The effects of oligomeric proanthocyanidins on hydroxychloroquine-induced retinopathy as revealed by nationwide medical claim data for South Korea

Although hydroxychloroquine (HCQ) is considered to be safe drug with anti-inflammatory, immunomodulatory, and antithrombotic effects,[1,2] rare cases of permanent visual impairment.[2,3] The prevalence of HCQ retinopathy is about 7.5% for more than five years, increasing after 20 years.[4] Oligomeric proanthocyanidins (OPCs) are antioxidants and rich in a grape seed extract.[5-7] The extract is effective in some patients with nonproliferative diabetic retinopathy.[8,9] The extract may protect retinal cells by inhibiting the oxidative stress-mediated apoptosis mediated by activation of the nuclear factor erythroid 2-related factor 2 (Nrf2) pathway in patients with diabetic retinopathy.[9] No study has explored whether the extract may protect against HCQ retinopathy.[10]

We used nationwide medical claims data of the Korean Health Insurance Review and Assessment Service (HIRA) to find the effect of co-administration of OPC, as single product name Entelon®, on the incidence of HCQ retinopathy was investigated in patients with rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE) who were receiving HCQ from 2007 to 2019 (Figure 1). Statistical analysis was performed using the SAS software (version 9.4; SAS Institute Inc., Seoul, Korea) and R statistical software (version 4.0.3; R Foundation for Statistical Computing, Vienna, Austria).

Figure 1. The study flow chart. The diagnosis encoded by the International Classification of Disease 10^th Revision (ICD-10). Patients with RA and SLE (M05, M06, L93, and M32 ICD-10 codes) on HCQ from 2007 to 2019 were identified n=62,077). The exclusion criteria were retinopathy (H35.0, H35.1, H35.2, H36.0, E10.3, E11.3, E12.3, E13.3, and E14.3 ICD-10 codes) within 1 year prior to HCQ commencement and HCQ use before diagnosis of a rheumatic disease. The start date of HCQ administration was defined as the index date, and follow-up ceased if HCQ retinopathy developed, defined as a new retinopathy, in a patient who then discontinued HCQ after use thereof for more than 60 months. HCQ: Hydroxychloroquine; OPC: Oligomeric proanthocyanidins.

We included 31,140 patients on HCQ in a no-OPC group and 7,785 in an OPC group after propensity score matching (Table 1a). The mean duration of HCQ use was 17.6±32.5 months and the mean cumulative dose 32.3±124.0 g (Table 1b). It was divided into three quantiles according to the HCQ durations and cumulative doses: low, medium, and high. By the duration of HCQ use, the cumulative incidence of retinopathy was 0 in the low and medium groups, but 3.92 (95% confidence interval [CI]: 3.52-4.35) in the high group (p<0.001). The cumulative incidence of HCQ retinopathy increased with HCQ duration and cumulative dose, as in previous studies (Figure 2). The cumulative incidence rate of retinopathy was somewhat higher in the OPC than in the no-OPC group, but it did not reach statistical significance (0.64 vs. 0.56 per 1,000 PY, p=0.681) (Figure 3a). When the incidence of HCQ retinopathy by OPC use was analyzed separately in RA and SLE patients, OPC made no significant difference to the incidence of retinopathy (Figure 3b, c). In the SLE subgroup, the cumulative incidence of retinopathy was somewhat lower in the OPC group without statistical significance. Multivariate analysis showed that such retinopathy was not affected by the duration of OPC use or cumulative dose of OPC. Longer duration of HCQ use (hazard ratio [HR]: 1.035, 95% CI: 1.032-1.037, p<0.001) were risk factors for HCQ retinopathy (Table 2).

Figure 2. Cumulative incidence of retinopathy by HCQ dose and duration using Kaplan-Meier curves. The cumulative incidence of HCQ retinopathy (excluding DM retinopathy) increased with HCQ duration and cumulative dose, as in previous studies. (a) Incidence of retinopathy by the duration of HCQ use; (b) Incidence of retinopathy in patients without diabetic retinopathy by the duration of HCQ use; (c) Incidence of retinopathy by the cumulative dose of HCQ; (d) Incidence of retinopathy in patients without diabetic retinopathy by the cumulative dose of HCQ. HCQ: Hydroxychloroquine; OPC: Oligomeric proanthocyanidins. It was divided into three quantiles according to the HCQ durations and cumulative doses: low, medium, and high.

Figure 3. Cumulative incidence of HCQ retinopathy by OPC use status using Kaplan-Meier curve. (a) Incidence of HCQ retinopathy in both groups (RA and SLE); (b) Incidence of HCQ retinopathy in RA patients; (c) Incidence of HCQ retinopathy in SLE patients. In the SLE group, the cumulative incidence of retinopathy was somewhat lower in the OPC group without statistical significance. HCQ: Hydroxychloroquine; OPC: Oligomeric proanthocyanidins; RA: Rheumatoid arthritis; SLE: Systemic lupus erythematosus.

Table 1. Baseline characteristics from nationwide claims data of almost all South Koreans (a) A comparison of rheumatic disease patients who used HCQ long-term before and after propensity score-matching

Table 1. b. (b) Baseline characteristics of patients with rheumatic disease by the long-term use of HCQ

Table 3. Factors that associated with HCQ-related retinopathy as revealed by Cox’s proportional hazard analysis. The female sex, age at diagnosis of rheumatic disease, age at the first HCQ prescription, a higher comorbidity index score, DM, CKD, and longer duration of HCQ use were risk factors for HCQ retinopathy

In conclusion, the HIRA aids research on rare conditions, adverse events, and preventative effects of drugs in socially marginalized groups such as older and disabled adults who are seldon enrolled in RCTs. Although co-use of OPC did not significantly reduce this, it may be necessary to repeat the analysis, when SLE patients accumulate longer OPC exposure. Efforts to avoid permanent visual loss caused by HCQ retinopathy must be redoubled.

Citation: Kim S, Nam H, Lee B, Lee KA, Choi KS, Kim HS. The effects of oligomeric proanthocyanidins on hydroxychloroquine-induced retinopathy as revealed by nationwide medical claim data for South Korea. Arch Rheumatol 2023;38(3):482-489. doi: 10.46497/ArchRheumatol.2023.9829.

The study was approved by the institutional review board with a waiver of any need for informed consent (IRB no. 2019-11-011).

Idea/concept: K.S.C., H.S.K.; Design: K.S.C., H.S.K.; Control/supervision: H.S.K.; Data collection and/or processing: H.N., B.L.; Analysis and/or interpretation : S.K., K.A.L.; Literature review: S.K.; Writing the article, materials: S.K., H.S.K.; Critical review: K.A.L., H.S.K.; References: H.S.K.; Funding: Hanlim Pharmaceutical Company.

The authors declared no conflicts of interest with respect to the authorship and/or publication of this article.

The authors received no financial support for the research and/or authorship of this article.

This study was funded by Soonchunhyang university and Hanlim Pharmaceutical Company (Seoul, Korea).

The data that support the findings of this study are available from the corresponding author upon reasonable request.

References

1. Belizna C. Hydroxychloroquine as an anti-thrombotic in antiphospholipid syndrome. Autoimmun Rev 2015;14:358-62. DOI: 10.1016/j.autrev.2014.12.006
2. Nirk EL, Reggiori F, Mauthe M. Hydroxychloroquine in rheumatic autoimmune disorders and beyond. EMBO Mol Med 2020;12:e12476. DOI: 10.15252/emmm.202012476
3. Marmor MF, Kellner U, Lai TY, Melles RB, Mieler WF; American Academy of Ophthalmology. Recommendations on screening for chloroquine and hydroxychloroquine retinopathy (2016 revision). Ophthalmology 2016;123:1386-94. DOI: 10.1016/j.ophtha.2016.01.058
4. Melles RB, Marmor MF. The risk of toxic retinopathy in patients on long-term hydroxychloroquine therapy. JAMA Ophthalmol 2014;132:1453-60. DOI: 10.1001/jamaophthalmol.2014.3459
5. Rauf A, Imran M, Abu-Izneid T, Iahtisham-Ul-Haq, Patel S, Pan X, et al. Proanthocyanidins: A comprehensive review. Biomed Pharmacother 2019;116:108999. DOI: 10.1016/j.biopha.2019.108999
6. Zeng YX, Wang S, Wei L, Cui YY, Chen YH. Proanthocyanidins: Components, pharmacokinetics and biomedical properties. Am J Chin Med 2020;48:813-69. DOI: 10.1142/S0192415X2050041X
7. Bagchi D, Garg A, Krohn RL, Bagchi M, Tran MX, Stohs SJ. Oxygen free radical scavenging abilities of vitamins C and E, and a grape seed proanthocyanidin extract in vitro. Res Commun Mol Pathol Pharmacol 1997;95:179-89.
8. Moon SW, Shin YU, Cho H, Bae SH, Kim HK; and for the Mogen Study Group. Effect of grape seed proanthocyanidin extract on hard exudates in patients with non-proliferative diabetic retinopathy. Medicine (Baltimore) 2019;98:e15515. DOI: 10.1097/MD.0000000000015515
9. Sun Y, Xiu C, Liu W, Tao Y, Wang J, Qu YI. Grape seed proanthocyanidin extract protects the retina against early diabetic injury by activating the Nrf2 pathway. Exp Ther Med 2016;11:1253-8. DOI: 10.3892/etm.2016.3033
10. Yusuf IH, Sharma S, Luqmani R, Downes SM. Hydroxychloroquine retinopathy. Eye (Lond) 2017;31:828-45. DOI: 10.1038/eye.2016.298