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Plaquenil Toxicity

Eye (Lond). 2017 Jun; 31(6): 828–845.

PMID: 28282061

Hydroxychloroquine (Plaquenil, HCQ) is used increasingly in the management of a variety of autoimmune disorders, with well established roles in dermatology and Rheumatology and emerging roles in oncology Hydroxychloroquine and chloroquine have been associated with irreversible visual loss due to retinal toxicity.Prevalence of 7.5% was identified in patients taking Palquenil for greater than 5 years, 20% after 20 years of treatment.risk factors such as tamoxifen use, dosing risk according to ideal body weight Asians visual field testing and retinal imaging should include a wider field for screening in this group Plaquenil was found to be less toxic and more effective than chloroquine against malaria (the disease it was developed to treat) Plaquenil is used to treat most commonly systemic lupus erythematosus and rheumatoid arthritis Plaquenil modulates immune responses through several mechanisms Plaquenil is available in 200 or 400 mg film-coated tablets The maximum dose of plaquenil of 6.5 mg/kg of IBW per day has traditionally been considered as safe for most adults (Ideal Body Weight)The maximum dose of plaquenil 5.0 mg/kg of ABW/day corresponded approximately to a dose of 6.5 mg/kg (Actual Body Weight) --more accepted now Children should still use IBW Plaquenil systemic side effects include people with known hepatic or renal dysfunction--caution should be used   also, Plaquenil has been reported to cause severe hypoglycaemia in patients with diabetes taking hypoglycaemic drugs Plaquenil has been demonstrated to reduce the risk of diabetes, thrombosis and dyslipidaemia in patients with SLE, and demonstrates a protective effect on renal function in lupus nephritis Retinal Toxicity Potential mechanism: it may be that phagocytosis of outer segments of photoreceptors, lysosomal function with the RPE and autophagy are impaired within  the RPE, affecting photoreceptor cell membrane stability and, ultimately, function inhibit the uptake activity of an organic anion transporting polypeptide 1A2 (which is in the RPE), which recycles all-trans retinol  Also, increase permeability of the RPE Drug accumulation within the RPE may explain the progression of HCQ retinopathy after drug cessation in some patients It is currently unclear why the photoreceptors in the parafovea/ perifovea are most vulnerable to the toxic effects of HCQ seen clinically degeneration in HCQ retinopathy is localized to the outer retina/photoreceptor layer (found in OCT scans), before any structural RPE  damage is apparent HCQ is known to affect the pH and function of lysosome Major Risk Factors >5.0 mg/kg ABW or CQ dose >2.3 mg/kg ABW, duration of use >5 years (assuming no other risk factors), renal impairment (defined as reduced  glomerularfiltration rate), tamoxifen use, and macular disease Risk after 5 years, but screening may begin before 5 years of therapy if additional risk factors are present (renal failure, tamoxifen use, etc) the risk of HCQ retinopathy is 2–3 times higher with doses of 5.0 compared with 4.0 mg/kg ABW/day The 2011 AAO guidelines stated that a cumulative dose of >1000 g increases the risk of retinopathy--NO LONGER USED Macular disease Risk: -No data to support patients with pre-existing macular disease are more susceptible to HCQ retinopathy, although subtle parafoveal structural and functional abnormalities secondary to HCQ may be difficult or impossible to detect with SD-OCT, AF or mfERG in the context of pre-existing macular disease-Isolated drusen with good photoreceptor function should not be considered a contraindication to HCQ treatment: a baseline SD-OCT, and AF imaging with a visual field test should be carried out in this context Renal disease-HCQ is renally excreted and consequently renal impairment is likely to increase the circulating concentration of the drug and risk of toxicity-a 50% decline in the GFR was associated with a doubling of the rate of HCQ-liver disease was not associated with increased risk of HCQ retinopathy Tamoxifen Risk-A retrospective case- control series of 2361 patients taking HCQ for at least 5 years found that there was a significant increased risk of retinopathy in patients taking tamoxifen-HCQ retinopathy in this patient group correlated with cumulative tamoxifen dose-A further study identified a profound decrease in the activity of lysosomal enzymes in cultured RPE cells with both  tamoxifen and HCQ these drugs may act synergistically therefore to further adversely affect the phagocytosis of the retinal outer segments as a common disease mechanism.-Crystalline retinopathy, macular oedema, pigmentary retinopathy, and reversible corneal changes have been associated with tamoxifenPharmacogenomics     -may well play an important role in increasing the safety of HCQ treatment by excluding those genetically predisposed to macular toxicity The overall prevalence of HCQ retinopathy was 7.5%, but this increased to around 20% after 20 years of use for those taking 4.0–5.0 mg/kg ABW/day and can exceed 50% at 20 years for those taking greater than 5.0 mg/kg ABW/day. Odds ratios were attributed to risk factors: daily dose (OR: 5.67), duration of use (OR: 3.22), kidney disease (OR: 2.06) and tamoxifen use (OR: 4.59).

Clinical features

-HCQ and chloroquine retinopathies, once symptomatic, are characterised by abnormalities of the retinal pigment epithelium, which are detectable clinically, and may later develop into the classic appearance of ‘bull’s eye maculopathy’ with central potentially extensive, concentric, parafoveal retinal pigment epithelial loss. This clinical state is associated with severe and irreversible visual loss that may be complicated by secondary cystoid macular oedema, epiretinal membrane and other sequalae-Patients of European descent exhibit a classic parafoveal pattern (2–6 degrees from the fovea) of structural and functional deficits, were more likely to manifest an extramacular or pericentral (more than 8 degrees from the fovea) pattern of disease in the early stages with structural and functional abnormalities identified near the vascular arcades. Pericentral HCQ retinopathy was seen in 50% of Asian patients in this series, but only 2% of Caucasian patients -Asian patients undergoing screening for HCQ retinopathy will require wider field structural (wide-field or off-axis SD-OCT and AF imaging) and functional investigation (24-2 or 30-2 visual field rather than 10-2) than Caucasian patients-HCQ is associated with the development of vortex keratopathy or corneal verticillata -- no retinopathy and reversible Screening and monitoring in HCQ/CQ patients-Visual field analysis (10-2, 24-2 or 30-2 as appropriate), and SD-OCT are widely available and the consensus is emerging that they should, in combination, be performed on every patient presenting for HCQ screening-Baseline screening is suggested by the AAO guidelines of 2011 and 2016 within one year of starting HCQ/CQ-non Asian (10-2 and OCT), Asian 24-2 and OCT) and followed yearly-It is important that patients are aware that monitoring for HCQ retinopathy cannot prevent the occurrence of retinopathy but timely cessation of therapy at the earliest sign of any potential damage is expected to help limit either development or progression of loss of visual function. VF testing-subtle scotomata on 10-2 visual fields may be evident before structural changes are evident on SD-OCT-Amsler grid testing, colour vision testing, fluorescein angiography, full-field ERG, time domain OCT and fundus photography have been removed from recommended protocols for screening as they are not considered sufficiently sensitive or specific to detect early-Contiguous scotoma points, and those identified in an annular zone between 2 and 8 degrees from fixation were found to be more likely to represent HCQ retinopathy in one study, with white targets     -superonasal scotomata are the most common abnormality as the inferotemporal paramacular region is often affected firstOCT testing-Typical findings of HCQ retinopathy on SD-OCT are parafoveal abnormalities of the outer segment, particularly thinning or loss of the photoreceptor layer, outer nuclear layer and/or ellipsoid zone (inner segment/ outer segment junction), and retinal pigment epithelium-Asian eyes may manifest an extra-macular pattern of disease with SD-OCT abnormalities identified towards or beyond the vascular arcades: wide-field SD-OCT may be necessary for screening in this patient groupFAF testing-Fundus autofluorescence (AF) using blue light of 488 nm wavelength, exploits the fluorescent property of lipofuscin within the retinal pigment epithelium (RPE).-parafoveal increased autofluorescence signal is detected in the early stages of disease, with mottled decrease in parafoveal autofluorescence as RPE degeneration becomes established in later stages of diseaseMultifocal ERG testing-It has in some series been considered the gold standard test for the detection of suspected HCQ testing-A recent systematic review suggested that mfERG may have the ability to detect HCQ retinopathy earlier than other tests used in HCQ screening

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