- Email: [email protected]
Screening for hydroxychloroquine retinal toxicity: Current recommendations
APME-404; No. of Pages 4 apollo medicine xxx (2017) xxx–xxx
Available online at www.sciencedirect.com
ScienceDirect journal homepage: www.elsevier.com/locate/apme
Short survey
Screening for hydroxychloroquine retinal toxicity: Current recommendations Nikunjkumar Dadhaniya a,*, Isha Sood a, Abhishek Patil a, Himanshu Aggarwal a, Sundeep Kumar Upadhyaya b, Rohini Handa b, Sirinder Jit Gupta b a b
DNB Trainee, Department of Rheumatology, Indraprastha Apollo Hospitals, Delhi, India Senior Consultant, Department of Rheumatology, Indraprastha Apollo Hospitals, Delhi, India
article info
abstract
Article history:
Hydroxychloroquine (HCQ) is a commonly used drug for the treatment of various autoim-
Received 5 January 2017
mune diseases including systemic lupus erythematosus and rheumatoid arthritis. Though
Accepted 12 January 2017
HCQ may be associated infrequently with systemic side effects, its long-term use is
Available online xxx
associated with retinal toxicity in some patients. Most patients with HCQ associated retinal toxicity are asymptomatic initially. Retinal toxicity if allowed to persist is usually associated
Keywords:
with irreversible damage. Therefore, screening is needed to detect retinal toxicity at an early
Hydroxychloroquine
stage to prevent visual loss. Various methods have been utilized for the screening of HCQ
Retinal toxicity
associated retinal toxicity, but until recently, no test(s) had been established as the gold
Screening recommendation
standard. Current recommendation is to screen for HCQ associated retinal toxicity with both
Optical coherence tomography
automated visual field and spectral domain optical coherence tomography after 5 years of
Visual field
use, provided baseline ocular examination is normal and there are no associated high risk factors. © 2017 Indraprastha Medical Corporation Ltd. All rights reserved.
1.
Introduction
Hydroxychloroquine (HCQ) is an effective drug used commonly in the treatment of rheumatoid arthritis (RA) and other connective tissue diseases (CTDs). HCQ lacks systemic toxicity usually seen with other conventional disease modifying antirheumatic drugs (DMARDs) like – bone marrow suppression, secondary infection and malignancy. However retinal toxicity is a major concern with long-term use of HCQ. Conventional methods of screening over the years, have
included – clinical ocular examination with testing of visual acuity, fundus examination with a dilated pupil, color vision, Amsler's Grid and visual field testing (perimetry). Once abnormalities are detected using these conventional methods of screening, retinal toxicity has already occurred and this toxicity may not be completely reversible.1 Continuing visual loss even after discontinuation of the drug is reported.1 It is therefore critical to detect retinal toxicity as early as possible to limit the extent of retinal toxicity. Newer methods of screening for HCQ related retinal toxicity include optical coherence tomography (OCT), fundus auto fluorescence (FAF) and
* Corresponding author. Tel.: +91 9712999726. E-mail address: [email protected] (N. Dadhaniya). http://dx.doi.org/10.1016/j.apme.2017.01.012 0976-0016/© 2017 Indraprastha Medical Corporation Ltd. All rights reserved.
Please cite this article in press as: Dadhaniya N, et al. Screening for hydroxychloroquine retinal toxicity: Current recommendations, Apollo Med. (2017), http://dx.doi.org/10.1016/j.apme.2017.01.012
APME-404; No. of Pages 4
2
apollo medicine xxx (2017) xxx–xxx
multifocal electroretinography (mfERG). These newer modalities are more sensitive for detection of HCQ associated retinal toxicity. Regular and effective screening can recognize toxicity at earlier stages before there is significant and irreversible visual loss.2
2.
Mechanism of HCQ retinal toxicity
The mechanism of HCQ associated retinal toxicity has been extensively studied but not well understood. HCQ toxicity appears to first affect retinal ganglion cells and photoreceptors, particularly in the perifoveal region.3 Accumulation of lipid complexes in ganglion cells, bipolar cells and glial cells in the retina is proposed as the triggering event in HCQ associated retinal toxicity.4 The primary damage involves photoreceptors, and as the outer nuclear layer degenerates, there is secondarily disruption of the retinal pigment epithelium (RPE).5 Anatomic features of retina that correlate specifically with the parafoveal or extra macular patterns of damage are not identified.1
3.
Clinical features of HCQ retinal toxicity
Most patients with HCQ associated retinal toxicity have no visual symptoms.1 A few patients may notice scotoma while reading. In advanced cases symptoms of HCQ associated retinal toxicity includes decreased vision, visual glare, night blindness, impaired color vision and visual field defects.6
4. Methods of screening for HCQ retinal toxicity Screening tests can be classified into those looking at morphological changes [fundus examination, FAF and spectral domain optical coherence tomography (SD-OCT)] and those looking at functional changes [mfERG and Humphrey visual field]. Although all tests have a value in identifying the retinal toxicity none is considered as 100% sensitive and specific and they usually complement each other.7 Fundus examination is usually normal in early toxicity but it is vital for baseline screening. Earliest changes on fundus examination are fine pigmentary stippling of macula, some irregular pigmentation and loss of foveal light reflex.8 Progressive changes of toxicity show irregular central pigmentation surrounded by a zone of depigmentation – the classical 'Bull's Eye' maculopathy. Automated visual field (perimetry) is very useful for screening HCQ toxicity. Visual field testing may show abnormalities before abnormal findings in other parameters including visual acuity or abnormalities on fundus examination.9 Visual field testing will reveal partial or complete ring defect in 28–68 with central foveal sparing on 10-2 white tests (Fig. 1) whereas on 24-2 or 30-2 testing it will reveal central scotoma affecting one or more of the 4 points around fixation (more evident on pattern deviation plots). Unfortunately patients frequently have nonspecific abnormalities on field examination, these findings should be interpreted with caution taking in account other test results and reproducibility of defects.10
Fig. 1 – (A) Normal 10-2 visual field. (B) 10-2 visual field showing paracentral ring scotoma. Please cite this article in press as: Dadhaniya N, et al. Screening for hydroxychloroquine retinal toxicity: Current recommendations, Apollo Med. (2017), http://dx.doi.org/10.1016/j.apme.2017.01.012
APME-404; No. of Pages 4 apollo medicine xxx (2017) xxx–xxx
SD-OCT is an objective, non-invasive imaging technique for the evaluation of retinal structure. Early changes of toxicity are usually subtle and involve focal loss of outer retinal substance on both sides of the fovea giving appearance of a flying saucer or sombrero.11 Retinal thickness map will also show thinning of parafoveal region in non-Asian eyes and near arcade in Asian eyes.1 Damage to the inner segment–outer segment line is a critical early sign of photoreceptor damage in HCQ retinal toxicity (Fig. 2).5 Patients with severe toxicity have diffuse thinning of retina. Electroretinography is a recording of electrical activity of the eye (retina) in response to light. As full field electroretinography is usually normal until almost 20% of retina becomes dysfunctional, mfERG, which evaluates functional defect in localized central retina, is used for HCQ associated retinal toxicity screening. mfERG can objectively document parafoveal or extra macular electroretinogram depression in early retinopathy.1 However mfERG is limited by patient cooperation, requirement of specialized training for administration and interpretation, clinical availability and cost. Fundus auto fluorescence (FAF) is a retinal imaging technique which is based on the principle of auto fluorescence of RPE. Early findings of HCQ associated retinal toxicity on FAF are pericentral ring of increased auto fluorescence.12 Late
3
toxicity with RPE loss appears as a dark area of reduced autofluorescence.1 FAF is reported to be less sensitive than SDOCT and mfERG in the early diagnosis of Chloroquine (CQ)/ HCQ retinal toxicity.5
5.
Statistical risk of toxicity
Earlier literature showed around 1–2% prevalence of toxicity. However recent reports suggest around 7.5% prevalence of HCQ associated retinal toxicity depending upon the dose and duration of use.13 Incidence of retinal toxicity in patients on HCQ doses less than 5 mg/kg (of actual body weight) is reported to be below 1% up to 5 years of use and below 2% after up to 10 years of use.13
6.
Screening recommendation
Guidelines and recommendations for screening for retinal toxicity have evolved over the years. In 2002 the American Academy of Ophthalmology (AAO) first proposed screening recommendations for HCQ associated retinal toxicity, with the salient points being14: 1. Baseline examination should be obtained within 1 year of starting HCQ and should include complete ophthalmologic examination including best-corrected visual acuity and examination of the cornea and retina and visual field testing with Amsler's grid or Humphrey 10-2 fields. 2. Further testing is not required for 5 years, provided – (i) the dose of HCQ is kept below 6.5 mg/kg (ideal body weight) of HCQ and 3 mg/kg of CQ and (ii) there is no renal or hepatic failure. 3. Those having high risk factors i.e. dose >6.5 mg/kg for HCQ and >3 mg/kg for CQ, renal or hepatic failure, or age >60 years, should have an annual examination. 4. Optional tests include color vision testing, fundus photograph recording and specialized tests such as fluorescein angiography or mfERG. Based on availability of newer tests like SD-OCT, FAF and data regarding reliability of mfERG the AAO published revised recommendation in 2011 as follows15:
Fig. 2 – (A) Normal SD-OCT scan inset figures showing retinal thickness. (B) Focal disruption of inner segment outer segment junction line in lower image.
1. Baseline examination should be obtained within 1 year of starting HCQ and should include careful bio microscopy, automated threshold testing with a white 10-2 protocol, and wherever available, testing with one or more of the recommended objective tests (SD-OCT, mfERG, or FAF). 2. Annual screening should be performed after 5 years of use in all patients and from initiation of therapy in patients with high risk factors such as – pre-existing maculopathy, renal or liver disease, elderly age and dose of HCQ >6.5 mg/kg ideal body weight. 3. Recommendation mentioned ideal weight for calculating safe dose. 4. Fundus photography, fluorescein angiography, time domain OCT, Amsler's grid and color vision are not recommended as screening test.
Please cite this article in press as: Dadhaniya N, et al. Screening for hydroxychloroquine retinal toxicity: Current recommendations, Apollo Med. (2017), http://dx.doi.org/10.1016/j.apme.2017.01.012
APME-404; No. of Pages 4
4
apollo medicine xxx (2017) xxx–xxx
From 2011 to 2016, few large studies were conducted on HCQ associated retinal toxicity. Melles et al. evaluated data on 2361 patients and found that HCQ retinal toxicity is more common than previously thought of.13 They also proposed real weight for calculation of dose and use of both visual field and OCT for HCQ associated retinal toxicity screening. It was also noted for Asian patients that noted that HCQ toxicity is manifested in more peripheral location and did not always occur in parafoveal location.16 Findings from these studies lead to second (2016) revision of the AAO recommendation on screening for CQ and HCQ associated retinal toxicity.1 Main highlights of this recommendation are: 1. Baseline ophthalmological examination should be obtained in all patients within 1 year of starting HCQ. Visual field and SD-OCT are not critical for baseline evaluation unless abnormalities like focal macular lesion or glaucoma are present. 2. Annual screening should be started after 5 years and should include both automated visual fields and SD OCT. 3. Patients using >5.0 mg/kg (actual body weight) of HCQ or >2.3 mg/kg of CQ or having renal disease or having concomitant tamoxifen use should have more frequent screening after starting HCQ. 4. Visual field testing with 10-2 is recommended for non-Asian patients while wider angle field 24-2 or 30-2 is recommended for Asian patients. 5. Similarly for Asian patients, SD-OCT should be obtained by using wider angle scans or scan directed across vascular arcade. 6. Recommended additional objective tests include mfERG and FAF while fundus examination, time-domain OCT, fluorescein angiography, full-field ERG, Amsler's grid, color testing and electro-oculogram are no longer recommended as screening tests. 7. Recommends using real weight for dose calculation as compared to ideal body weight. 8. Daily dose is suggested as most important factor in toxicity. 9. Recommends a daily dose of HCQ <5 mg/kg and that of CQ <2.3 mg/kg.
7.
Conclusion
HCQ is an effective drug in the treatment of RA, systemic lupus erythematosus and other connective tissue diseases, with few systemic side effects. Though the risk of HCQ retinal toxicity is higher than previously thought, this risk can be reduced by paying attention to risk factors, using appropriate doses of the drug and adequate screening for retinal toxicity. The goal of screening should be recognition of definitive signs of toxicity at an early stage to prevent visual loss and not to stop valuable drugs at the first signs of borderline abnormality.
references
1. Marmor MF, Kellner U, Lai TYY, Melles RB, Mieler WF. Recommendations on screening for chloroquine and hydroxychloroquine retinopathy (2016 revision). Ophthalmology. 2016;123:1386–1394. 2. Costedoat-Chalumeau N, Dunogué B, Leroux G, et al. A critical review of the effects of hydroxychloroquine and chloroquine on the eye. Clin Rev Allergy Immunol. 2015;49 (December (3)):317–326. 3. Rodriguez-Padilla JA, Hedges TR, Monson B, et al. Highspeed ultra-high-resolution optical coherence tomography findings in hydroxychloroquine retinopathy. Arch Ophthalmol. 2007;125(June (6)):775–780. 4. Pasadhika S, Fishman GA, Choi D, Shahidi M. Selective thinning of the perifoveal inner retina as an early sign of hydroxychloroquine retinal toxicity. Eye (Lond). 2010;24(May (5)):756–762. 5. Marmor MF. Comparison of screening procedures in hydroxychloroquine toxicity. Arch Ophthalmol. 2012;130:461– 469. 6. Yam JC, Kwok AK. Ocular toxicity of hydroxychloroquine. Hong Kong Med J. 2006;12(August (4)):294–304. 7. Farrell DF. Retinal toxicity to antimalarial drugs: chloroquine and hydroxychloroquine: a neurophysiologic study. Clin Ophthalmol. 2012;6:37783. 8. Geamănu (Pancă) A, Popa-Cherecheanu A, Marinescu B, Geamănu CD, Voinea LM. Retinal toxicity associated with chronic exposure to hydroxychloroquine and its ocular screening. Review. J Med Life. 2014;7(3):322–326. 9. Elder M, Rahman AM, McLay J. Early paracentral visual field loss in patients taking hydroxychloroquine. Arch Ophthalmol. 2006;124(December (12)):1729–1733. 10. Pandya HK, Robinson M, Mandal N, Shah VA. Hydroxychloroquine retinopathy: a review of imaging. Indian J Ophthalmol. 2015;63:570–574. 11. Chen E, Brown DM, Benz MS, et al. Spectral domain optical coherence tomography as an effective screening test for hydroxychloroquine retinopathy (the ‘‘flying saucer’’ sign). Clin Ophthalmol. 2010;4:1151–1158. 12. Kellner U, Renner AB, Tillack H, et al. Fundus auto fluorescence and mfERG for early detection of retinal alterations in patients using chloroquine/ hydroxychloroquine. Invest Ophthalmol Vis Sci. 2006;47 (8):3531–3538. 13. Melles RB, Marmor MF. The risk of toxic retinopathy in patients on long-term hydroxychloroquine therapy. JAMA Ophthalmol. 2014;132:1453–1460. 14. Marmor MF, Carr RE, Easterbrook M, Farjo AA, Mieler WF, American Academy of Ophthalmology. Recommendations on screening for chloroquine and hydroxychloroquine retinopathy: a report by the American Academy of Ophthalmology. Ophthalmology. 2002;109(July (7)):1377–1382. 15. Marmor MF, Kellner U, Lai TY, Lyons JS, Mieler WF, American Academy of Ophthalmology. Revised recommendations on screening for chloroquine and hydroxychloroquine retinopathy. Ophthalmology. 2011;118 (February (2)):415–422. 16. Melles RB, Marmor MF. Pericentral retinopathy and racial differences in hydroxychloroquine toxicity. Ophthalmology. 2015;122:110–116.
Please cite this article in press as: Dadhaniya N, et al. Screening for hydroxychloroquine retinal toxicity: Current recommendations, Apollo Med. (2017), http://dx.doi.org/10.1016/j.apme.2017.01.012
Available online at www.sciencedirect.com
ScienceDirect journal homepage: www.elsevier.com/locate/apme
Short survey
Screening for hydroxychloroquine retinal toxicity: Current recommendations Nikunjkumar Dadhaniya a,*, Isha Sood a, Abhishek Patil a, Himanshu Aggarwal a, Sundeep Kumar Upadhyaya b, Rohini Handa b, Sirinder Jit Gupta b a b
DNB Trainee, Department of Rheumatology, Indraprastha Apollo Hospitals, Delhi, India Senior Consultant, Department of Rheumatology, Indraprastha Apollo Hospitals, Delhi, India
article info
abstract
Article history:
Hydroxychloroquine (HCQ) is a commonly used drug for the treatment of various autoim-
Received 5 January 2017
mune diseases including systemic lupus erythematosus and rheumatoid arthritis. Though
Accepted 12 January 2017
HCQ may be associated infrequently with systemic side effects, its long-term use is
Available online xxx
associated with retinal toxicity in some patients. Most patients with HCQ associated retinal toxicity are asymptomatic initially. Retinal toxicity if allowed to persist is usually associated
Keywords:
with irreversible damage. Therefore, screening is needed to detect retinal toxicity at an early
Hydroxychloroquine
stage to prevent visual loss. Various methods have been utilized for the screening of HCQ
Retinal toxicity
associated retinal toxicity, but until recently, no test(s) had been established as the gold
Screening recommendation
standard. Current recommendation is to screen for HCQ associated retinal toxicity with both
Optical coherence tomography
automated visual field and spectral domain optical coherence tomography after 5 years of
Visual field
use, provided baseline ocular examination is normal and there are no associated high risk factors. © 2017 Indraprastha Medical Corporation Ltd. All rights reserved.
1.
Introduction
Hydroxychloroquine (HCQ) is an effective drug used commonly in the treatment of rheumatoid arthritis (RA) and other connective tissue diseases (CTDs). HCQ lacks systemic toxicity usually seen with other conventional disease modifying antirheumatic drugs (DMARDs) like – bone marrow suppression, secondary infection and malignancy. However retinal toxicity is a major concern with long-term use of HCQ. Conventional methods of screening over the years, have
included – clinical ocular examination with testing of visual acuity, fundus examination with a dilated pupil, color vision, Amsler's Grid and visual field testing (perimetry). Once abnormalities are detected using these conventional methods of screening, retinal toxicity has already occurred and this toxicity may not be completely reversible.1 Continuing visual loss even after discontinuation of the drug is reported.1 It is therefore critical to detect retinal toxicity as early as possible to limit the extent of retinal toxicity. Newer methods of screening for HCQ related retinal toxicity include optical coherence tomography (OCT), fundus auto fluorescence (FAF) and
* Corresponding author. Tel.: +91 9712999726. E-mail address: [email protected] (N. Dadhaniya). http://dx.doi.org/10.1016/j.apme.2017.01.012 0976-0016/© 2017 Indraprastha Medical Corporation Ltd. All rights reserved.
Please cite this article in press as: Dadhaniya N, et al. Screening for hydroxychloroquine retinal toxicity: Current recommendations, Apollo Med. (2017), http://dx.doi.org/10.1016/j.apme.2017.01.012
APME-404; No. of Pages 4
2
apollo medicine xxx (2017) xxx–xxx
multifocal electroretinography (mfERG). These newer modalities are more sensitive for detection of HCQ associated retinal toxicity. Regular and effective screening can recognize toxicity at earlier stages before there is significant and irreversible visual loss.2
2.
Mechanism of HCQ retinal toxicity
The mechanism of HCQ associated retinal toxicity has been extensively studied but not well understood. HCQ toxicity appears to first affect retinal ganglion cells and photoreceptors, particularly in the perifoveal region.3 Accumulation of lipid complexes in ganglion cells, bipolar cells and glial cells in the retina is proposed as the triggering event in HCQ associated retinal toxicity.4 The primary damage involves photoreceptors, and as the outer nuclear layer degenerates, there is secondarily disruption of the retinal pigment epithelium (RPE).5 Anatomic features of retina that correlate specifically with the parafoveal or extra macular patterns of damage are not identified.1
3.
Clinical features of HCQ retinal toxicity
Most patients with HCQ associated retinal toxicity have no visual symptoms.1 A few patients may notice scotoma while reading. In advanced cases symptoms of HCQ associated retinal toxicity includes decreased vision, visual glare, night blindness, impaired color vision and visual field defects.6
4. Methods of screening for HCQ retinal toxicity Screening tests can be classified into those looking at morphological changes [fundus examination, FAF and spectral domain optical coherence tomography (SD-OCT)] and those looking at functional changes [mfERG and Humphrey visual field]. Although all tests have a value in identifying the retinal toxicity none is considered as 100% sensitive and specific and they usually complement each other.7 Fundus examination is usually normal in early toxicity but it is vital for baseline screening. Earliest changes on fundus examination are fine pigmentary stippling of macula, some irregular pigmentation and loss of foveal light reflex.8 Progressive changes of toxicity show irregular central pigmentation surrounded by a zone of depigmentation – the classical 'Bull's Eye' maculopathy. Automated visual field (perimetry) is very useful for screening HCQ toxicity. Visual field testing may show abnormalities before abnormal findings in other parameters including visual acuity or abnormalities on fundus examination.9 Visual field testing will reveal partial or complete ring defect in 28–68 with central foveal sparing on 10-2 white tests (Fig. 1) whereas on 24-2 or 30-2 testing it will reveal central scotoma affecting one or more of the 4 points around fixation (more evident on pattern deviation plots). Unfortunately patients frequently have nonspecific abnormalities on field examination, these findings should be interpreted with caution taking in account other test results and reproducibility of defects.10
Fig. 1 – (A) Normal 10-2 visual field. (B) 10-2 visual field showing paracentral ring scotoma. Please cite this article in press as: Dadhaniya N, et al. Screening for hydroxychloroquine retinal toxicity: Current recommendations, Apollo Med. (2017), http://dx.doi.org/10.1016/j.apme.2017.01.012
APME-404; No. of Pages 4 apollo medicine xxx (2017) xxx–xxx
SD-OCT is an objective, non-invasive imaging technique for the evaluation of retinal structure. Early changes of toxicity are usually subtle and involve focal loss of outer retinal substance on both sides of the fovea giving appearance of a flying saucer or sombrero.11 Retinal thickness map will also show thinning of parafoveal region in non-Asian eyes and near arcade in Asian eyes.1 Damage to the inner segment–outer segment line is a critical early sign of photoreceptor damage in HCQ retinal toxicity (Fig. 2).5 Patients with severe toxicity have diffuse thinning of retina. Electroretinography is a recording of electrical activity of the eye (retina) in response to light. As full field electroretinography is usually normal until almost 20% of retina becomes dysfunctional, mfERG, which evaluates functional defect in localized central retina, is used for HCQ associated retinal toxicity screening. mfERG can objectively document parafoveal or extra macular electroretinogram depression in early retinopathy.1 However mfERG is limited by patient cooperation, requirement of specialized training for administration and interpretation, clinical availability and cost. Fundus auto fluorescence (FAF) is a retinal imaging technique which is based on the principle of auto fluorescence of RPE. Early findings of HCQ associated retinal toxicity on FAF are pericentral ring of increased auto fluorescence.12 Late
3
toxicity with RPE loss appears as a dark area of reduced autofluorescence.1 FAF is reported to be less sensitive than SDOCT and mfERG in the early diagnosis of Chloroquine (CQ)/ HCQ retinal toxicity.5
5.
Statistical risk of toxicity
Earlier literature showed around 1–2% prevalence of toxicity. However recent reports suggest around 7.5% prevalence of HCQ associated retinal toxicity depending upon the dose and duration of use.13 Incidence of retinal toxicity in patients on HCQ doses less than 5 mg/kg (of actual body weight) is reported to be below 1% up to 5 years of use and below 2% after up to 10 years of use.13
6.
Screening recommendation
Guidelines and recommendations for screening for retinal toxicity have evolved over the years. In 2002 the American Academy of Ophthalmology (AAO) first proposed screening recommendations for HCQ associated retinal toxicity, with the salient points being14: 1. Baseline examination should be obtained within 1 year of starting HCQ and should include complete ophthalmologic examination including best-corrected visual acuity and examination of the cornea and retina and visual field testing with Amsler's grid or Humphrey 10-2 fields. 2. Further testing is not required for 5 years, provided – (i) the dose of HCQ is kept below 6.5 mg/kg (ideal body weight) of HCQ and 3 mg/kg of CQ and (ii) there is no renal or hepatic failure. 3. Those having high risk factors i.e. dose >6.5 mg/kg for HCQ and >3 mg/kg for CQ, renal or hepatic failure, or age >60 years, should have an annual examination. 4. Optional tests include color vision testing, fundus photograph recording and specialized tests such as fluorescein angiography or mfERG. Based on availability of newer tests like SD-OCT, FAF and data regarding reliability of mfERG the AAO published revised recommendation in 2011 as follows15:
Fig. 2 – (A) Normal SD-OCT scan inset figures showing retinal thickness. (B) Focal disruption of inner segment outer segment junction line in lower image.
1. Baseline examination should be obtained within 1 year of starting HCQ and should include careful bio microscopy, automated threshold testing with a white 10-2 protocol, and wherever available, testing with one or more of the recommended objective tests (SD-OCT, mfERG, or FAF). 2. Annual screening should be performed after 5 years of use in all patients and from initiation of therapy in patients with high risk factors such as – pre-existing maculopathy, renal or liver disease, elderly age and dose of HCQ >6.5 mg/kg ideal body weight. 3. Recommendation mentioned ideal weight for calculating safe dose. 4. Fundus photography, fluorescein angiography, time domain OCT, Amsler's grid and color vision are not recommended as screening test.
Please cite this article in press as: Dadhaniya N, et al. Screening for hydroxychloroquine retinal toxicity: Current recommendations, Apollo Med. (2017), http://dx.doi.org/10.1016/j.apme.2017.01.012
APME-404; No. of Pages 4
4
apollo medicine xxx (2017) xxx–xxx
From 2011 to 2016, few large studies were conducted on HCQ associated retinal toxicity. Melles et al. evaluated data on 2361 patients and found that HCQ retinal toxicity is more common than previously thought of.13 They also proposed real weight for calculation of dose and use of both visual field and OCT for HCQ associated retinal toxicity screening. It was also noted for Asian patients that noted that HCQ toxicity is manifested in more peripheral location and did not always occur in parafoveal location.16 Findings from these studies lead to second (2016) revision of the AAO recommendation on screening for CQ and HCQ associated retinal toxicity.1 Main highlights of this recommendation are: 1. Baseline ophthalmological examination should be obtained in all patients within 1 year of starting HCQ. Visual field and SD-OCT are not critical for baseline evaluation unless abnormalities like focal macular lesion or glaucoma are present. 2. Annual screening should be started after 5 years and should include both automated visual fields and SD OCT. 3. Patients using >5.0 mg/kg (actual body weight) of HCQ or >2.3 mg/kg of CQ or having renal disease or having concomitant tamoxifen use should have more frequent screening after starting HCQ. 4. Visual field testing with 10-2 is recommended for non-Asian patients while wider angle field 24-2 or 30-2 is recommended for Asian patients. 5. Similarly for Asian patients, SD-OCT should be obtained by using wider angle scans or scan directed across vascular arcade. 6. Recommended additional objective tests include mfERG and FAF while fundus examination, time-domain OCT, fluorescein angiography, full-field ERG, Amsler's grid, color testing and electro-oculogram are no longer recommended as screening tests. 7. Recommends using real weight for dose calculation as compared to ideal body weight. 8. Daily dose is suggested as most important factor in toxicity. 9. Recommends a daily dose of HCQ <5 mg/kg and that of CQ <2.3 mg/kg.
7.
Conclusion
HCQ is an effective drug in the treatment of RA, systemic lupus erythematosus and other connective tissue diseases, with few systemic side effects. Though the risk of HCQ retinal toxicity is higher than previously thought, this risk can be reduced by paying attention to risk factors, using appropriate doses of the drug and adequate screening for retinal toxicity. The goal of screening should be recognition of definitive signs of toxicity at an early stage to prevent visual loss and not to stop valuable drugs at the first signs of borderline abnormality.
references
1. Marmor MF, Kellner U, Lai TYY, Melles RB, Mieler WF. Recommendations on screening for chloroquine and hydroxychloroquine retinopathy (2016 revision). Ophthalmology. 2016;123:1386–1394. 2. Costedoat-Chalumeau N, Dunogué B, Leroux G, et al. A critical review of the effects of hydroxychloroquine and chloroquine on the eye. Clin Rev Allergy Immunol. 2015;49 (December (3)):317–326. 3. Rodriguez-Padilla JA, Hedges TR, Monson B, et al. Highspeed ultra-high-resolution optical coherence tomography findings in hydroxychloroquine retinopathy. Arch Ophthalmol. 2007;125(June (6)):775–780. 4. Pasadhika S, Fishman GA, Choi D, Shahidi M. Selective thinning of the perifoveal inner retina as an early sign of hydroxychloroquine retinal toxicity. Eye (Lond). 2010;24(May (5)):756–762. 5. Marmor MF. Comparison of screening procedures in hydroxychloroquine toxicity. Arch Ophthalmol. 2012;130:461– 469. 6. Yam JC, Kwok AK. Ocular toxicity of hydroxychloroquine. Hong Kong Med J. 2006;12(August (4)):294–304. 7. Farrell DF. Retinal toxicity to antimalarial drugs: chloroquine and hydroxychloroquine: a neurophysiologic study. Clin Ophthalmol. 2012;6:37783. 8. Geamănu (Pancă) A, Popa-Cherecheanu A, Marinescu B, Geamănu CD, Voinea LM. Retinal toxicity associated with chronic exposure to hydroxychloroquine and its ocular screening. Review. J Med Life. 2014;7(3):322–326. 9. Elder M, Rahman AM, McLay J. Early paracentral visual field loss in patients taking hydroxychloroquine. Arch Ophthalmol. 2006;124(December (12)):1729–1733. 10. Pandya HK, Robinson M, Mandal N, Shah VA. Hydroxychloroquine retinopathy: a review of imaging. Indian J Ophthalmol. 2015;63:570–574. 11. Chen E, Brown DM, Benz MS, et al. Spectral domain optical coherence tomography as an effective screening test for hydroxychloroquine retinopathy (the ‘‘flying saucer’’ sign). Clin Ophthalmol. 2010;4:1151–1158. 12. Kellner U, Renner AB, Tillack H, et al. Fundus auto fluorescence and mfERG for early detection of retinal alterations in patients using chloroquine/ hydroxychloroquine. Invest Ophthalmol Vis Sci. 2006;47 (8):3531–3538. 13. Melles RB, Marmor MF. The risk of toxic retinopathy in patients on long-term hydroxychloroquine therapy. JAMA Ophthalmol. 2014;132:1453–1460. 14. Marmor MF, Carr RE, Easterbrook M, Farjo AA, Mieler WF, American Academy of Ophthalmology. Recommendations on screening for chloroquine and hydroxychloroquine retinopathy: a report by the American Academy of Ophthalmology. Ophthalmology. 2002;109(July (7)):1377–1382. 15. Marmor MF, Kellner U, Lai TY, Lyons JS, Mieler WF, American Academy of Ophthalmology. Revised recommendations on screening for chloroquine and hydroxychloroquine retinopathy. Ophthalmology. 2011;118 (February (2)):415–422. 16. Melles RB, Marmor MF. Pericentral retinopathy and racial differences in hydroxychloroquine toxicity. Ophthalmology. 2015;122:110–116.
Please cite this article in press as: Dadhaniya N, et al. Screening for hydroxychloroquine retinal toxicity: Current recommendations, Apollo Med. (2017), http://dx.doi.org/10.1016/j.apme.2017.01.012