International Journal of Medical Science and Pharmaceutical Research

Antimalarial drugs, particularly hydroxychloroquine (HCQ) and chloroquine (CQ), have been used for decades as cornerstone therapies in the management of immune‑mediated rheumatic diseases (IMRDs). Beyond their classical role in disease activity control, these agents exert pleiotropic effects encompassing immunomodulation, anti‑inflammatory signaling, antithrombotic activity, and metabolic and cardiovascular protection. Robust clinical evidence supports their ability to reduce disease flares, limit cumulative organ damage, improve long‑term survival, and decrease infection risk, especially in systemic lupus erythematosus (SLE). This review provides an in‑depth and updated analysis of the mechanisms of action, clinical applications across autoimmune diseases, metabolic and vascular effects, safety profile, and emerging therapeutic perspectives of HCQ and CQ, highlighting their enduring relevance and expanding role in contemporary rheumatology and systemic medicine.

Hydroxychloroquine, Chloroquine, Immune mediated rheumatic diseases, Systemic lupus erythematosus, Immunomodulation.

1. 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;78:736–45.
2. Mota L, Kakehasi AM, Gomides APM, Duarte A, Cruz BA, Brenol CV, et al. 2017 recommendations of the Brazilian Society of Rheumatology for the pharmacological treatment of rheumatoid arthritis. AdvRheumatol. 2018;58:2.
3. van Vollenhoven RF, Mosca M, Bertsias G, Isenberg D, Kuhn A, Lerstrom K, et al. Treat-to-target in systemic lupus erythematosus: recommendations from an international task force. Ann Rheum Dis. 2014;73:958–67. 
4. Marmor MF, Kellner U, Lai TY, Melles RB, Mieler WF. Recommendations on screening for Chloroquine and Hydroxychloroquine retinopathy (2016 revision). Ophthalmology. 2016;123:1386–94.
5. Tsakonas E, Joseph L, Esdaile JM, Choquette D, Senecal JL, Cividino A, et al. A long-term study of hydroxychloroquine withdrawal on exacerbations in systemic lupus erythematosus. Canadian Hydroxychloroquine Study Group. Lupus. 1998;7:80–5.
6. Cavazzana I, Sala R, Bazzani C, Ceribelli A, Zane C, Cattaneo R, et al. Treatment of lupus skin involvement with quinacrine and hydroxychloroquine. Lupus. 2009;18:735–9. 
7. Bezerra EL, Vilar MJ, da TrindadeNeto PB, Sato EI. Double-blind, randomized, controlled clinical trial of clofazimine compared with chloroquine in patients with systemic lupus erythematosus. Arthritis Rheum. 2005;52:3073–8. 
8. Pons-Estel GJ, Alarco´n 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(6):830.
9. Fessler BJ, Alarcon GS, McGwin G Jr, Roseman J, Bastian HM, Friedman AW, et al. Systemic lupus erythematosus in three ethnic groups: XVI. Association of hydroxychloroquine use with reduced risk of damage accrual. Arthritis Rheum. 2005;52:1473–80. 
10. Ibanez D, Gladman DD, Urowitz MB. Adjusted mean systemic lupus Erythematosus disease activity index-2K is a predictor of outcome in SLE. J Rheumatol. 2005;32(5):824–7. 
11. Ruiz-Irastorza G, Egurbide MV, Pijoan JI, Garmendia M, Villar I, Martinez­Berriotxoa A, et al. Effect of antimalarials on thrombosis and survival in patients with systemic lupus erythematosus. Lupus. 2006;15:577–83. 
12. Shinjo SK, Bonfa E, Wojdyla D, Borba EF, Ramirez LA, Scherbarth HR, et al. Antimalarial treatment may have a time-dependent effect on lupus survival: data from a multinational Latin American inception cohort. Arthritis Rheum. 2010;62:855–62.
13. Ruiz-Irastorza G, Olivares N, Ruiz-Arruza I, Martinez-Berriotxoa A, Egurbide MV, Aguirre C. Predictors of major infections in systemic lupus erythematosus. Arthritis Res Ther 2009;11(4):R109.
14. Costedoat-Chalumeau N, Dunogue B, Morel N, Le Guern V, Guettrot-Imbert G. Hydroxychloroquine: a multifaceted treatment in lupus. Presse Med. 2014;43(6 Pt 2):e167–80.
15. HERA Study Group. A randomized trial of hydroxychloroquine in early rheumatoid arthritis: the HERA study. Am J Med. 1995;98:156–68.
16. Wasko MC, Hubert HB, Lingala VB, Elliott JR, Luggen ME, Fries JF, et al. Hydroxychloroquine and risk of diabetes in patients with rheumatoid arthritis. Jama. 2007;298:187–93. 
17. Avina-Zubieta JA, Choi HK, Sadatsafavi M, Etminan M, Esdaile JM, Lacaille D. Risk of cardiovascular mortality in patients with rheumatoid arthritis: a meta­analysis of observational studies. Arthritis Rheum. 2008;59:1690–7.
18. Ramos-Casals M, Brito-Zeron P, Bombardieri S, Bootsma H, De Vita S, Dorner T, et al. EULAR recommendations for the management of Sjogren's syndrome with topical and systemic therapies. Ann Rheum Dis. 2020;79:3–18. 
19. Valim V, Trevisani VF, Pasoto SG, Serrano EV, Ribeiro SL, Fidelix TS, et al. Recommendations for the treatment of Sjogren's syndrome. Rev Bras Reumatol. 2015;55:446–57.
20. Tektonidou MG, Andreoli L, Limper M, Amoura Z, Cervera R, Costedoat­Chalumeau N, et al. EULAR recommendations for the management of antiphospholipid syndrome in adults. Ann Rheum Dis. 2019;78:1296–304.
21. Beegle SH, Barba K, Gobunsuy R, Judson MA. Current and emerging pharmacological treatments for sarcoidosis: a review. Drug Des DevelTher. 2013;7:325–38.
22. Cortegiani A, Ingoglia G, Ippolito M, Giarratano A, Einav S. A systematic review on the efficacy and safety of chloroquine for the treatment of COVID-19. J Crit Care 2020; pii:S0883-9441(20)30390-7. doi:10.1016/j.jcrc.2020.03.005.
23. Rynes RI: Antimalarial drugs in the treatment of rheumatological diseases. Br J Rheumatol 36: 799-805, 1997.
24. Kalia S, Dutz JP: New concepts in antimalarial use and mode of action in dermatology. DermatolTher 20: 160-74, 2007.
25. Schrezenmeier E, Dorner T. Mechanisms of action of hydroxychloroquine and chloroquine: implications for rheumatology. Nat Rev Rheumatol. 2020; 16:155–66.
26. Wallace DJ. Does hydroxychloroquine sulfate prevent clot formation in systemic lupus erythematosus? Arthritis Rheum 1987;30(12):1435–6.
27. Johansson E, Forsberg K, Johnsson H. Clinical and experimental evaluation of the thromboprophylactic effect of hydroxychloroquine sulfate after total hip replacement. Haemostasis 1981;10(2):89–96.
28. Johnson R, Charnley J. Hydroxychloroquine in prophylaxis of pulmonary embolism following hip arthroplasty. ClinOrthopRelat Res 1979;144: 174–7.
29. SisóA, Ramos-Casals M, BovéA, Brito-Zerón P, Soria N, Muñoz S, et al. Previous antimalarial therapy in patients diagnosed with lupus nephritis: influence on outcomes and survival. Lupus 2008;17(4):281–8.
30. Sotelo J, BriceñoE ,López-González MA. Adding chloroquine to conventional treatment for glioblastoma multiforme: a randomized, double-blind, placebo-controlled trial. Ann Intern Med 2006;144(5):337–4.
31. Ponticelli C, Moroni G. Hydroxychloroquine in systemic lupus erythematosus (SLE). Expert OpinDrugSaf. 2017;16:411–9.
32. Sharma AN, Mesinkovska NA, Paravar T. Characterizing the adverse dermatologic effects of hydroxychloroquine: a systematic review. J Am AcadDermatol. 2020. https://doi.org/10.1016/j.jaad.2020.04.024.
33. Jallouli M, Frances C, Piette JC, du LT H, Moguelet P, Factor C, et al. Hydroxychloroquine-induced pigmentation in patients with systemic lupuserythematosus: a case-control study. JAMA Dermatol. 2013;149:935–40.
34. Jorge A, Ung C, Young LH, Melles RB, Choi HK. Hydroxychloroquine retinopathy- implications of research advances for rheumatology care. Nat Rev Rheumatol. 2018;14:693–703.
35. Yusuf IH, Sharma S, Luqmani R, Downes SM. Hydroxychloroquineretinopathy. Eye (Lond). 2017;31:828–45.
36. 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;41:919–31.
37. 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. 2020. https://doi.org/10.1007/s00393-020-00785-4.
38. Levy RA, Vilela VS, Cataldo MJ, Ramos RC, Duarte JL, Tura BR, et al. Hydroxychloroquine (HCQ) in lupus pregnancy: double-blind and placebocontrolled study. Lupus. 2001;10:401–4.
39. Andreoli L, Bertsias GK, Agmon-Levin N, Brown S, Cervera R, CostedoatChalumeau 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;76:476–85.
40. Izmirly PM, Costedoat-Chalumeau N, Pisoni CN, Khamashta MA, Kim MY, Saxena A, et al. Maternal use of hydroxychloroquine is associated with a reduced risk of recurrent anti-SSA/Ro-antibody-associated cardiac manifestations of neonatal lupus. Circulation. 2012;126:76–82.
41. Tunks RD, Clowse ME, Miller SG, Brancazio LR, Barker PC. Maternal autoantibody levels in congenital heart block and potential prophylaxis with antiinflammatory agents. Am J Obstet Gynecol. 2013;208:64.e1–7.