Prevalence and Predictors of Hydroxychloroquine-Induced Retinopathy in Rheumatic Disorders

INTRODUCTION

Rheumatic diseases (RD) include a wide variety of illnesses including more than 200 types of diseases interrelated with autoimmune conditions with major clinical manifestations such as inflammation, pain, and swelling in the joints and muscles. Common rheumatic disorders are rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE).^[1-3]

The anti-malarial medication hydroxychloroquine (HCQ) has immune-modulating qualities widely used for lupus, RA, and scleroderma, and other connective tissue illnesses among the RD.^[2,3] HCQ background therapy has demonstrated a considerable benefit in the management of SLE, frequently with a better response than HCQ monotherapy. Since HCQ is not known to have significant disease-modifying impact in RA, other slow-acting antirheumatic drugs (SAARDs) like methotrexate are often given as combination therapy with HCQ. It is often well tolerated and has less frequent systemic adverse effects when compared to other standard SAARDs.^[2,4,5]

In patients with RD such as SLE, HCQ long-term therapy is frequently recommended. Due to its interaction with melanotropin, HCQ tends to build up in tissues that are rich in melanin, such as the ciliary body and retinal pigment epithelium. Melanin binding raises the drug’s concentration in the retina and lengthens or intensifies its harmful effects. In addition, stopping the medication does not stop retinopathy from progressing. Therefore, prolonged HCQ use may increase the chance of developing irreversible retinopathy, resulting in visual loss.^[5-7] Reading difficulties, diminished color vision, and central scotomas are among the central visual loss symptoms that most typically define retinal toxicity. Therefore, within a year of beginning treatment for long-term HCQ, the patient should have a baseline ophthalmologic examination (visual field [VF] test, optical coherence tomography [OCT], and multifocal electroretinogram). Up to 7.5% of patients experience retinal damage from prolonged HCQ use. There is no known cure for the retinal damage caused by HCQ use, and it is largely irreversible.^[1,8-11] Retinal toxicity is dependent on daily dose and length of therapy, according to the American Academy of Ophthalmology’s “recommendations for screening retinopathy in the patients with HCQ therapy (2016).” Based on actual body weight (ABW), the maximum daily dose of HCQ is 5 mg/kg. When using HCQ at the recommended levels, patients have a 1% risk of developing retinopathy after 5 years, a 2% risk after 10 years, and a 20% risk after 20 years. Patients who intend to take HCQ for prolonged periods of time > 5 years are advised to get a baseline ophthalmological examination, preferably within 6 months of beginning HCQ and definitely before 12 months. Patients receiving HCQ therapy should have annual screening after 5 years. The study objective was to evaluate the use of HCQ in RD patients and to identify the risk factors for HCQ retinopathy. There is no gold standard test to conclusively diagnose HCQ toxicity and, as screening assays vary substantially, it important to identify the risk factors for toxicity as a part of proper management. According to recommendations, spectral–domain [SD]-OCT, Humphrey VF, fundus autofluorescence, and multifocal electroretinography should all be performed on a yearly basis. In high-risk individuals or those where toxicity is suspected, more frequent testing can be helpful.^{[4,7,8,12,13]}

MATERIALS AND METHODS

RESULTS

A total of 150 patients were screened, and 108 were given consent to participate in the study. The demographic details and commodity details of the participants are shown in Table 1.

Dosage of HCQ

The mean total dosage in SLE was greater compared to RA and other diseases (Sjogren’s syndrome, scleroderma, and anti-phospholipid syndrome). The median duration of therapy and range for RA was greater. In RA, 20.8% of patients used HCQ beyond 5 years, in SLE, 36.3% patients used HCQ beyond 5 years and in other RDs (Sjogren’s syndrome, systemic sclerosis, and anti-phospholipid syndrome), 21.4% patients used HCQ beyond 5 years. None of our patients was prescribed HCQ >5 mg/kg (ABW), as shown in Table 2 and Figure 1.

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Figure 1:

Mean dose of Hydroxychloroquine in grams for RA, SLE, and other conditions.

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Ophthalmological findings

Among 108 patients, six patients had definitive retinopathy (SD-OCT, VFs) and one patient had possible retinopathy (SD-OCT). Six of the seven individuals had RA, while one had SLE. Subjects using HCQ >5 years are more at risk of retinopathy with a P = 0.002, as shown in Figures 2 and 3.

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Figure 2:

(a-d) Evolution of the spectral-domain optical coherence tomography subject with risk of retinopathy showed retinal thickness maps and cross-sectional images of both eyes (Ocular dexter [OD] and Ocular Sinister [OS]), indicating normal foveal contour with central macular thickness.

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Figure 3:

(a-d) Humphrey visual field analyzer grayscale, thresholds total deviation map, and pattern deviation map with mean deviation and pattern standard deviation results are shown. A 62-year-old male of retinopathy on hydroxychloroquine 300 mg/day for 72 months as a total cumulative dose of 657 g, showing central scotomas in visual field (24–2) and (10–2), altered foveal contour.

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DISCUSSION

Women outnumbered men, like a study conducted by Espandar et al. (2018) and Roy et al. (2020).^[7,9,12] The prevalence of retinopathy in our study was 13.5%, which is greater than the 6.5% reported by Roy et al (2020). Male gender has significantly as a risk factor for the retinopathy with the incidence of 25%. This predominance reflects disease epidemiology than increased risk, these findings are due to sampling variability or differential drug exposure.^[9]

The average age, average dose of HCQ, and the percentage of patients with RA, SLE, and other RDs in this study are like those in other studies and the average HCQ duration in our study is higher than that reported by Roy et al. (2020). These findings are consistent with already exiting studies and Ethnicity and this higher average HCQ usage might be a reason for higher incidence of retinopathy (13.5) in this study. This discrepancy may be relatively attributed to difference in population characteristics and limited sample size.^[9,12]

The average duration of the HCQ usage is beyond 5 years and development of retinopathy was significantly associated with P = 0.002 in our study when compared to other studies it is consistent and it states treatment duration is important predictor of toxicity. It also identified male gender as a risk factor for the development of retinopathy with an incidence of 25%, which contrasts with the findings of other studies. We didn’t find significant association between the age or comorbidities and the development of retinopathy, which differs from some earlier reports that have identified due to advanced age and renal dysfunction [Table 3].^[13]

CONCLUSION

In our study, 7 (6.5%) patients had HCQ-induced retinopathy and the charactersitics that were significantly related with retinopathy were gender, cumulative dose, dose/day, and duration of HCQ therapy, whereas factors such as age and comorbidities were not significantly related with HCQ retinopathy. Hence, the patients with HCQ therapy > 5 years and patients with more cumulative doses need frequent ophthalmological screening.