Research Original Investigation
Toxic Retinopathy With Hydroxychloroquine Therapy
20. Carmichael SJ, Day RO, Tett SE. A cross-sectional study of hydroxychloroquine concentrations and effects in people with systemic lupus erythematosus. Intern Med J. 2013;43(5):547553. 21. Costedoat-Chalumeau N, Pouchot J, Guettrot-Imbert G, et al. Adherence to treatment in systemic lupus erythematosus patients. Best Pract Res Clin Rheumatol. 2013;27(3):329-340. 22. Kellner U, Renner AB, Tillack H. Fundus autofluorescence and mfERG for early detection of
retinal alterations in patients using chloroquine/hydroxychloroquine. Invest Ophthalmol Vis Sci. 2006;47(8):3531-3538. 23. Lyons JS, Severns ML. Detection of early hydroxychloroquine retinal toxicity enhanced by ring ratio analysis of multifocal electroretinography. Am J Ophthalmol. 2007;143(5):801-809.
25. Marmor MF, Hu J. Effect of disease stage on progression of hydroxychloroquine retinopathy [published online June 12, 2014]. JAMA Ophthalmol. doi:10.1001/jamaophthalmol.2014.1099. 26. Kaiser-Kupfer MI, Lippman ME. Tamoxifen retinopathy. Cancer Treat Rep. 1978;62(3):315-320.
24. Marmor MF, Melles RB. Disparity between visual fields and optical coherence tomography in hydroxychloroquine retinopathy. Ophthalmology. 2014;121(6):1257-1262.
Invited Commentary
We Need to Be Better Prepared for Hydroxychloroquine Retinopathy Hendrik P. N. Scholl, MD, MA; Syed Mahmood Ali Shah, MBBS
From the first discovery of chloroquine by Hans Andersag at Bayer in 1939 and later development of its hydroxyl and less toxic form hydroxychloroquine (HCQ), these medications have been one of the most abundantly used around the world and have been instrumental in saving countless lives from malaria. Hydroxychloroquine is currently listed in the World Related article page 1453 Health Organization Model List of Essential Medicines as a disease-modifying agent for rheumatoid arthritis. Its use is becoming ubiquitous for a variety of autoimmune disorders from lupus to rheumatoid arthritis and now finding its way into dermatology and oncology.1 There are more than 50 studies evaluating HCQ in various disorders including many tumors. With the results of the LUMINA (Lupus in Minorities: Nature vs Nurture) trial showing clear benefit of HCQ use by decreasing mortality and end organ damage, HCQ use has significantly increased and is being advocated by the rheumatology community with clinical trials reporting its use in 50% of patients with lupus, with tertiary care centers reporting the rate of up to 90% (Baltimore Lupus Cohort; Michele Petri, MD, MPH, Johns Hopkins Hospital, written communication, June 25, 2014). Given the increasing use of HCQ and retinopathy being the only absolute contraindication for its use, it is more critical than ever to advocate for screening, detection, and prevention of retinopathy. Of note, most of these screenings are not performed by retina spec ialists but by general ophthalmologists.2 The American Academy of Ophthalmology recently issued revised guidelines including the recommendation of more sensitive tests such as multifocal electroretinography, spectraldomain optical coherence tomography, and fundus autofluorescence. Although advanced screening is not recommended until 5 years of receiving HCQ, considering the number of patients receiving the medication and the actual practice of performing those tests every year adds significant cost to the overall health care system.2 In an article in JAMA Ophthalmology, Melles and Marmor3 suggest that approximately 350 000 patients in the United States should receive an annual eye screen1460
ing when applying the current guidelines. However, that number may be much higher if we add the current use in both adult and juvenile rheumatoid arthritis, not to mention the newly found use in oncology, where it may end up being used in higher than normal doses, and in some cases for maintenance, resulting in high cumulative doses.4 Melles and Marmor3 report retinopathy in 7.5% of longterm HCQ users screened with modern techniques, which is about 3 times higher than previous estimates. Those previous estimates had been primarily based on clinical examination and visual fields. Current widespread presence and use of optical coherence tomography as a sensitive and reproducible test, which even allows exact anatomical placement of follow-up scans, may prove to be more sensitive and allow detection of changes well before bull’s-eye maculopathy has developed. Such precise investigation of the retinal morphology does not, however, make functional tests obsolete since a recent study by Marmor and Melles5 suggests that visual field loss can actually be a more sensitive marker than the loss of the ellipsoid zone on optical coherence tomography. There is extensive discussion in the literature (comprehensively summarized by Melles and Marmor3) about the use of ideal and real body weight. Within the rheumatology community, there may be a new drive to guide the dose based on blood levels, rather than body weight. Instead of using it as an adjunct, it should be a primary method to achieve a steady state, which would address both compliance and overdosing in high-risk patients. Most of the discussion about body weight is trying to find a balance between the safety and efficacy of HCQ, but to our knowledge, no randomized studies have shown that dosing based on either ideal or real body weight is superior for the disease itself. The retrospective study of Melles and Marmor3 suggests that the real body weight is a better predictor of toxic effects but not essentially better at striking the best balance between safety and efficacy. How do we deal as ophthalmologists with HCQ being increasingly used and finding new indications? We need to acknowledge that HCQ reduces mortality and decreases end organ damage in lupus6 and need to be prepared that HCQ will
JAMA Ophthalmology December 2014 Volume 132, Number 12
Copyright 2014 American Medical Association. All rights reserved.
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jamaophthalmology.com
Toxic Retinopathy With Hydroxychloroquine Therapy
Original Investigation Research
be used more and/or for longer durations. Unless we have more efficient and precise screening methods, we will be adding to the already staggering health care costs. Also, we need more clinical research that must teach us how reversible HCQ retinopathy can be and how it progresses after stopping the drug vs continuing to receive the drug. The literature suggests that there is dramatic variability in the individual risk to develop HCQ retinopathy.7 This makes an important argument for using pharmacogenomics to explore the relationship of genetic factors and the risk to develop HCQ retinopathy. A genetic study by Shroyer et al8 suggested that some individuals who carry mutations in the ABCA4 gene may be predisposed to develop retinal toxic effects when exposed to chloroquine/HCQ. An ongoing study sponsored by the National Eye Institute will shed more light on ABCA4 variants being a risk factor (ClinicalTrials.gov identifier NCT01145196). This hypothesis is further supported by
the finding in the study of Melles and Marmor3 that tamoxifen appears to promote HCQ retinopathy. Breast cancer resistance protein is a member of the adenosine triphosphate– binding cassette transporter protein family, which is implicated as a cause of resistance to multiple cancer drugs including tamoxifen. There is evidence that HCQ may have synergistic effects on tamoxifen for breast cancer in vitro,4 which could involve modification of the adenosine triphosphate–binding cassette family of proteins, hence increasing the effect of tamoxifen. This may be just the tip of the iceberg, as our techniques to sequence genes are becoming more sophisticated and rapid and should allow us to find more interactions between genes and drug effects, such as HCQ toxicity. Such findings should allow us to tailor both the medication and the dose to the patient’s individual risk and to institute more appropriate screening programs.
ARTICLE INFORMATION
REFERENCES
Author Affiliations: Wilmer Eye Institute, Johns Hopkins University, Baltimore, Maryland.
1. Olsen NJ, Schleich MA, Karp DR. Multifaceted effects of hydroxychloroquine in human disease. Semin Arthritis Rheum. 2013;43(2):264-272.
Corresponding Author: Hendrik P. N. Scholl, MD, MA, Wilmer Eye Institute, Johns Hopkins University, 600 N Wolfe St, 748 Maumenee Bldg, Baltimore, MD 21287 ([email protected]). Published Online: October 2, 2014. doi:10.1001/jamaophthalmol.2014.4090. Conflict of Interest Disclosures: All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr Scholl has received grants from the National Institutes of Health, Foundation Fighting Blindness, Clark Charitable Foundation, and The Shulsky Foundation and personal fees from OLT Inc, StemCells Inc, Genzyme, Fovea Pharmaceuticals, Trevena, Guidepoint Global LLC, and Gerson Lehrman Group. No other disclosures were reported.
jamaophthalmology.com
2. Browning DJ. Impact of the revised American Academy of Ophthalmology guidelines regarding hydroxychloroquine screening on actual practice. Am J Ophthalmol. 2013;155(3):418-428. 3. Melles RB, Marmor MF. The risk of toxic retinopathy in patients on long-term hydroxychloroquine therapy [published online October 2, 2014]. JAMA Ophthalmol. doi:10.1001 /jamaophthalmol.2014.3459. 4. Cook KL, Wärri A, Soto-Pantoja DR, et al. Hydroxychloroquine inhibits autophagy to potentiate antiestrogen responsiveness in ER+ breast cancer. Clin Cancer Res. 2014;20(12):32223232.
5. Marmor MF, Melles RB. Disparity between visual fields and optical coherence tomography in hydroxychloroquine retinopathy. Ophthalmology. 2014;121(6):1257-1262. 6. Petri M. Lupus in Baltimore: evidence-based ‘clinical pearls’ from the Hopkins Lupus Cohort. Lupus. 2005;14(12):970-973. 7. Johnson MW, Vine AK. Hydroxychloroquine therapy in massive total doses without retinal toxicity. Am J Ophthalmol. 1987;104(2):139-144. 8. Shroyer NF, Lewis RA, Lupski JR. Analysis of the ABCR (ABCA4) gene in 4-aminoquinoline retinopathy: is retinal toxicity by chloroquine and hydroxychloroquine related to Stargardt disease? Am J Ophthalmol. 2001;131(6):761-766.
JAMA Ophthalmology December 2014 Volume 132, Number 12
Copyright 2014 American Medical Association. All rights reserved.
Downloaded From: http://archopht.jamanetwork.com/ by a New York University User on 05/14/2015
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Toxic Retinopathy With Hydroxychloroquine Therapy
20. Carmichael SJ, Day RO, Tett SE. A cross-sectional study of hydroxychloroquine concentrations and effects in people with systemic lupus erythematosus. Intern Med J. 2013;43(5):547553. 21. Costedoat-Chalumeau N, Pouchot J, Guettrot-Imbert G, et al. Adherence to treatment in systemic lupus erythematosus patients. Best Pract Res Clin Rheumatol. 2013;27(3):329-340. 22. Kellner U, Renner AB, Tillack H. Fundus autofluorescence and mfERG for early detection of
retinal alterations in patients using chloroquine/hydroxychloroquine. Invest Ophthalmol Vis Sci. 2006;47(8):3531-3538. 23. Lyons JS, Severns ML. Detection of early hydroxychloroquine retinal toxicity enhanced by ring ratio analysis of multifocal electroretinography. Am J Ophthalmol. 2007;143(5):801-809.
25. Marmor MF, Hu J. Effect of disease stage on progression of hydroxychloroquine retinopathy [published online June 12, 2014]. JAMA Ophthalmol. doi:10.1001/jamaophthalmol.2014.1099. 26. Kaiser-Kupfer MI, Lippman ME. Tamoxifen retinopathy. Cancer Treat Rep. 1978;62(3):315-320.
24. Marmor MF, Melles RB. Disparity between visual fields and optical coherence tomography in hydroxychloroquine retinopathy. Ophthalmology. 2014;121(6):1257-1262.
Invited Commentary
We Need to Be Better Prepared for Hydroxychloroquine Retinopathy Hendrik P. N. Scholl, MD, MA; Syed Mahmood Ali Shah, MBBS
From the first discovery of chloroquine by Hans Andersag at Bayer in 1939 and later development of its hydroxyl and less toxic form hydroxychloroquine (HCQ), these medications have been one of the most abundantly used around the world and have been instrumental in saving countless lives from malaria. Hydroxychloroquine is currently listed in the World Related article page 1453 Health Organization Model List of Essential Medicines as a disease-modifying agent for rheumatoid arthritis. Its use is becoming ubiquitous for a variety of autoimmune disorders from lupus to rheumatoid arthritis and now finding its way into dermatology and oncology.1 There are more than 50 studies evaluating HCQ in various disorders including many tumors. With the results of the LUMINA (Lupus in Minorities: Nature vs Nurture) trial showing clear benefit of HCQ use by decreasing mortality and end organ damage, HCQ use has significantly increased and is being advocated by the rheumatology community with clinical trials reporting its use in 50% of patients with lupus, with tertiary care centers reporting the rate of up to 90% (Baltimore Lupus Cohort; Michele Petri, MD, MPH, Johns Hopkins Hospital, written communication, June 25, 2014). Given the increasing use of HCQ and retinopathy being the only absolute contraindication for its use, it is more critical than ever to advocate for screening, detection, and prevention of retinopathy. Of note, most of these screenings are not performed by retina spec ialists but by general ophthalmologists.2 The American Academy of Ophthalmology recently issued revised guidelines including the recommendation of more sensitive tests such as multifocal electroretinography, spectraldomain optical coherence tomography, and fundus autofluorescence. Although advanced screening is not recommended until 5 years of receiving HCQ, considering the number of patients receiving the medication and the actual practice of performing those tests every year adds significant cost to the overall health care system.2 In an article in JAMA Ophthalmology, Melles and Marmor3 suggest that approximately 350 000 patients in the United States should receive an annual eye screen1460
ing when applying the current guidelines. However, that number may be much higher if we add the current use in both adult and juvenile rheumatoid arthritis, not to mention the newly found use in oncology, where it may end up being used in higher than normal doses, and in some cases for maintenance, resulting in high cumulative doses.4 Melles and Marmor3 report retinopathy in 7.5% of longterm HCQ users screened with modern techniques, which is about 3 times higher than previous estimates. Those previous estimates had been primarily based on clinical examination and visual fields. Current widespread presence and use of optical coherence tomography as a sensitive and reproducible test, which even allows exact anatomical placement of follow-up scans, may prove to be more sensitive and allow detection of changes well before bull’s-eye maculopathy has developed. Such precise investigation of the retinal morphology does not, however, make functional tests obsolete since a recent study by Marmor and Melles5 suggests that visual field loss can actually be a more sensitive marker than the loss of the ellipsoid zone on optical coherence tomography. There is extensive discussion in the literature (comprehensively summarized by Melles and Marmor3) about the use of ideal and real body weight. Within the rheumatology community, there may be a new drive to guide the dose based on blood levels, rather than body weight. Instead of using it as an adjunct, it should be a primary method to achieve a steady state, which would address both compliance and overdosing in high-risk patients. Most of the discussion about body weight is trying to find a balance between the safety and efficacy of HCQ, but to our knowledge, no randomized studies have shown that dosing based on either ideal or real body weight is superior for the disease itself. The retrospective study of Melles and Marmor3 suggests that the real body weight is a better predictor of toxic effects but not essentially better at striking the best balance between safety and efficacy. How do we deal as ophthalmologists with HCQ being increasingly used and finding new indications? We need to acknowledge that HCQ reduces mortality and decreases end organ damage in lupus6 and need to be prepared that HCQ will
JAMA Ophthalmology December 2014 Volume 132, Number 12
Copyright 2014 American Medical Association. All rights reserved.
Downloaded From: http://archopht.jamanetwork.com/ by a New York University User on 05/14/2015
jamaophthalmology.com
Toxic Retinopathy With Hydroxychloroquine Therapy
Original Investigation Research
be used more and/or for longer durations. Unless we have more efficient and precise screening methods, we will be adding to the already staggering health care costs. Also, we need more clinical research that must teach us how reversible HCQ retinopathy can be and how it progresses after stopping the drug vs continuing to receive the drug. The literature suggests that there is dramatic variability in the individual risk to develop HCQ retinopathy.7 This makes an important argument for using pharmacogenomics to explore the relationship of genetic factors and the risk to develop HCQ retinopathy. A genetic study by Shroyer et al8 suggested that some individuals who carry mutations in the ABCA4 gene may be predisposed to develop retinal toxic effects when exposed to chloroquine/HCQ. An ongoing study sponsored by the National Eye Institute will shed more light on ABCA4 variants being a risk factor (ClinicalTrials.gov identifier NCT01145196). This hypothesis is further supported by
the finding in the study of Melles and Marmor3 that tamoxifen appears to promote HCQ retinopathy. Breast cancer resistance protein is a member of the adenosine triphosphate– binding cassette transporter protein family, which is implicated as a cause of resistance to multiple cancer drugs including tamoxifen. There is evidence that HCQ may have synergistic effects on tamoxifen for breast cancer in vitro,4 which could involve modification of the adenosine triphosphate–binding cassette family of proteins, hence increasing the effect of tamoxifen. This may be just the tip of the iceberg, as our techniques to sequence genes are becoming more sophisticated and rapid and should allow us to find more interactions between genes and drug effects, such as HCQ toxicity. Such findings should allow us to tailor both the medication and the dose to the patient’s individual risk and to institute more appropriate screening programs.
ARTICLE INFORMATION
REFERENCES
Author Affiliations: Wilmer Eye Institute, Johns Hopkins University, Baltimore, Maryland.
1. Olsen NJ, Schleich MA, Karp DR. Multifaceted effects of hydroxychloroquine in human disease. Semin Arthritis Rheum. 2013;43(2):264-272.
Corresponding Author: Hendrik P. N. Scholl, MD, MA, Wilmer Eye Institute, Johns Hopkins University, 600 N Wolfe St, 748 Maumenee Bldg, Baltimore, MD 21287 ([email protected]). Published Online: October 2, 2014. doi:10.1001/jamaophthalmol.2014.4090. Conflict of Interest Disclosures: All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr Scholl has received grants from the National Institutes of Health, Foundation Fighting Blindness, Clark Charitable Foundation, and The Shulsky Foundation and personal fees from OLT Inc, StemCells Inc, Genzyme, Fovea Pharmaceuticals, Trevena, Guidepoint Global LLC, and Gerson Lehrman Group. No other disclosures were reported.
jamaophthalmology.com
2. Browning DJ. Impact of the revised American Academy of Ophthalmology guidelines regarding hydroxychloroquine screening on actual practice. Am J Ophthalmol. 2013;155(3):418-428. 3. Melles RB, Marmor MF. The risk of toxic retinopathy in patients on long-term hydroxychloroquine therapy [published online October 2, 2014]. JAMA Ophthalmol. doi:10.1001 /jamaophthalmol.2014.3459. 4. Cook KL, Wärri A, Soto-Pantoja DR, et al. Hydroxychloroquine inhibits autophagy to potentiate antiestrogen responsiveness in ER+ breast cancer. Clin Cancer Res. 2014;20(12):32223232.
5. Marmor MF, Melles RB. Disparity between visual fields and optical coherence tomography in hydroxychloroquine retinopathy. Ophthalmology. 2014;121(6):1257-1262. 6. Petri M. Lupus in Baltimore: evidence-based ‘clinical pearls’ from the Hopkins Lupus Cohort. Lupus. 2005;14(12):970-973. 7. Johnson MW, Vine AK. Hydroxychloroquine therapy in massive total doses without retinal toxicity. Am J Ophthalmol. 1987;104(2):139-144. 8. Shroyer NF, Lewis RA, Lupski JR. Analysis of the ABCR (ABCA4) gene in 4-aminoquinoline retinopathy: is retinal toxicity by chloroquine and hydroxychloroquine related to Stargardt disease? Am J Ophthalmol. 2001;131(6):761-766.
JAMA Ophthalmology December 2014 Volume 132, Number 12
Copyright 2014 American Medical Association. All rights reserved.
Downloaded From: http://archopht.jamanetwork.com/ by a New York University User on 05/14/2015
1461
