Despite advances in therapy for rheumatic diseases, hydroxychloroquine remains almost universally recommended for the treatment of systemic lupus erythematosus (SLE), and is often used in the management of other rheumatic diseases such as rheumatoid arthritis (RA). However, the major dose-limiting toxicity of hydroxychloroquine is retinopathy that can lead to loss of vision. New highly sensitive screening methods can identify early stages of retinopathy, and studies that include these modalities have indicated a substantially higher prevalence of hydroxychloroquine retinopathy than was previously recognized, resulting in revisions to ophthalmology guidelines and the recommendation of a low dose of hydroxychloroquine for many patients. However, the efficacy of low-dose hydroxychloroquine for treating SLE and other rheumatic diseases is unknown. Further studies are required to establish the effectiveness and retinal safety of the latest hydroxychloroquine treatment recommendations.
Hydroxychloroquine is almost universally recommended for patients with systemic lupus erythematosus (SLE) and has wide-ranging benefits, but risks include toxic retinopathy.
A proposed mechanism of hydroxychloroquine retinopathy is impaired lysosomal degradation of photoreceptor outer segments by the retinal pigment epithelium.
Early changes associated with hydroxychloroquine retinopathy can be detected by modern highly sensitive screening modalities.
Hydroxychloroquine retinopathy prevalence is lower in studies of older screening modalities than in studies of highly sensitive screening methods that include early stages of disease (<2% versus ≤8%).
The most important predictors of hydroxychloroquine retinopathy are thought to be high-dose (>5 mg/kg) and long-term (>5 years) use, but existing evidence is limited to retrospective studies of prevalence data.
Despite the wide-ranging benefits of hydroxychloroquine therapy for patients with SLE, rheumatoid arthritis (RA) or other conditions, data on the dose–response relationship with outcomes are scarce.
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Alarcon, G. S. 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. 66, 1168–1172 (2007).
Ruiz-Irastorza, G., Ramos-Casals, M., Brito-Zeron, P. & Khamashta, M. A. Clinical efficacy and side effects of antimalarials in systemic lupus erythematosus: a systematic review. Ann. Rheum. Dis. 69, 20–28 (2010).
Ruiz-Irastorza, G. et al. Effect of antimalarials on thrombosis and survival in patients with systemic lupus erythematosus. Lupus 15, 577–583 (2006).
The Canadian Hydroxychloroquine Study Group. A Randomized study of the effect of withdrawing hydroxychloroquine sulfate in systemic lupus erythematosus. N. Engl. J. Med. 324, 150–154 (1991).
Pons-Estel, G. J. et al. Protective effect of hydroxychloroquine on renal damage in patients with lupus nephritis: LXV, data from a multiethnic US cohort. Arthritis Rheum. 61, 830–839 (2009).
Petri, M. Use of hydroxychloroquine to prevent thrombosis in systemic lupus erythematosus and in antiphospholipid antibody-positive patients. Curr. Rheumatol. Rep. 13, 77–80 (2011).
Clowse, M. E., Magder, L., Witter, F. & Petri, M. Hydroxychloroquine in lupus pregnancy. Arthritis Rheum. 54, 3640–3647 (2006).
Jorge, A. & Ramsey-Goldman, R. in Systemic Lupus Erythematosus 117–135 (Oxford Univ. Press, 2016).
Cairoli, E., Rebella, M., Danese, N., Garra, V. & Borba, E. F. Hydroxychloroquine reduces low-density lipoprotein cholesterol levels in systemic lupus erythematosus: a longitudinal evaluation of the lipid-lowering effect. Lupus 21, 1178–1182 (2012).
Pons-Estel, G. J. 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) 51, 1293–1298 (2012).
Wallace, D. J., Gudsoorkar, V. S., Weisman, M. H. & Venuturupalli, S. R. New insights into mechanisms of therapeutic effects of antimalarial agents in SLE. Nat. Rev. Rheumatol. 8, 522–533 (2012).
O’Dell, J. R. et al. Therapies for active rheumatoid arthritis after methotrexate failure. N. Engl. J. Med. 369, 307–318 (2013).
Moreland, L. W. et al. A randomized comparative effectiveness study of oral triple therapy versus etanercept plus methotrexate in early aggressive rheumatoid arthritis: the Treatment of Early Aggressive Rheumatoid Arthritis trial. Arthritis Rheum. 64, 2824–2835 (2012).
Bansback, N. et al. Triple therapy versus biologic therapy for active rheumatoid arthritis: a cost-effectiveness analysis. Ann. Int. Med. 167, 8–16 (2017).
Rempenault, C. et al. Metabolic and cardiovascular benefits of hydroxychloroquine in patients with rheumatoid arthritis: a systematic review and meta-analysis. Ann. Rheum. Dis. 77, 98–103 (2018).
Wasko, M. C. et al. Hydroxychloroquine and risk of diabetes in patients with rheumatoid arthritis. JAMA 298, 187–193 (2007).
Chen, Y. M. et al. Hydroxychloroquine reduces risk of incident diabetes mellitus in lupus patients in a dose-dependent manner: a population-based cohort study. Rheumatology (Oxford) 54, 1244–1249 (2015).
Braslow, R. A., Shiloach, M. & Macsai, M. S. Adherence to hydroxychloroquine dosing guidelines by rheumatologists: an electronic medical record-based study in an integrated health care system. Ophthalmology 124, 604–608 (2017).
Melles, R. B. & Marmor, M. F. The risk of toxic retinopathy in patients on long-term hydroxychloroquine therapy. JAMA Ophthalmol. 132, 1453–1460 (2014).
Melles, R. B. & Marmor, M. F. The prevalence of hydroxychloroquine retinopathy and toxic dosing, and the role of the ophthalmologist in reducing both. Am. J. Ophthalmol. 170, 240 (2016).
Johnston, J. L., Darvill, P. & Thomson, G. T. Spectral-domain optical coherence tomography in hydroxychloroquine retinopathy. Ophthalmology 122, 651–652 (2015).
Eo, D. R. et al. Frequency and clinical characteristics of hydroxychloroquine retinopathy in Korean patients with rheumatologic diseases. J. Kor. Med. Sci. 32, 522–527 (2017).
Lee, D. H. et al. Pericentral hydroxychloroquine retinopathy in Korean patients. Ophthalmology 122, 1252–1256 (2015).
Browning, D. J. & Lee, C. Somatotype, the risk of hydroxychloroquine retinopathy, and safe daily dosing guidelines. Clin. Ophthalmol. (Auckland, N. Z.) 12, 811–818 (2018).
Mavrikakis, I. et al. The incidence of irreversible retinal toxicity in patients treated with hydroxychloroquine. Ophthalmology 110, 1321–1326 (2003).
Wang, C. et al. Discontinuation of antimalarial drugs in systemic lupus erythematosus. J. Rheumatol. 26, 808–815 (1999).
Levy, G. D. et al. Incidence of hydroxychloroquine retinopathy in 1,207 patients in a large multicenter outpatient practice. Arthritis Rheum. 40, 1482–1486 (1997).
Elder, M., Rahman, A. M. & McLay, J. Early paracentral visual field loss in patients taking hydroxychloroquine. Arch. Ophthalmol. 124, 1729–1733 (2006).
Easterbrook, M. Ocular effects and safety of antimalarial agents. Am. J. Med. 85, 23–29 (1988).
Mills, P. V., Beck, M. & Power, B. J. Assessment of the retinal toxicity of hydroxychloroquine. Trans. Ophthalmol. Soc. UK 101, 109–113 (1981).
Bell, C. L. Hydroxychloroquine sulfate in rheumatoid arthritis: long-term response rate and predictive parameters. Am. J. Med. 75, 46–51 (1983).
Wolfe, F. & Marmor, M. F. Rates and predictors of hydroxychloroquine retinal toxicity in patients with rheumatoid arthritis and systemic lupus erythematosus. Arthritis Care Res. (Hoboken) 62, 775–784 (2010).
Jover, J. A. et al. Long-term use of antimalarial drugs in rheumatic diseases. Clin. Exp. Rheumatol. 30, 380–387 (2012).
Tsang, A. S. M. W., Bultink, I. E. & Voskuyl, A. E. Long-term evaluation of antimalarials in a Dutch SLE cohort: intolerance and other reasons for non-use. Clin. Exp. Rheumatol. 32, 95–100 (2014).
Marmor, M. F. Comparison of screening procedures in hydroxychloroquine toxicity. Arch. Ophthalmol. 130, 461–469 (2012).
Browning, D. J. & Lee, C. Relative sensitivity and specificity of 10–12 visual fields, multifocal electroretinography, and spectral domain optical coherence tomography in detecting hydroxychloroquine and chloroquine retinopathy. Clin. Ophthalmol. 8, 1389–1399 (2014).
Marmor, M. F. Fundus autofluorescence is not the best early screen for hydroxychloroquine toxicity. JAMA Ophthalmol. 131, 1487–1488 (2013).
U.S. Centers for Medicare & Medicaid Services. Physician fee schedule search. CMS.gov https://www.cms.gov/apps/physician-fee-schedule/search/search-criteria.aspx (2018).
Marmor, M. F. et al. Recommendations on screening for chloroquine and hydroxychloroquine retinopathy (2016 revision). Ophthalmology 123, 1386–1394 (2016).
Marmor, M. F. The demise of the bull’s eye (screening for hydroxychloroquine retinopathy). Retina 36, 1803–1805 (2016).
Cukras, C. et al. Subjective and objective screening tests for hydroxychloroquine toxicity. Ophthalmology 122, 356–366 (2015).
Marmor, M. F. & Hu, J. Effect of disease stage on progression of hydroxychloroquine retinopathy. JAMA Ophthalmol. 132, 1105–1112 (2014).
Melles, R. B. & Marmor, M. F. Pericentral retinopathy and racial differences in hydroxychloroquine toxicity. Ophthalmology 122, 110–116 (2015).
Browning, D. J. The prevalence of hydroxychloroquine retinopathy and toxic dosing, and the role of the ophthalmologist in reducing both. Am J. Ophthalmol. 166, ix–xi (2016).
Marmor, M. F. Hydroxychloroquine screening alert: change is in the wind. Ophthalm. Surg. Lasers Imag. Retina 48, 96–98 (2017).
McChesney, E. W., Shekosky, J. M. & Hernandez, P. H. Metabolism of chloroquine 3-14C in the rhesus monkey. Biochem. Pharmacol. 16, 2444–2447 (1967).
McChesney, E. W. Animal toxicity and pharmacokinetics of hydroxychloroquine sulfate. Am. J. Med. 75, 11–18 (1983).
Bernstein, H. N. Ophthalmologic considerations and testing in patients receiving long-term antimalarial therapy. Am. J. Med. 75, 25–34 (1983).
MacKenzie, A. H. Pharmacologic action of 4-aminoquinolone compounds. Am. J. Med. 75, 5–10 (1983).
Titus, E. O. Recent developments in the understanding of the pharmacokinetics and mechanism of action of chloroquine. Ther. Drug Monitor. 11, 369–379 (1989).
Costedoat-Chalumeau, N. et al. Adherence to treatment in systemic lupus erythematosus patients. Best Pract. Res. Clin. Rheumatol. 27, 329–340 (2013).
Feldman, C. H. et al. Dynamic patterns and predictors of hydroxychloroquine nonadherence among Medicaid beneficiaries with systemic lupus erythematosus. Semin. Arthritis Rheum. https://doi.org/10.1016/j.semarthrit.2018.01.002 (2018).
Lau, B., Cole, S. R. & Gange, S. J. Competing risk regression models for epidemiologic data. Am. J. Epidemiol. 170, 244–256 (2009).
Jorge, A. M., Lu, N., Zhang, Y., Rai, S. K. & Choi, H. K. Unchanging premature mortality trends in systemic lupus erythematosus: a general population-based study (1999–2014). Rheumatology (Oxford) 57, 337–344 (2018).
Lu, N., Choi, H. K., Jorge, A. & Zhang, Y. Is risk of retinopathy among hydroxychloroquine users of SLE patients accurate? A simulation study accounting for competing risk of death [abstract]. Arthritis Rheumatol. 69 (Suppl. 10), 2990 (2017).
Ding, H. J., Denniston, A. K., Rao, V. K. & Gordon, C. Hydroxychloroquine-related retinal toxicity. Rheumatology (Oxford) 55, 957–967 (2016).
Young, R. W. The renewal of photoreceptor cell outer segments. J. Cell Biol. 33, 61–72 (1967).
Young, R. W. & Bok, D. Participation of the retinal pigment epithelium in the rod outer segment renewal process. J. Cell Biol. 42, 392–403 (1969).
Nandrot, E. F. et al. Essential role for MFG-E8 as ligand for αvβ5 integrin in diurnal retinal phagocytosis. Proc. Natl Acad. Sci. USA 104, 12005–12010 (2007).
Sparrrow, J., Hicks, D. & Hamel, C. The retinal pigment epithelium in health and disease. Curr. Mol. Med. 10, 802–823 (2010).
McBee, J. K. et al. Isomerization of all-trans-retinol to cis-retinols in bovine retinal pigment epithelial cells: dependence on the specificity of retinoid-binding proteins. Biochemistry 39, 11370–11380 (2000).
Korthagen, N. M. et al. Chloroquine and hydroxychloroquine increase retinal pigment epithelial layer permeability. J. Biochem. Mol. Toxicol. 29, 299–304 (2015).
Yoon, Y. H. et al. Induction of lysosomal dilatation, arrested autophagy, and cell death by chloroquine in cultured ARPE-19 cells. Invest. Ophthalmol. Vis. Sci. 51, 6030–6037 (2010).
Fox, R. Anti-malarial drugs: possible mechanisms of action in autoimmune disease and prospects for drug development. Lupus 5(Suppl. 1), S4–S10 (1996).
Sundelin, S. P. & Terman, A. Different effects of chloroquine and hydroxychloroquine on lysosomal function in cultured retinal pigment epithelial cells. APMIS 110, 481–489 (2002).
Michaelides, M., Stover, N. B., Francis, P. J. & Weleber, R. G. Retinal toxicity associated with hydroxychloroquine and chloroquine: risk factors, screening, and progression despite cessation of therapy. Arch. Ophthalmol. 129, 30–39 (2011).
Xu, C. et al. Chloroquine and hydroxychloroquine are novel inhibitors of human organic anion transporting polypeptide 1A2. J. Pharm. Sci. 105, 884–890 (2016).
Maeda, A., Maeda, T., Golczak, M. & Palczewski, K. Retinopathy in mice induced by disrupted all-trans-retinal clearance. J. Biol. Chem. 283, 26684–26693 (2008).
Rosenthal, A. R., Kolb, H., Bergsma, D., Huxsoll, D. & Hopkins, J. L. Chloroquine retinopathy in the rhesus monkey. Invest. Ophthalmol. Vis. Sci. 17, 1158–1175 (1978).
Ramsey, M. S. & Fine, B. S. Chloroquine toxicity in the human eye. Histopathologic observations by electron microscopy. Am. J. Ophthalmol. 73, 229–235 (1972).
Pasadhika, S. & Fishman, G. A. Effects of chronic exposure to hydroxychloroquine or chloroquine on inner retinal structures. Eye (Lond.) 24, 340–346 (2010).
Pasadhika, S., Fishman, G. A., Choi, D. & Shahidi, M. Selective thinning of the perifoveal inner retina as an early sign of hydroxychloroquine retinal toxicity. Eye (Lond.) 24, 756–762 (2010).
Canadian Rheumatology Association. Canadian Consensus Conference on hydroxychloroquine. J. Rheumatol. 27, 2919–2921 (2000).
Marmor, M. F., Carr, R. E., Easterbrook, M., Farjo, A. A. & Mieler, W. F. Recommendations on screening for chloroquine and hydroxychloroquine retinopathy: a report by the American Academy of Ophthalmology. Opthamology 109, 1377–1382 (2002).
Bertsias, G. et al. EULAR recommendations for the management of systemic lupus erythematosus. Report of a Task Force of the EULAR Standing Committee for international clinical studies including therapeutics. Ann. Rheum. Dis. 67, 195–205 (2008).
Durcan, L., Clarke, W. A., Magder, L. S. & Petri, M. Hydroxychloroquine blood levels in systemic lupus erythematosus: clarifying dosing controversies and improving adherence. J. Rheumatol. 42, 2092–2097 (2015).
Fryar, C. D., Gu, Q., Ogden, C. L. & Flegal, K. M. Anthropometric reference data for children and adults: United States, 2011–2014. Vital Health Stat. 3 39, 1–46 (2016).
Health and Social Care Information Centre. National statistics: statistics on obesity, physical activity and diet. NHS Digital https://digital.nhs.uk/data-and-information/publications/statistical/statistics-on-obesity-physical-activity-and-diet/statistics-on-obesity-physical-activity-and-diet-england-2018 (2016).
Browning, D. J., Lee, C. & Rotberg, D. The impact of different algorithms for ideal body weight on screening for hydroxychloroquine retinopathy in women. Clin. Ophthalmol. 8, 1401–1407 (2014).
Devine, B. Clinical pharmacy case studies: case number 25: gentamicin therapy. Drug Intell. Clin. Pharm. 8, 650–655 (1974).
Gianfrancesco, M. A. et al. Hydroxychloroquine dosing in immune-mediated diseases: implications for patient safety. Rheumatol. Int. 7, 1611–1618 (2017).
Melles, R. B., Jorge, A. M., Marmor, M. F., Zhang, Y. & Choi, H. K. Sharp decline in hydroxychloroquine dosing-analysis of 17,797 initiators from 2007 to 2016. Clin. Rheumatol. 37, 1853–1859 (2018).
Jorge, A. M. et al. Hydroxychloroquine prescription trends and predictors for excess dosing per recent ophthalmology guidelines. Arthritis Res. Ther. 20, 133 (2018).
Leung, L. S., Neal, J. W., Wakelee, H. A., Sequist, L. V. & Marmor, M. F. Rapid onset of retinal toxicity from high-dose hydroxychloroquine given for cancer therapy. Am J. Ophthalmol. 160, 799–805 (2015).
The Royal College of Ophthalmologists. Clinical guidelines: hydroxychloroquine and chloroquine retinopathy: recommendations on screening. RCOphth https://www.rcophth.ac.uk/wp-content/uploads/2018/07/Hydroxychloroquine-and-Chloroquine-Retinopathy-Screening-Guideline-Recommendations.pdf (2018).
Duarte-Garcia, A., Barr, E., Magder, L. S. & Petri, M. Predictors of incident proteinuria among patients with SLE. Lupus Sci. Med. 4, e000200 (2017).
Mok, C. C. et al. Hydroxychloroquine serum concentrations and flares of systemic lupus erythematosus: a longitudinal cohort analysis. Arthritis Care Res. (Hoboken) 68, 1295–1302 (2016).
Costedoat-Chalumeau, N. et al. Low blood concentration of hydroxychloroquine is a marker for and predictor of disease exacerbations in patients with systemic lupus erythematosus. Arthritis Rheum. 54, 3284–3290 (2006).
Feldman, C. H., Yazdany, J., Guan, H., Solomon, D. H. & Costenbader, K. H. Medication nonadherence is associated with increased subsequent acute care utilization among medicaid beneficiaries with systemic lupus erythematosus. Arthritis Care Res. (Hoboken) 67, 1712–1721 (2015).
The Royal College of Ophthalmologists. Hydroxychloroquine and ocular toxicity recommendations on screening. BAD http://www.bad.org.uk/shared/get-file.ashx?id=774&itemtype=document (2009).
Marmor, M. F., Kellner, U., Lai, T. Y., Lyons, J. S. & Mieler, W. F. Revised recommendations on screening for chloroquine and hydroxychloroquine retinopathy. Ophthalmology 118, 415–422 (2011).
Bertsias, G. K. et al. Joint European League Against Rheumatism and European Renal Association-European Dialysis and Transplant Association (EULAR/ERA-EDTA) recommendations for the management of adult and paediatric lupus nephritis. Ann. Rheum. Dis. 71, 1771–1782 (2012).
The authors would like to thank A. Thanos of Legacy Devers Eye Institute in Portland, OR, USA, for assistance with the formulation of figure 2.
Nature Reviews Rheumatology thanks N. Costedoat-Chalumeau, J. Rosenbaum and the other anonymous reviewer(s) for their contribution to the peer review of this work.
The authors declare no competing interests.
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Region of the retina that surrounds the central fovea, within the macula. The macula is the region responsible for high-acuity central vision.
- Visual field
The entire area that can be seen with the eyes fixed in one region.
- Actual body weight
(ABW).True (measured) body weight.
- Ideal body weight
(IBW). An estimate of body weight based on lean mass, calculated from factors including height and sex.
A specialized test measuring differences in electrical potential in the eyes.
- Retinal pigment epithelium
(RPE). A monolayer of pigmented cells that coats the outer retina.
- Bull’s eye damage
The classic late-stage finding of hydroxychloroquine retinopathy, seen as a ring of retinal damage in the parafoveal region.
- Visual cycle
The biological conversion of a photon into an electrical signal in the retina.
- Loading dose
The short-term (typically ~3 months) use of a higher dose of a medication than will be used as the maintenance dose.
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Jorge, A., Ung, C., Young, L.H. et al. Hydroxychloroquine retinopathy — implications of research advances for rheumatology care. Nat Rev Rheumatol 14, 693–703 (2018). https://doi.org/10.1038/s41584-018-0111-8
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