Research progress on the pathogenesis of hydroxychloroquine retinopathy and the related fundus changes_Chinese Journal of Ocular Fundus Diseases

Authors：

Zhong Yongfang , Xu Xuemei ,  Wang Haibin

Department of Ophthalmology, Affiliated Hospital of Chengde Medical College, Chengde 067000, China;

Corresponding author：

Wang Haibin, Email: Wanghaibin1975_0@163.com

Keywords：

Hydroxychloroquine; Retinopathy; Fundus changes; Pathogenesis; Review

DOI：

10.3760/cma.j.cn511434-20231226-00509

Video：

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Hydroxychloroquine retinopathy is an ocular lesions that develops following long-term or excessive use of hydroxychloroquine. The early clinical presentation of this lesion is nonspecific and is often detected when severe central vision impairment occurs in late stage. It currently mainly includes hydroxychloroquine binding to melanin, inducing degeneration of the retinal pigment epithelium, increasing the pH of lysosomes in the retinal pigment epithelium and interfering with the visual cycle. In recent years, with the development of retinal imaging technology and the in-depth study of hydroxychloroquine retinopathy, characteristic fundus structural changes such as retinal and choroidal thickness and blood vessels may occur in the early stage. This not only provides an important basis for the early diagnosis of hydroxychloroquine retinopathy, but also provides important clues for investigating its pathogenesis. Clinicians' proficiency in relevant fundus changes and pathogenesis will facilitate early diagnosis and treatment, while also minimizing irreversible central vision impairment in patients.

Citation： Zhong Yongfang, Xu Xuemei, Wang Haibin. Research progress on the pathogenesis of hydroxychloroquine retinopathy and the related fundus changes. Chinese Journal of Ocular Fundus Diseases, 2024, 40(9): 729-732. doi: 10.3760/cma.j.cn511434-20231226-00509 Copy

1.	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.
2.	Dima A, Jurcut C, Arnaud L. Hydroxychloroquine in systemic and autoimmune diseases: where are we now?[J/OL]. Joint Bone Spine, 2021, 88(3): 105143[2021-01-28]. https://pubmed.ncbi.nlm.nih.gov/33515791/. DOI: 10.1016/j.jbspin.2021.105143.
3.	Anjos R, Ferreira A, Barkoudah E, et al. Application of optical coherence tomography angiography macular analysis for systemic hypertension. A systematic review and meta-analysis[J]. Am J Hypertens, 2022, 35(4): 356-364. DOI: 10.1093/ajh/hpab172.
4.	Nicolò M, Ferro Desideri L, Bassetti M, et al. Hydroxychloroquine and chloroquine retinal safety concerns during COVID-19 outbreak[J]. Int Ophthalmol, 2021, 41(2): 719-725. DOI: 10.1007/s10792-020-01593-0.
5.	Shah S, Das S, Jain A, et al. A systematic review of the prophylactic role of chloroquine and hydroxychloroquine in coronavirus disease-19 (COVID-19)[J]. Int J Rheum Dis, 2020, 23(5): 613-619. DOI: 10.1111/1756-185X.13842.
6.	Abdulaziz N, Shah AR, McCune WJ. Hydroxychloroquine: balancing the need to maintain therapeutic levels with ocular safety: an update[J]. Curr Opin Rheumatol, 2018, 30(3): 249-255. DOI: 10.1097/bor.0000000000000500.
7.	Mititelu M, Wong BJ, Brenner M, et al. Progression of hydroxychloroquine toxic effects after drug therapy cessation: new evidence from multimodal imaging[J]. JAMA Ophthalmol, 2013, 131(9): 1187-1197. DOI: 10.1001/jamaophthalmol.2013.4244.
8.	Melles RB, Marmor MF. The risk of toxic retinopathy in patients on long-term hydroxychloroquine therapy[J]. JAMA Ophthalmol, 2014, 132(12): 1453-1460. DOI: 10.1001/jamaophthalmol.2014.3459.
9.	Melles RB, Marmor MF. Pericentral retinopathy and racial differences in hydroxychloroquine toxicity[J]. Ophthalmology, 2015, 122(1): 110-116. DOI: 10.1016/j.ophtha.2014.07.018.
10.	Yusuf IH, Charbel Issa P, Ahn SJ. Hydroxychloroquine-induced retinal toxicity[J/OL]. Front Pharmacol, 2023, 14: 1196783[2023-05-30]. https://pubmed.ncbi.nlm.nih.gov/37324471/. DOI: 10.3389/fphar.2023.1196783.
11.	de Sisternes L, Hu J, Rubin DL, et al. Localization of damage in progressive hydroxychloroquine retinopathy on and off the drug: inner versus outer retina, parafovea versus peripheral fovea[J]. Invest Ophthalmol Vis Sci, 2015, 56(5): 3415-3426. DOI: 10.1167/iovs.14-16345.
12.	Rosenthal AR, Kolb H, Bergsma D, et al. Chloroquine retinopathy in the rhesus monkey[J]. Invest Ophthalmol Vis Sci, 1978, 17(12): 1158-1175.
13.	Pasadhika S, Fishman GA, Choi D, et al. Selective thinning of the perifoveal inner retina as an early sign of hydroxychloroquine retinal toxicity[J]. Eye (Lond), 2010, 24(5): 756-762. DOI: 10.1038/eye.2010.21.
14.	Ulviye Y, Betul T, Nur TH, et al. Spectral domain optical coherence tomography for early detection of retinal alterations in patients using hydroxychloroquine[J]. Indian J Ophthalmol, 2013, 61(4): 168-171. DOI: 10.4103/0301-4738.112161.
15.	Bulut M, Akıdan M, Gözkaya O, et al. Optical coherence tomography angiography for screening of hydroxychloroquine-induced retinal alterations[J]. Graefe's Arch Clin Exp Ophthalmol, 2018, 256(11): 2075-2081. DOI: 10.1007/s00417-018-4117-3.
16.	Kim KE, Kim YH, Kim J, et al. Macular ganglion cell complex and peripapillary retinal nerve fiber layer thicknesses in hydroxychloroquine retinopathy[J]. Am J Ophthalmol, 2023, 245: 70-80. DOI: 10.1016/j.ajo.2022.07.028.
17.	Lee MG, Kim SJ, Ham DI, et al. Macular retinal ganglion cell-inner plexiform layer thickness in patients on hydroxychloroquine therapy[J]. Invest Ophthalmol Vis Sci, 2014, 56(1): 396-402. DOI: 10.1167/iovs.14-15138.
18.	Casado A, López-de-Eguileta A, Fonseca S, et al. Outer nuclear layer damage for detection of early retinal toxicity of hydroxychloroquine[J]. Biomedicines, 2020, 8(3): 54. DOI: 10.3390/biomedicines8030054.
19.	Cinar E, Yuce B, Aslan F. Evaluation of retinal and choroidal microvascular changes in patients who received hydroxychloroquine by optical coherence tomography angiography[J]. Arq Bras Oftalmol, 2021, 84(1): 2-10. DOI: 10.5935/0004-2749.20210001.
20.	Goker YS, Ucgul Atılgan C, Tekin K, et al. The validity of optical coherence tomography angiography as a screening test for the early detection of retinal changes in patients with hydroxychloroquine therapy[J]. Curr Eye Res, 2019, 44(3): 311-315. DOI: 10.1080/02713683.2018.1545912.
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.	Ozek D, Onen M, Karaca EE, et al. The optical coherence tomography angiography findings of rheumatoid arthritis patients taking hydroxychloroquine[J]. Eur J Ophthalmol, 2019, 29(5): 532-537. DOI: 10.1177/1120672118801125.
23.	Mihailovic N, Leclaire MD, Eter N, et al. Altered microvascular density in patients with systemic lupus erythematosus treated with hydroxychloroquine-an optical coherence tomography angiography study[J]. Graefe's Arch Clin Exp Ophthalmol, 2020, 258(10): 2263-2269. DOI: 10.1007/s00417-020-04788-4.
24.	Conigliaro P, Cesareo M, Chimenti MS, et al. Response to: 'OCTA, a sensitive screening for asymptomatic retinopathy, raises alarm over systemic involvements in patients with SLE' by Mizuno et al[J/OL]. Ann Rheum Dis, 2020, 79(2): e18[2018-12-20]. https://pubmed.ncbi.nlm.nih.gov/30573654/. DOI: 10.1136/annrheumdis-2018-214796.
25.	Ahn SJ, Ryu SJ, Joung JY, et al. Choroidal thinning associated with hydroxychloroquine retinopathy[J]. Am J Ophthalmol, 2017, 183: 56-64. DOI: 10.1016/j.ajo.2017.08.022.
26.	Kurihara T, Westenskow PD, Bravo S, et al. Targeted deletion of VRGFA in adult mice induces vision loss[J]. J Clin Invest, 2012, 122(11): 4213-4217. DOI: 10.1172/jci65157.
27.	Iovino C, Pellegrini M, Bernabei F, et al. Choroidal vascularity index: an in-depth analysis of this novel optical coherence tomography parameter[J]. J Clin Med, 2020, 9(2): 595. DOI: 10.3390/jcm9020595.
28.	Ding HJ, Denniston AK, Rao VK, et al. Hydroxychloroquine-related retinal toxicity[J]. Rheumatology (Oxford), 2016, 55(6): 957-967. DOI: 10.1093/rheumatology/kev357.
29.	Remolí-Sargues L, Monferrer-Adsuara C, Hernández-Garfella ML, et al. Optical coherence tomography angiography features in a case of hydroxychloroquine retinopathy[J]. Int J Ophthalmol, 2023, 16(2): 325-327. DOI: 10.18240/ijo.2023.02.24.
30.	Polat OA, Okçu M, Yılmaz M. Hydroxychloroquine treatment alters retinal layers and choroid without apparent toxicity in optical coherence tomography[J/OL]. Photodiagnosis Photodyn Ther, 2022, 38: 102806[2022-03-11]. https://pubmed.ncbi.nlm.nih.gov/35288317/. DOI: 10.1016/j.pdpdt.2022.102806.
31.	Remolí Sargues L, Monferrer Adsuara C, Castro Navarro V, et al. New insights in pathogenic mechanism of hydroxychloroquine retinal toxicity through optical coherence tomography angiography analysis[J]. Eur J Ophthalmol, 2022, 32(6): 3599-3608. DOI: 10.1177/11206721221076313.
32.	Michaelides M, Stover NB, Francis PJ, et al. Retinal toxicity associated with hydroxychloroquine and chloroquine: risk factors, screening, and progression despite cessation of therapy[J]. Arch Ophthalmol, 2011, 129(1): 30-39. DOI: 10.1001/archophthalmol.2010.321.
33.	Korthagen NM, Bastiaans J, van Meurs JC, et al. Chloroquine and hydroxychloroquine increase retinal pigment epithelial layer permeability[J]. J Biochem Mol Toxicol, 2015, 29(7): 299-304. DOI: 10.1002/jbt.21696.
34.	Yoon YH, Cho KS, Hwang JJ, et al. Induction of lysosomal dilatation, arrested autophagy, and cell death by chloroquine in cultured ARPE-19 cells[J]. Invest Ophthalmol Vis Sci, 2010, 51(11): 6030-6037. DOI: 10.1167/iovs.10-5278.
35.	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.

1. 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.
2. Dima A, Jurcut C, Arnaud L. Hydroxychloroquine in systemic and autoimmune diseases: where are we now?[J/OL]. Joint Bone Spine, 2021, 88(3): 105143[2021-01-28]. https://pubmed.ncbi.nlm.nih.gov/33515791/. DOI: 10.1016/j.jbspin.2021.105143.
3. Anjos R, Ferreira A, Barkoudah E, et al. Application of optical coherence tomography angiography macular analysis for systemic hypertension. A systematic review and meta-analysis[J]. Am J Hypertens, 2022, 35(4): 356-364. DOI: 10.1093/ajh/hpab172.
4. Nicolò M, Ferro Desideri L, Bassetti M, et al. Hydroxychloroquine and chloroquine retinal safety concerns during COVID-19 outbreak[J]. Int Ophthalmol, 2021, 41(2): 719-725. DOI: 10.1007/s10792-020-01593-0.
5. Shah S, Das S, Jain A, et al. A systematic review of the prophylactic role of chloroquine and hydroxychloroquine in coronavirus disease-19 (COVID-19)[J]. Int J Rheum Dis, 2020, 23(5): 613-619. DOI: 10.1111/1756-185X.13842.
6. Abdulaziz N, Shah AR, McCune WJ. Hydroxychloroquine: balancing the need to maintain therapeutic levels with ocular safety: an update[J]. Curr Opin Rheumatol, 2018, 30(3): 249-255. DOI: 10.1097/bor.0000000000000500.
7. Mititelu M, Wong BJ, Brenner M, et al. Progression of hydroxychloroquine toxic effects after drug therapy cessation: new evidence from multimodal imaging[J]. JAMA Ophthalmol, 2013, 131(9): 1187-1197. DOI: 10.1001/jamaophthalmol.2013.4244.
8. Melles RB, Marmor MF. The risk of toxic retinopathy in patients on long-term hydroxychloroquine therapy[J]. JAMA Ophthalmol, 2014, 132(12): 1453-1460. DOI: 10.1001/jamaophthalmol.2014.3459.
9. Melles RB, Marmor MF. Pericentral retinopathy and racial differences in hydroxychloroquine toxicity[J]. Ophthalmology, 2015, 122(1): 110-116. DOI: 10.1016/j.ophtha.2014.07.018.
10. Yusuf IH, Charbel Issa P, Ahn SJ. Hydroxychloroquine-induced retinal toxicity[J/OL]. Front Pharmacol, 2023, 14: 1196783[2023-05-30]. https://pubmed.ncbi.nlm.nih.gov/37324471/. DOI: 10.3389/fphar.2023.1196783.
11. de Sisternes L, Hu J, Rubin DL, et al. Localization of damage in progressive hydroxychloroquine retinopathy on and off the drug: inner versus outer retina, parafovea versus peripheral fovea[J]. Invest Ophthalmol Vis Sci, 2015, 56(5): 3415-3426. DOI: 10.1167/iovs.14-16345.
12. Rosenthal AR, Kolb H, Bergsma D, et al. Chloroquine retinopathy in the rhesus monkey[J]. Invest Ophthalmol Vis Sci, 1978, 17(12): 1158-1175.
13. Pasadhika S, Fishman GA, Choi D, et al. Selective thinning of the perifoveal inner retina as an early sign of hydroxychloroquine retinal toxicity[J]. Eye (Lond), 2010, 24(5): 756-762. DOI: 10.1038/eye.2010.21.
14. Ulviye Y, Betul T, Nur TH, et al. Spectral domain optical coherence tomography for early detection of retinal alterations in patients using hydroxychloroquine[J]. Indian J Ophthalmol, 2013, 61(4): 168-171. DOI: 10.4103/0301-4738.112161.
15. Bulut M, Akıdan M, Gözkaya O, et al. Optical coherence tomography angiography for screening of hydroxychloroquine-induced retinal alterations[J]. Graefe's Arch Clin Exp Ophthalmol, 2018, 256(11): 2075-2081. DOI: 10.1007/s00417-018-4117-3.
16. Kim KE, Kim YH, Kim J, et al. Macular ganglion cell complex and peripapillary retinal nerve fiber layer thicknesses in hydroxychloroquine retinopathy[J]. Am J Ophthalmol, 2023, 245: 70-80. DOI: 10.1016/j.ajo.2022.07.028.
17. Lee MG, Kim SJ, Ham DI, et al. Macular retinal ganglion cell-inner plexiform layer thickness in patients on hydroxychloroquine therapy[J]. Invest Ophthalmol Vis Sci, 2014, 56(1): 396-402. DOI: 10.1167/iovs.14-15138.
18. Casado A, López-de-Eguileta A, Fonseca S, et al. Outer nuclear layer damage for detection of early retinal toxicity of hydroxychloroquine[J]. Biomedicines, 2020, 8(3): 54. DOI: 10.3390/biomedicines8030054.
19. Cinar E, Yuce B, Aslan F. Evaluation of retinal and choroidal microvascular changes in patients who received hydroxychloroquine by optical coherence tomography angiography[J]. Arq Bras Oftalmol, 2021, 84(1): 2-10. DOI: 10.5935/0004-2749.20210001.
20. Goker YS, Ucgul Atılgan C, Tekin K, et al. The validity of optical coherence tomography angiography as a screening test for the early detection of retinal changes in patients with hydroxychloroquine therapy[J]. Curr Eye Res, 2019, 44(3): 311-315. DOI: 10.1080/02713683.2018.1545912.
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. Ozek D, Onen M, Karaca EE, et al. The optical coherence tomography angiography findings of rheumatoid arthritis patients taking hydroxychloroquine[J]. Eur J Ophthalmol, 2019, 29(5): 532-537. DOI: 10.1177/1120672118801125.
23. Mihailovic N, Leclaire MD, Eter N, et al. Altered microvascular density in patients with systemic lupus erythematosus treated with hydroxychloroquine-an optical coherence tomography angiography study[J]. Graefe's Arch Clin Exp Ophthalmol, 2020, 258(10): 2263-2269. DOI: 10.1007/s00417-020-04788-4.
24. Conigliaro P, Cesareo M, Chimenti MS, et al. Response to: 'OCTA, a sensitive screening for asymptomatic retinopathy, raises alarm over systemic involvements in patients with SLE' by Mizuno et al[J/OL]. Ann Rheum Dis, 2020, 79(2): e18[2018-12-20]. https://pubmed.ncbi.nlm.nih.gov/30573654/. DOI: 10.1136/annrheumdis-2018-214796.
25. Ahn SJ, Ryu SJ, Joung JY, et al. Choroidal thinning associated with hydroxychloroquine retinopathy[J]. Am J Ophthalmol, 2017, 183: 56-64. DOI: 10.1016/j.ajo.2017.08.022.
26. Kurihara T, Westenskow PD, Bravo S, et al. Targeted deletion of VRGFA in adult mice induces vision loss[J]. J Clin Invest, 2012, 122(11): 4213-4217. DOI: 10.1172/jci65157.
27. Iovino C, Pellegrini M, Bernabei F, et al. Choroidal vascularity index: an in-depth analysis of this novel optical coherence tomography parameter[J]. J Clin Med, 2020, 9(2): 595. DOI: 10.3390/jcm9020595.
28. Ding HJ, Denniston AK, Rao VK, et al. Hydroxychloroquine-related retinal toxicity[J]. Rheumatology (Oxford), 2016, 55(6): 957-967. DOI: 10.1093/rheumatology/kev357.
29. Remolí-Sargues L, Monferrer-Adsuara C, Hernández-Garfella ML, et al. Optical coherence tomography angiography features in a case of hydroxychloroquine retinopathy[J]. Int J Ophthalmol, 2023, 16(2): 325-327. DOI: 10.18240/ijo.2023.02.24.
30. Polat OA, Okçu M, Yılmaz M. Hydroxychloroquine treatment alters retinal layers and choroid without apparent toxicity in optical coherence tomography[J/OL]. Photodiagnosis Photodyn Ther, 2022, 38: 102806[2022-03-11]. https://pubmed.ncbi.nlm.nih.gov/35288317/. DOI: 10.1016/j.pdpdt.2022.102806.
31. Remolí Sargues L, Monferrer Adsuara C, Castro Navarro V, et al. New insights in pathogenic mechanism of hydroxychloroquine retinal toxicity through optical coherence tomography angiography analysis[J]. Eur J Ophthalmol, 2022, 32(6): 3599-3608. DOI: 10.1177/11206721221076313.
32. Michaelides M, Stover NB, Francis PJ, et al. Retinal toxicity associated with hydroxychloroquine and chloroquine: risk factors, screening, and progression despite cessation of therapy[J]. Arch Ophthalmol, 2011, 129(1): 30-39. DOI: 10.1001/archophthalmol.2010.321.
33. Korthagen NM, Bastiaans J, van Meurs JC, et al. Chloroquine and hydroxychloroquine increase retinal pigment epithelial layer permeability[J]. J Biochem Mol Toxicol, 2015, 29(7): 299-304. DOI: 10.1002/jbt.21696.
34. Yoon YH, Cho KS, Hwang JJ, et al. Induction of lysosomal dilatation, arrested autophagy, and cell death by chloroquine in cultured ARPE-19 cells[J]. Invest Ophthalmol Vis Sci, 2010, 51(11): 6030-6037. DOI: 10.1167/iovs.10-5278.
35. 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.

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