Autoimmune-Related Retinopathy and Optic Neuropathy (ARRON) is a rare autoimmune eye disease characterized by painless, usually bilateral visual impairment. The core definition includes evidence of both retinopathy and optic neuropathy without evidence of a neoplastic process. It is also called autoimmune retinopathy (AIR) or non-paraneoplastic autoimmune retinopathy and optic neuropathy.
The epidemiology of ARRON is so rare that it is not precisely known. According to a report by Keltner et al., 12 ARRON patients have been described, with a female predominance and a mean age of onset of 50 years (range 37–75 years).
Paraneoplastic diseases with similar clinical presentations to ARRON include cancer-associated retinopathy (CAR) and melanoma-associated retinopathy (MAR). CAR is a paraneoplastic syndrome in which autoantibodies against a retina-specific antigen (recoverin) ectopically expressed in tumor tissue damage retinal photoreceptors. MAR is associated with cutaneous malignant melanoma and involves autoantibodies against retinal bipolar cells. Unlike these, ARRON is not associated with malignancy.
ARRON is diagnosed on the premise that there is no malignant tumor. CAR is a paraneoplastic syndrome, and the presence of a malignant tumor is essential. Because the clinical pictures of both are similar, a thorough malignancy screening is necessary for ARRON diagnosis. For details, see the “Diagnosis and Testing Methods” section.
Symptoms of ARRON progress insidiously, so patients often delay seeking medical attention.
GFAP astrocytopathy is an important disease concept associated with ARRON. In a large analysis of 592 patients, visual system involvement was found in 25%.
Symptoms often progress insidiously, leading to delayed consultation. Because the course is bilateral and painless, even if abnormalities are noticed, they tend to be considered minor. If there is a combination of photopsia, night blindness, and visual field defects, early consultation with an ophthalmologist is recommended.
The pathophysiology of ARRON is presumed to involve autoantibodies against the optic nerve and retina that are pathogenic. However, whether these autoantibodies are pathogenic, an epiphenomenon, or a normal immune response after exposure of the immune-privileged retina remains a matter of debate.
The diagnosis of ARRON is based on a comprehensive assessment combining multiple tests.
The following criteria are used for the definitive diagnosis of ARRON.
Four essential items (all must be met)
| Item | Description |
|---|---|
| 1 | Visual impairment confirmed by visual acuity and visual field tests |
| 2 | No malignancy found on extensive evaluation |
| 3 | Evidence of optic nerve or retinal abnormality |
| 4 | No identifiable cause |
Plus one of the following
Modifying factors: Classified as type A (with other autoimmune diseases) or type B (without).
Detection of GFAPα-IgG in cerebrospinal fluid or serum is essential. Diagnosis is made in combination with clinical features of meningitis, encephalitis, myelitis, and optic disc edema. On brain MRI, bilateral hyperintensity in the posterior thalamus is a characteristic finding.
Important diseases to differentiate from ARRON are listed below.
CAR
Cancer-associated retinopathy: Diffuse electroretinogram reduction (both a-wave and b-wave decreased).
Primary tumor: Lung cancer (small cell carcinoma) is most common. Ocular symptoms often precede the discovery of the primary cancer.
Autoantibodies: Anti-recoverin antibody is representative.
MAR
Melanoma-associated retinopathy: Negative electroretinogram (a-wave nearly normal, b-wave absent) is characteristic, indicating bipolar cell dysfunction.
Background disease: Many cases have a prior diagnosis of cutaneous melanoma. More common in men.
Autoantibodies: TRPM1 is the target.
Optic Neuritis and Related Diseases
Typical optic neuritis: Acute onset with eye movement pain. Predominantly affects women aged 15–45.
MOG-ON: Bilateral optic neuritis and optic disc swelling. Bilateral in 31–84% of cases.
NMOSD (AQP4 antibody): Associated with longitudinally extensive optic neuritis and transverse myelitis.
Non-arteritic anterior ischemic optic neuropathy (NAION): Acute unilateral painless vision loss. Underlying disc at risk.
Other differential diagnoses include AZOOR (acute vision loss, visual field defects, photopsia; common in young myopic women).
Detection of autoantibodies is only an aid to diagnosis and does not confirm the diagnosis. Whether the antibodies are pathogenic or an epiphenomenon is still under debate; meeting the diagnostic criteria of Oyama et al. is required for a definitive diagnosis. Antibody titers fluctuate with disease activity, so evaluation requires measurement at least three times.
There is no consensus on the treatment of ARRON. The following are representative treatment options at present.
| Treatment | Role | Notes |
|---|---|---|
| Systemic corticosteroids | First-line | Limited to ARRON application |
| Methotrexate | Immunomodulator | Considered for steroid-resistant cases |
| Cyclophosphamide | Immunomodulatory drug | Considered for steroid-resistant cases |
| Rituximab | Biologic agent | Efficacy shown at case report level |
| IVIG (intravenous immunoglobulin) | Considered for refractory cases | Steroid/immunomodulator-resistant cases |
| PLEX (plasma exchange) | Considered for refractory cases | Steroid/immunomodulator-resistant cases |
| Autologous hematopoietic stem cell transplantation | Last resort | One case report available |
If there is a coexisting autoimmune disease, treatment of that disease takes priority.
Treatment of GFAP astrocytopathy: Approximately 70% respond rapidly to high-dose steroids and follow a monophasic course. Cases with NMDA-R-IgG or coexisting cancer tend not to respond to first-line treatment. Relapse has been reported in about 18% of patients with follow-up data.
Since there is no established treatment consensus, effectiveness varies from case to case. While some cases respond to immunosuppressive therapy, others are reported to be treatment-resistant. In the diagnostic criteria by Oyama et al., “response to immunomodulatory therapy” is one of the supportive diagnostic criteria, and treatment responsiveness itself may contribute to diagnosis.
The role of autoantibodies in ARRON remains controversial. Whether they are pathogenic, an epiphenomenon, or a normal immune response following exposure of the retina (an immune-privileged site) has not been established.
Pathogenesis of CAR
The proposed pathway is: ectopic expression of tumor-specific antigens → activation of adaptive immune mechanisms → production of autoantibodies against retinal-specific antigens (recoverin) → retinal photoreceptor damage. The main autoantibody targets in CAR are recoverin (a Ca²⁺-binding protein), hsc70 (heat-shock-cognate-protein 70), and enolase.
Pathogenesis of MAR
Autoantibodies against retinal bipolar cells are involved, and the involvement of TRPM1 (Transient receptor potential cation channel, subfamily M, member 1) has been suggested. The negative electroretinogram pattern (marked reduction of b-wave) reflects this bipolar cell dysfunction.
Pathogenesis of GFAP astrocytopathy
Since GFAPα-IgG is intracellular, it is unlikely that the antibody itself is directly pathogenic. T-cell-mediated immune responses against astrocytes are presumed to be the main mechanism of injury. Disease triggers are ovarian teratoma (ectopic GFAPα secretion) or idiopathic.
ICI-related pathogenesis
As a Type 3 reaction to immune checkpoint inhibitors (ICIs), it is hypothesized that T cell activation leads to B cell clonal proliferation, autoantibody production, and progression to AIR, CAR, and MAR. CTLA-4 inhibition causes non-specific T cell proliferation, Treg suppression, and B cell activation, while PD-1 inhibition stimulates oligoclonal T cell populations in target tissues.
With the widespread use of immune checkpoint inhibitors (ICIs), cases of AIR, CAR, and MAR developing after ICI use have been reported. Regular ophthalmologic monitoring in patients receiving ICI therapy will be a future challenge.
In CAR model rats using anti-recoverin and anti-hsc70 antibodies, calcium channel blockers have been suggested to be effective. Further research is needed for clinical application.
A large-scale review of 592 patients showed that in serum-only positive patients, there is no significant difference in phenotype between adulthood and childhood. Expert opinion suggests that in cases of severe bilateral optic neuritis with negative AQP4 antibodies, GFAP cerebrospinal fluid antibody testing is recommended.
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