hydroxychloroquine‐treated systemic lupus erythematosus patients. Rheumatology (Oxford). 2022;62:450–456.
Chatre C, Roubille F, Vernhet H, Jorgensen C, Pers YM. Cardiac complications attributed to chloroquine and hydroxychloroquine: a systematic review of the literature. Drug Saf. 2018;41:919–931.
Fiehn C, Ness T, Weseloh C, Specker C, Hadjiski D, Detert J, et al. Safety management in treatment with antimalarials in rheumatology. Interdisciplinary recommendations on the basis of a systematic literature review. Z Rheumatol. 2021;80(Suppl 1):1–9.
Stein M, Bell MJ, Ang LC. Hydroxychloroquine neuromyotoxicity. J Rheumatol. 2000;27:2927–2931.
Aviña‐Zubieta JA, Galindo‐Rodriguez G, Newman S, Suarez‐Almazor ME, Russell AS. Long‐term effectiveness of antimalarial drugs in rheumatic diseases. Ann Rheum Dis. 1998;57:582–587.
Tétu P, Hamelin A, Lebrun‐Vignes B, Soria A, Barbaud A, Francès C, et al. Prevalence of hydroxychloroquine‐induced side‐effects in dermatology patients: a retrospective survey of 102 patients. Ann Dermatol Venereol. 2018;145:395–404.
Sharma AN, Mesinkovska NA, Paravar T. Characterizing the adverse dermatologic effects of hydroxychloroquine: a systematic review. J Am Acad Dermatol. 2020;83:563–578.
Jallouli M, Francès C, Piette JC, Huong du LT, Moguelet P, Factor C, et al. Hydroxychloroquine‐induced pigmentation in patients with systemic lupus erythematosus: a case‐control study. JAMA Dermatol. 2013;149:935–940.
Andreoli L, Bertsias GK, Agmon‐Levin N, Brown S, Cervera R, Costedoat‐Chalumeau N, et al. EULAR recommendations for women's health and the management of family planning, assisted reproduction, pregnancy and menopause in patients with systemic lupus erythematosus and/or antiphospholipid syndrome. Ann Rheum Dis. 2017;76:476–485.
European Medical Agency. Best Practice Guide on the Processing of Renewals in the Mutual Recognition and Decentralised Procedures [Internet]. 2023 [cited 2023 Mar 1]. Available from: https://www.hma.eu/fileadmin/dateien/Human_Medicines/CMD_h_/CMDh_pressreleases/2023/CMDh_press_release_‐_February_2023.pdf.
Huybrechts KF, Bateman BT, Zhu Y, Straub L, Mogun H, Kim SC, et al. Hydroxychloroquine early in pregnancy and risk of birth defects. Am J Obstet Gynecol. 2021;224:290.e1–290.e22.
Schreiber K, Giles I, Costedoat‐Chalumeau N, Nelson‐Piercy C, Dolhain RJEM, Mosca M, et al. Global comment on the use of hydroxychloroquine during the periconception period and pregnancy in women with autoimmune diseases. Lancet Rheumatol. 2023;5:e501–e506.
Andersson NW, Skov L, Andersen JT. Fetal safety of chloroquine and hydroxychloroquine use during pregnancy: a nationwide cohort study. Rheumatology (Oxford). 2021;60:2317–2326.
Chambers CD, Johnson DL, Xu R, Luo Y, Felix R, Fine M, et al. Birth outcomes in women who have taken hydroxycholoroquine during pregnancy: a prospective cohort study. Arthritis Rheumatol. 2022;74:711–724.

Keywords: antimalarials; cutaneous lupus erythematosus; hydroxychloroquine; lupus

0 (Antimalarials)
4QWG6N8QKH (Hydroxychloroquine)
886U3H6UFF (Chloroquine)
H0C805XYDE (Quinacrine)

Date Created: 20240314 Date Completed: 20240703 Latest Revision: 20240703

20240703

10.1111/1346-8138.17177

38482997