Research progress of hydroxychloroquine related retinal toxicity_Chinese Journal of Ocular Fundus Diseases

Authors：

Li Yueming , Duan Lianhai , Wu Huqiang ,  Kang Jianshu

Department of Ophthalmology, Yunnan Provincial Hospital of Traditional Chinese Medicine, Kunming 650000;

Corresponding author：

Kang Jianshu, Email: 601475967@qq.com

Keywords：

Hydroxychloroquine; Retinal toxicity; Visual impairment; Review

DOI：

10.3760/cma.j.cn511434-20240730-00287

Video：

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Hydroxychloroquine is widely used in the treatment of autoimmune diseases and skin diseases, mainly for the treatment of diseases such as systemic lupus erythematosus, rheumatoid arthritis and other diseases. Hydroxychloroquine has many benefits to patients, but long-term use of the drug may lead to retinal chronic toxicity changes, seriously affect the patient’s vision and quality of their lives. However, there are few studies on retinal toxicity of hydroxychloroquine in the world, easy to miss diagnosis and misdiagnosis. ophthalmologists should increase the knowledge with the etiology and pathology of hydroxychloroquine retinal toxicity, through relevant auxiliary check early detection of the drug to the retina and timely suggest patients to stop, so as not to cause further retinal toxicity damage.

1.	Jorge A, Mccormick N, Lu N, et al. Hydroxychloroquine and mortality among patients with systemic lupus erythematosus in the general population[J]. Arthritis Care Res (Hoboken), 2021, 73(8): 1219-1223. DOI: 10.1002/acr.24255.
2.	Martinez GP, Zabaleta ME, Di Giulio C, et al. The role of chloroquine and hydroxychloroquine in immune regulation and diseases[J]. Curr Pharm Des, 2020, 26(35): 4467-4485. DOI: 10.2174/1381612826666200707132920.
3.	Liu LJ, Yang YZ, Shi SF, et al. Effects of hydroxychloroquine on proteinuria in IgA nephropathy: a randomized controlled trial[J]. Am J Kidney Dis, 2019, 74(1): 15-22. DOI: 10.1053/j.ajkd.2019.01.026.
4.	Sayar Z, Moll R, Isenberg D, et al. Thrombotic antiphospholipid syndrome: a practical guide to diagnosis and management[J]. Thromb Res, 2021, 198: 213-221. DOI: 10.1016/j.thromres.2020.10.010.
5.	McCullough PA. Regarding: "Hydroxychloroquine: a comprehensive review and its controversial role in coronavirus disease 2019"[J]. Ann Med, 2021, 53(1): 286-286. DOI: 10.1080/07853890.2021.1872094.
6.	Pandya HK, Robinson M, Mandal N, et al. Hydroxychloroquine retinopathy: a review of imaging[J]. Indian J Ophthalmol, 2015, 63(7): 570-574. DOI: 10.4103/0301-4738.167120.
7.	Marmor MF, Kellner U, Lai TY, et al. Recommendations on screening for chloroquine and hydroxychloroquine retinopathy (2016 Revision)[J]. Ophthalmology, 2016, 123(6): 1386-1394. DOI: 10.1016/j.ophtha.2016.01.058.
8.	Kim KE, Ahn SJ, Woo SJ, et al. Use of OCT retinal thickness deviation map for hydroxychloroquine retinopathy screening[J]. Ophthalmology, 2021, 128(1): 110-119. DOI: 10.1016/j.ophtha.2020.06.021.
9.	Mondal K, Porter H, Cole J 2nd, et al. Hydroxychloroquine causes early inner retinal toxicity and affects autophagosome-lysosomal pathway and sphingolipid metabolism in the retina[J]. Mol Neurobiol, 2022, 59(6): 3873-3887. DOI: 10.1007/s12035-022-02825-3.
10.	Jorge A, Ung C, Young LH, et al. Hydroxychloroquine retinopathy-implications of research advances for rheumatology care[J]. Nat Rev Rheumatol, 2018, 14(12): 693-703. DOI: 10.1038/s41584-018-0111-8.
11.	Fröhlich F, González Montoro A. The role of lysosomes in lipid homeostasis[J]. Biol Chem, 2023, 404(5): 455-465. DOI: 10.1515/hsz-2022-0287.
12.	Simon MV, Basu SK, Qaladize B, et al. Sphingolipids as critical players in retinal physiology and pathology[J/OL]. J Lipid Res, 2021, 62: 100037[2021-02-06]. https://pubmed.ncbi.nlm.nih.gov/32948663/. DOI: 10.1194/jlr.TR120000972.
13.	Mandal N, Grambergs R, Mondal K, et al. Role of ceramides in the pathogenesis of diabetes mellitus and its complications[J/OL]. J Diabetes Complications, 2021, 35(2): 107734[2020-09-16]. https://pubmed.ncbi.nlm.nih.gov/33268241/. DOI: 10.1016/j.jdiacomp.2020.107734.
14.	Kaufmann AM, Krise JP. Lysosomal sequestration of amine-containing drugs: analysis and therapeutic implications[J]. J Pharm Sci, 2007, 96(4): 729-746. DOI: 10.1002/jps.20792.
15.	Marmor MF, Durbin M, de Sisternes L, et al. Sequential retinal thickness analysis shows hydroxychloroquine damage before other screening techniques[J]. Retin Cases Brief Rep, 2021, 15(3): 185-196. DOI: 10.1097/ICB.0000000000001108.
16.	Kim KE, Ryu SJ, Kim YH, et al. Visual field examinations using different strategies in Asian patients taking hydroxychloroquine[J/OL]. Sci Rep, 2022, 12(1): 14778[2022-08-30]. https://pubmed.ncbi.nlm.nih.gov/36042337/. DOI: 10.1038/s41598-022-19048-0.
17.	Mohapatra A, Gupta P, Ratra D. Accelerated hydroxychloroquine toxic retinopathy[J]. Doc Ophthalmol, 2024, 148(1): 37-45. DOI: 10.1007/s10633-023-09950-x.
18.	Yung M, Klufas MA, Sarraf D. Clinical applications of fundus autofluorescence in retinal disease[J]. Int J Retina Vitreous, 2016, 2: 12. DOI: 10.1186/s40942-016-0035-x.
19.	Yusuf IH, Latheef F, Ardern-Jones M, et al. New recommendations for retinal monitoring in hydroxychloroquine users: baseline testing is no longer supported[J]. Br J Dermatol, 2021, 185(2): 435-438. DOI: 10.1111/bjd.20073.
20.	Ahn SJ, Joung J, Lee BR. Evaluation of hydroxychloroquine retinopathy using ultra-widefield fundus autofluorescence: peripheral findings in the retinopathy[J]. Am J Ophthalmol, 2020, 209: 35-44. DOI: 10.1016/j.ajo.2019.09.008.
21.	Forte R, Haulani H, Dyrda A, et al. Swept source optical coherence tomography angiography in patients treated with hydroxychloroquine: correlation with morphological and functional tests[J]. Br J Ophthalmol, 2021, 105(9): 1297-1301. DOI: 10.1136/bjophthalmol-2018-313679.
22.	Akhlaghi M, Kianersi F, Radmehr H, et al. Evaluation of optical coherence tomography angiography parameters in patients treated with hydroxychloroquine[J]. BMC Ophthalmol, 2021, 21(1): 209. DOI: 10.1186/s12886-021-01977-5.
23.	Ahn SJ , Ryu SJ , Lim HW, et al. Toxic effects of hydroxychloroquine on the choroid: evidence from multimodal imaging[J]. Retina, 2019, 39(5): 1016-1026. DOI: 10.1097/IAE.0000000000002047.
24.	Ghasemi Falavarjani K, Wang K, Khadamy J, et al. Ultra-wide-field imaging in diabetic retinopathy, an overview[J]. J Curr Ophthalmol, 2016, 28(2): 57-60. DOI: 10.1016/j.joco.2016.04.001.
25.	Corradetti G, Violanti S, Au A, et al. Wide field retinal imaging and the detection of drug associated retinal toxicity[J]. Int J Retina Vitreous, 2019, 5(Suppl 1): S26-39. DOI: 10.1186/s40942-019-0172-0.
26.	Yusuf IH, Charbel Issa P, Ahn SJ. Novel imaging techniques for hydroxychloroquine retinopathy[J/OL]. Front Med (Lausanne), 2022, 9: 1026934[2022-10-13]. https://pubmed.ncbi.nlm.nih.gov/36314000/. DOI: 10.3389/fmed.2022.1026934.
27.	Gordon C, Amissah-Arthur MB, Gayed M, et al. The British society for rheumatology guideline for the management of systemic lupus erythematosus in adults: executive summary[J]. Rheumatology (Oxford), 2018, 57(1): 14-18. DOI: 10.1093/rheumatology/kex291.
28.	Bowman SJ, Guest L. The national clinical audit for rheumatoid and early inflammatory arthritis[J]. Clin Med (Lond), 2016, 16(6): 500-501. DOI: 10.7861/clinmedicine.16-6-500.
29.	Melles RB, Jorge AM, Marmor MF, et al. Hydroxychloroquine dose and risk for incident retinopathy: a cohort study[J]. Ann Intern Med, 2023, 176(2): 166-173. DOI: 10.7326/M22-2453.
30.	Yeo B, Hamad R, Paul A, et al. Hydroxychloroquine baseline retinopathy screening: when to refer patients? A practical approach to optimise resource use[J]. Eye (Lond), 2020, 34(8): 1305-1306. DOI: 10.1038/s41433-020-0794-3.
31.	Xu C, Zhu L, Chan T, et al. Chloroquine and hydroxychloroquine are novel inhibitors of human organic anion transporting polypeptide 1A2[J]. J Pharm Sci, 2016, 105(2): 884-890. DOI: 10.1002/jps.24663.
32.	Gobbett A, Kotagiri A, Bracewell C, et al. Two years' experience of screening for hydroxychloroquine retinopathy[J]. Eye (Lond), 2021, 35(4): 1171-1177. DOI: 10.1038/s41433-020-1028-4.
33.	Melles RB, Marmor MF. Rapid macular thinning is an early indicator of hydroxychloroquine retinal toxicity[J]. Ophthalmology, 2022, 129(9): 1004-1013. DOI: 10.1016/j.ophtha.2022.05.002.
34.	Aduriz-Lorenzo PM, Aduriz-Llaneza P, Araiz-Iribarren J, et al. Current opinion on hydroxychloroquine-related retinal toxicity screening: where do we stand now?[J]. Lupus, 2020, 29(7): 671-675. DOI: 10.1177/0961203320919499.

1. Jorge A, Mccormick N, Lu N, et al. Hydroxychloroquine and mortality among patients with systemic lupus erythematosus in the general population[J]. Arthritis Care Res (Hoboken), 2021, 73(8): 1219-1223. DOI: 10.1002/acr.24255.
2. Martinez GP, Zabaleta ME, Di Giulio C, et al. The role of chloroquine and hydroxychloroquine in immune regulation and diseases[J]. Curr Pharm Des, 2020, 26(35): 4467-4485. DOI: 10.2174/1381612826666200707132920.
3. Liu LJ, Yang YZ, Shi SF, et al. Effects of hydroxychloroquine on proteinuria in IgA nephropathy: a randomized controlled trial[J]. Am J Kidney Dis, 2019, 74(1): 15-22. DOI: 10.1053/j.ajkd.2019.01.026.
4. Sayar Z, Moll R, Isenberg D, et al. Thrombotic antiphospholipid syndrome: a practical guide to diagnosis and management[J]. Thromb Res, 2021, 198: 213-221. DOI: 10.1016/j.thromres.2020.10.010.
5. McCullough PA. Regarding: "Hydroxychloroquine: a comprehensive review and its controversial role in coronavirus disease 2019"[J]. Ann Med, 2021, 53(1): 286-286. DOI: 10.1080/07853890.2021.1872094.
6. Pandya HK, Robinson M, Mandal N, et al. Hydroxychloroquine retinopathy: a review of imaging[J]. Indian J Ophthalmol, 2015, 63(7): 570-574. DOI: 10.4103/0301-4738.167120.
7. Marmor MF, Kellner U, Lai TY, et al. Recommendations on screening for chloroquine and hydroxychloroquine retinopathy (2016 Revision)[J]. Ophthalmology, 2016, 123(6): 1386-1394. DOI: 10.1016/j.ophtha.2016.01.058.
8. Kim KE, Ahn SJ, Woo SJ, et al. Use of OCT retinal thickness deviation map for hydroxychloroquine retinopathy screening[J]. Ophthalmology, 2021, 128(1): 110-119. DOI: 10.1016/j.ophtha.2020.06.021.
9. Mondal K, Porter H, Cole J 2nd, et al. Hydroxychloroquine causes early inner retinal toxicity and affects autophagosome-lysosomal pathway and sphingolipid metabolism in the retina[J]. Mol Neurobiol, 2022, 59(6): 3873-3887. DOI: 10.1007/s12035-022-02825-3.
10. Jorge A, Ung C, Young LH, et al. Hydroxychloroquine retinopathy-implications of research advances for rheumatology care[J]. Nat Rev Rheumatol, 2018, 14(12): 693-703. DOI: 10.1038/s41584-018-0111-8.
11. Fröhlich F, González Montoro A. The role of lysosomes in lipid homeostasis[J]. Biol Chem, 2023, 404(5): 455-465. DOI: 10.1515/hsz-2022-0287.
12. Simon MV, Basu SK, Qaladize B, et al. Sphingolipids as critical players in retinal physiology and pathology[J/OL]. J Lipid Res, 2021, 62: 100037[2021-02-06]. https://pubmed.ncbi.nlm.nih.gov/32948663/. DOI: 10.1194/jlr.TR120000972.
13. Mandal N, Grambergs R, Mondal K, et al. Role of ceramides in the pathogenesis of diabetes mellitus and its complications[J/OL]. J Diabetes Complications, 2021, 35(2): 107734[2020-09-16]. https://pubmed.ncbi.nlm.nih.gov/33268241/. DOI: 10.1016/j.jdiacomp.2020.107734.
14. Kaufmann AM, Krise JP. Lysosomal sequestration of amine-containing drugs: analysis and therapeutic implications[J]. J Pharm Sci, 2007, 96(4): 729-746. DOI: 10.1002/jps.20792.
15. Marmor MF, Durbin M, de Sisternes L, et al. Sequential retinal thickness analysis shows hydroxychloroquine damage before other screening techniques[J]. Retin Cases Brief Rep, 2021, 15(3): 185-196. DOI: 10.1097/ICB.0000000000001108.
16. Kim KE, Ryu SJ, Kim YH, et al. Visual field examinations using different strategies in Asian patients taking hydroxychloroquine[J/OL]. Sci Rep, 2022, 12(1): 14778[2022-08-30]. https://pubmed.ncbi.nlm.nih.gov/36042337/. DOI: 10.1038/s41598-022-19048-0.
17. Mohapatra A, Gupta P, Ratra D. Accelerated hydroxychloroquine toxic retinopathy[J]. Doc Ophthalmol, 2024, 148(1): 37-45. DOI: 10.1007/s10633-023-09950-x.
18. Yung M, Klufas MA, Sarraf D. Clinical applications of fundus autofluorescence in retinal disease[J]. Int J Retina Vitreous, 2016, 2: 12. DOI: 10.1186/s40942-016-0035-x.
19. Yusuf IH, Latheef F, Ardern-Jones M, et al. New recommendations for retinal monitoring in hydroxychloroquine users: baseline testing is no longer supported[J]. Br J Dermatol, 2021, 185(2): 435-438. DOI: 10.1111/bjd.20073.
20. Ahn SJ, Joung J, Lee BR. Evaluation of hydroxychloroquine retinopathy using ultra-widefield fundus autofluorescence: peripheral findings in the retinopathy[J]. Am J Ophthalmol, 2020, 209: 35-44. DOI: 10.1016/j.ajo.2019.09.008.
21. Forte R, Haulani H, Dyrda A, et al. Swept source optical coherence tomography angiography in patients treated with hydroxychloroquine: correlation with morphological and functional tests[J]. Br J Ophthalmol, 2021, 105(9): 1297-1301. DOI: 10.1136/bjophthalmol-2018-313679.
22. Akhlaghi M, Kianersi F, Radmehr H, et al. Evaluation of optical coherence tomography angiography parameters in patients treated with hydroxychloroquine[J]. BMC Ophthalmol, 2021, 21(1): 209. DOI: 10.1186/s12886-021-01977-5.
23. Ahn SJ , Ryu SJ , Lim HW, et al. Toxic effects of hydroxychloroquine on the choroid: evidence from multimodal imaging[J]. Retina, 2019, 39(5): 1016-1026. DOI: 10.1097/IAE.0000000000002047.
24. Ghasemi Falavarjani K, Wang K, Khadamy J, et al. Ultra-wide-field imaging in diabetic retinopathy, an overview[J]. J Curr Ophthalmol, 2016, 28(2): 57-60. DOI: 10.1016/j.joco.2016.04.001.
25. Corradetti G, Violanti S, Au A, et al. Wide field retinal imaging and the detection of drug associated retinal toxicity[J]. Int J Retina Vitreous, 2019, 5(Suppl 1): S26-39. DOI: 10.1186/s40942-019-0172-0.
26. Yusuf IH, Charbel Issa P, Ahn SJ. Novel imaging techniques for hydroxychloroquine retinopathy[J/OL]. Front Med (Lausanne), 2022, 9: 1026934[2022-10-13]. https://pubmed.ncbi.nlm.nih.gov/36314000/. DOI: 10.3389/fmed.2022.1026934.
27. Gordon C, Amissah-Arthur MB, Gayed M, et al. The British society for rheumatology guideline for the management of systemic lupus erythematosus in adults: executive summary[J]. Rheumatology (Oxford), 2018, 57(1): 14-18. DOI: 10.1093/rheumatology/kex291.
28. Bowman SJ, Guest L. The national clinical audit for rheumatoid and early inflammatory arthritis[J]. Clin Med (Lond), 2016, 16(6): 500-501. DOI: 10.7861/clinmedicine.16-6-500.
29. Melles RB, Jorge AM, Marmor MF, et al. Hydroxychloroquine dose and risk for incident retinopathy: a cohort study[J]. Ann Intern Med, 2023, 176(2): 166-173. DOI: 10.7326/M22-2453.
30. Yeo B, Hamad R, Paul A, et al. Hydroxychloroquine baseline retinopathy screening: when to refer patients? A practical approach to optimise resource use[J]. Eye (Lond), 2020, 34(8): 1305-1306. DOI: 10.1038/s41433-020-0794-3.
31. Xu C, Zhu L, Chan T, et al. Chloroquine and hydroxychloroquine are novel inhibitors of human organic anion transporting polypeptide 1A2[J]. J Pharm Sci, 2016, 105(2): 884-890. DOI: 10.1002/jps.24663.
32. Gobbett A, Kotagiri A, Bracewell C, et al. Two years' experience of screening for hydroxychloroquine retinopathy[J]. Eye (Lond), 2021, 35(4): 1171-1177. DOI: 10.1038/s41433-020-1028-4.
33. Melles RB, Marmor MF. Rapid macular thinning is an early indicator of hydroxychloroquine retinal toxicity[J]. Ophthalmology, 2022, 129(9): 1004-1013. DOI: 10.1016/j.ophtha.2022.05.002.
34. Aduriz-Lorenzo PM, Aduriz-Llaneza P, Araiz-Iribarren J, et al. Current opinion on hydroxychloroquine-related retinal toxicity screening: where do we stand now?[J]. Lupus, 2020, 29(7): 671-675. DOI: 10.1177/0961203320919499.

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