Autoimmune retinopathy (AIR) is a rare group of diseases in which autoantibodies target retinal antigens and cause photoreceptor degeneration1). Autoimmune retinopathy is broadly classified into two types.
Paraneoplastic autoimmune retinopathy
Cancer-associated retinopathy: Associated with malignant tumors such as small cell lung cancer. Caused by cross-reactivity between tumor antigens and retinal antigens.
Melanoma-associated retinopathy: Associated with malignant melanoma. Characterized by a negative b-wave on electroretinography.
Non-paraneoplastic autoimmune retinopathy
Non-paraneoplastic autoimmune retinopathy: Develops without an associated malignancy. It is thought to be due to systemic autoimmune abnormalities.
Hypothyroidism: The most common systemic disease associated with non-paraneoplastic autoimmune retinopathy.
The prevalence of non-paraneoplastic autoimmune retinopathy is unknown. It predominantly affects women (63–66%), with a mean age at diagnosis of 65 years1), although cases in young women as young as 30 have been reported1). The first case of non-paraneoplastic autoimmune retinopathy was reported in 1997, noting clinical similarities to cancer-associated retinopathy.
Autoimmune diseases (such as hypothyroidism, rheumatoid arthritis, multiple sclerosis, and Hashimoto’s disease) are often present. Differentiation from paraneoplastic retinopathy is extremely important; when autoimmune retinopathy is suspected, screening for malignancy is essential.
The biggest difference is the presence or absence of an underlying malignant tumor. Cancer-associated retinopathy is associated with small cell lung cancer and other malignancies, with anti-recoverin antibody being a representative autoantibody. Non-paraneoplastic autoimmune retinopathy does not involve a malignant tumor, but because the clinical symptoms are similar, tumor screening according to age and sex is necessary. For details, see the “Causes and Risk Factors” section.
Symptoms of non-paraneoplastic autoimmune retinopathy are bilateral and progressive, but often asymmetric.
Symptoms may show temporary spontaneous improvement, which can delay diagnosis.
The fundus often appears normal in the early stages, which is the major factor making diagnosis difficult.
In the case report by Nair et al. (2024), a 30-year-old woman had markedly reduced corrected visual acuity of 3/60 in the right eye and 2/60 in the left eye, sluggish pupillary light reflex, mild optic disc pallor and vascular narrowing on fundus examination, and multiple pin-point leakages with perivascular staining on FFA1).
In non-paraneoplastic autoimmune retinopathy, the fundus examination often shows no obvious abnormalities in the early stages. This can lead to misdiagnosis as optic neuritis. Electroretinography and optical coherence tomography are useful tools for detecting abnormalities, and these tests should be actively performed in cases of unexplained progressive vision loss.
The development of non-paraneoplastic autoimmune retinopathy involves the production of anti-retinal autoantibodies due to a breakdown of immune tolerance 1). While paraneoplastic autoimmune retinopathy is triggered by cross-reactivity between tumor antigens and retinal antigens, non-paraneoplastic autoimmune retinopathy is thought to be associated with systemic autoimmune abnormalities.
Non-paraneoplastic autoimmune retinopathy is a diagnosis of exclusion. There is no specific definitive diagnostic method, and it is determined by a comprehensive assessment of clinical findings, electrophysiological tests, imaging tests, and serological tests 2).
Electroretinography is a key test for diagnosis.
In the case reported by Grewal et al. (2021), a 29-year-old woman showed marked response reduction and negative waveforms predominantly in the left eye on full-field electroretinography3).
| Test Method | Main Findings |
|---|---|
| Optical coherence tomography | Thinning of outer granular layer and ellipsoid zone, cystoid macular edema |
| Fundus autofluorescence | Patchy hyperfluorescence and hypofluorescence |
| Fluorescein angiography | Punctate leakage, perivascular staining |
Anti-retinal antibodies detected by Western blot, immunohistochemistry, enzyme-linked immunosorbent assay, and multiplex assay include the following.
In the case reported by Grewal et al., anti-carbonic anhydrase II and anti-enolase antibodies were detected in the serum, and immunohistochemistry stained the photoreceptor layer3).
However, a positive finding of anti-retinal antibodies alone does not lead to a definitive diagnosis 1). Since ARA is also detected in other retinal diseases such as age-related macular degeneration and retinitis pigmentosa, comprehensive judgment with clinical findings is essential.
When AIR is suspected, malignancy screening according to age and sex, such as mammography, chest-abdomen-pelvis CT, brain MRI, and colonoscopy, should be performed to exclude paraneoplastic etiology 1)3). PET examination is also useful; in the case of Nair et al., neoplastic disease was excluded by PET and other blood tests 1).
The differential diagnoses of npAIR are diverse.
Bonilla-Escobar et al. (2025) initially diagnosed a 49-year-old woman with systemic autoimmune disease as having npAIR, but genetic testing identified a pathogenic variant in the PRPH2 gene, and the diagnosis was revised to hereditary retinal degeneration 2). The same variant was confirmed in her father, consistent with an autosomal dominant inheritance pattern.
Currently, genetic testing is not recommended for all cases, but it is desirable when hereditary retinal degeneration is suspected in patients with autoimmune disease or when treatment response is poor. Since differentiating between IRD and npAIR significantly affects treatment strategy, it should be actively considered 2).
Treatment of npAIR centers on immunosuppressive therapy, but no standardized protocol exists 1)3). The goal of treatment is to suppress the autoimmune response and prevent further retinal damage.
High-dose oral steroids are used as first-line therapy in the acute phase.
To avoid side effects from long-term steroid use, the following immunosuppressive drugs are used in combination.
Considered when steroids and conventional immunosuppressants are ineffective.
Cystoid macular edema in npAIR is frequently observed and is an indicator of a more severe and rapidly progressive disease type 3). It is associated with a more rapid decline in electroretinogram amplitude and loss of the ellipsoid zone. The following treatments are performed for cystoid macular edema.
The pathology of npAIR is based on a breakdown of immune tolerance. Autoantibodies against retinal antigens are produced, leading to photoreceptor degeneration and damage to the retinal pigment epithelium (RPE) 1).
The main anti-retinal antibodies and target antigens associated with npAIR are as follows.
These autoantibodies destroy photoreceptor cells, ganglion cells, and bipolar cells via apoptosis mediated by caspase activation and intracellular calcium influx.
In paraneoplastic AIR, retinal antigens ectopically expressed in tumors are recognized by the immune system, leading to cross-reactivity 1). In npAIR, the following mechanisms are presumed.
In recent years, animal models and clinical studies have shown that excessive activation of innate immunity promotes neuroinflammation even in inherited retinal degenerations (IRD)2). In retinitis pigmentosa, cystoid macular edema, retinal vascular leakage, and elevated inflammatory cytokines in the vitreous have been reported, and it remains unclear whether inflammation is the initial trigger of retinal degeneration or a secondary response to photoreceptor cell death2). This finding further complicates the differentiation between npAIR and IRD.
Interleukin-6 (IL-6) is a multifunctional cytokine that plays a central role in posterior uveitis 3). IL-6 levels are elevated in the vitreous humor and aqueous humor of patients with uveitis. IL-6 is essential for the differentiation of Th17 cells, which are involved in the pathogenesis of several autoimmune diseases. IL-6 signaling is also thought to contribute to cystoid macular edema and perivascular leakage in npAIR 3).
Inhibition of IL-6 signaling is attracting attention as a new therapeutic strategy for refractory cystoid macular edema associated with npAIR.
Grewal et al. (2021) reported a 29-year-old woman with cystoid macular edema associated with npAIR who was resistant to azathioprine (225 mg/day) and adalimumab, and was treated with subcutaneous sarilumab (anti-IL-6 receptor antibody) 200 mg every two weeks 3). After two doses, the cystoid macular edema markedly improved, and after four doses (6 weeks), the cystoid macular edema in the right eye completely resolved. Visual acuity improved from 20/70 to 20/32 in the right eye, and a slight improvement in electroretinogram amplitudes was observed at 6 months. No systemic side effects were noted.
In the SATURN trial (Phase 2), subcutaneous sarilumab 200 mg every two weeks for 16 weeks showed improvement in vitreous haze, cystoid macular edema, and visual acuity in non-infectious posterior uveitis 3).
There are also case reports showing the efficacy of tocilizumab (another IL-6 inhibitor) for npAIR-associated cystoid macular edema 3).
In the case by Bonilla-Escobar et al. (2025), a patient diagnosed with npAIR underwent genetic panel testing (250 genes), which identified a PRPH2 gene mutation, leading to a revised diagnosis of hereditary retinal degeneration 2). PRPH2 mutations can present with diverse clinical phenotypes and may include inflammatory findings such as retinal vascular leakage and cystoid macular edema, making differentiation from npAIR difficult.
Genetic testing can lead to fundamental changes in treatment strategy and should be actively considered, especially in atypical or treatment-resistant cases 2).
