Woman presents for second opinion regarding medication use

A 32-year-old woman was referred by the rheumatology service for a second opinion regarding high-risk medication use evaluation.

The patient’s medical history was notable for systemic lupus erythematosus, complicated by lupus nephritis, as well as miscarriage at 11 weeks’ gestation. She never had ocular surgery but had a history of kidney biopsy and neck lymph node biopsy. She was allergic to penicillin and nifedipine. She had no history of smoking, alcohol use or drug use. Family history was noncontributory, with no family history of systemic autoimmune or known ocular diseases. At the time of initial evaluation, the patient had used 200 mg of hydroxychloroquine twice a day for 8 years, but her ophthalmologist had recommended stopping for the past 8 months due to presumed toxicity based on vague findings seen on a dilated fundus exam.

Examination

On initial exam, best corrected visual acuity was 20/20-1 in the right eye and 20/20-2 in the left eye. IOP was 9 mm Hg in both eyes. Pupillary examination, confrontation visual fields and extraocular motility were normal in both eyes. Anterior segment exam was normal in both eyes. The anterior vitreous was clear and quiet. Dilated fundus examination revealed healthy optic discs and vessels, with few scattered drusen and retinal pigment epithelial (RPE) changes just temporal to the foveal center in both eyes (Figure 1).

Further imaging

OCT of the macula showed perifoveal preservation of the inner segment (IS) and outer segment (OS) layers in both eyes (Figure 2). Fundus autofluorescence revealed faint loss of hypoautofluorescence in the temporal macula in both eyes (Figure 3). Humphrey visual fields 10-2 showed nonspecific scattered temporal losses in both eyes (Figure 4).

What is your diagnosis?

See answer below.

Lupus nephritis-associated temporal macular drusen

The differential diagnosis for this patient’s presentation includes glomerulopathy-associated drusen, age-related macular degeneration, pattern dystrophy and medication toxicity (hydroxychloroquine). In our patient’s case, the differential diagnosis was narrowed by her young age, lack of family history and systemic condition of lupus nephritis. The patient, diagnosed with lupus about 9 years before her arrival in our clinic, presented as a second opinion regarding possible hydroxychloroquine toxicity because her rheumatology team wished to resume use for treatment of lupus. She did not have the classic findings seen with hydroxychloroquine toxicity, such as disruption in the parafoveal ellipsoid zone on OCT or paracentral scotoma on Humphrey visual field 10-2 testing (Yam and colleagues). Therefore, other causes of drusen in a young patient were considered.

Discussion

Ophthalmologists are familiar with drusen, and the relatively common associations with drusen such as age-related macular degeneration. When the patient is young, however, one must question further etiologies.

This patient had been diagnosed with biopsy-proven lupus nephritis class 3. In lupus nephritis class 3, autoantibodies to dsDNA, IgG, IgA, IgM and complement (C1, C3 and properdin) deposit focally in the mesangial, subendothelial or subepithelial space (Musa and colleagues). Several shared developmental pathways between the kidneys and the retina exist, making these distinct organ systems interconnected (Savige and colleagues). For example, both the retina and the kidney are reliant upon ciliated cells to function, and they both contain type IV collagen in their basement membrane. Further, the choriocapillaris network is similar to the fenestrated capillaries seen in the glomerulus (Savige and colleagues). It is widely accepted that the pathogenesis of drusen is largely related to dysregulated complement, especially including variants of the CFH gene (DeAngelis and colleagues). Therefore, it is understood that complement-activating disease processes, such as lupus or other autoimmune conditions, also promote drusen deposition in the retina. As such, complement factor H may prove to be a possible treatment target for patients with lupus nephritis.

In this case, the location of the drusen deposition is also relevant. Our patient had drusen specifically seen temporal to the foveal center. Khan and colleagues reviewed many retinal disorders associated with drusen, characterizing them by the location of the drusen in the macula. Particularly, one study exploring the drusen seen in patients with lupus found the greatest proportion of drusen in the temporal quadrant of the macula (Ham and colleagues). This was thought to be due to limitations in blood supply temporally or possibly from the temporal quadrant being thinner than other quadrants, enabling it to house bulkier deposits (Invernizzi and colleagues). Therefore, considering the location of drusen within the macula may help to correlate with a systemic disorder.

Clinical course

When this patient was first referred to our clinic, she had no noticeable changes in her visual acuity, but she did notice occasional flickering lights one to two times per day in both eyes. Her rheumatology team was limited in treatment choices given her previous diagnosis of “hydroxychloroquine toxicity.” We did not feel that her exam was consistent with medication toxicity, but we felt she had a higher risk for retinal toxicity given her preexisting renal impairment. With this in mind, we recommended her rheumatology team to proceed at the lowest dose possible to keep her disease under control with frequent ophthalmic monitoring. We also acquired a baseline multifocal electroretinogram (mfERG) (Figure 5), which showed slightly reduced retinal response in the right eye relative to the left eye. This testing can be useful to monitor for early hydroxychloroquine toxicity, which could present with a normal fundus exam but appear to have pericentral depressions on mfERG (So and colleagues). In patients who are being followed for hydroxychloroquine use without evidence of toxicity, it is recommended to repeat mfERG testing annually to capture early changes.

At a subsequent follow-up, the patient had restarted hydroxychloroquine at a dose of 400 mg daily, and her repeat OCT and fundus autofluorescence imaging were unchanged. She will be examined every 6 months to monitor for retinal changes.

• References:
• DeAngelis MM, et al. Hum Mol Genet. 2017;doi:10.1093/hmg/ddx228.
• Ham YJ, et al. Kidney Int Rep. 2022;doi:10.1016/j.ekir.2022.01.1063.
• Invernizzi A, et al. Am J Ophthalmol. 2017;doi:10.1016/j.ajo.2016.11.014.
• Khan KN, et al. Prog Retin Eye Res. 2016;doi:10.1016/j.preteyeres.2016.04.008.
• Musa R, et al. Lupus nephritis. In: StatPearls [Internet]. StatPearls Publishing; updated July 31, 2023.
• Savige J, et al. J Am Soc Nephrol. 2011;doi:10.1681/ASN.2010090965.
• So SC, et al. Ophthalmic Surg Lasers Imaging. 2003;34(3):251-258.
• Yam JC, et al. Hong Kong Med J. 2006;12(4):294-304.

• For more information:
• Edited by William W. Binotti, MD, and Julia Ernst, MD, PhD, of New England Eye Center, Tufts University School of Medicine. They can be reached at william.binotti@tuftsmedicine.org and julia.ernst@tuftsmedicine.org.

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