Ocular Signs of Autoimmune Diseases

Key Points at a Glance

Highlights of this disease

• Systemic autoimmune diseases cause various ocular lesions through vasculitis, demyelination, immune complex deposition, and hypercoagulability.
• Major neuro-ophthalmic signs include optic neuritis, ischemic optic neuropathy, orbital inflammatory syndrome, retinal vasculitis, occlusive retinopathy, and amaurosis fugax.
• Anti-AQP4 antibody-positive optic neuritis is steroid-resistant with poor visual prognosis and may require plasma exchange therapy.
• In SLE, retinopathy develops in approximately 10-30% of cases, with characteristic findings of cotton-wool spots, retinal hemorrhages, and Roth spots.
• Giant cell arteritis is the most important cause of arteritic anterior ischemic optic neuropathy and can lead to permanent vision loss.
• Up to 42.5% of patients with retinal vasculitis have an undiagnosed systemic disease.
• Ocular symptoms may precede the discovery of systemic autoimmune disease, making it important for ophthalmologists to investigate systemic conditions.

1. Ocular Signs of Autoimmune Diseases

Systemic autoimmune diseases can threaten vision directly through immunological mechanisms or indirectly through secondary conditions such as hypercoagulability, arteritis, hypertension, and side effects of treatment (e.g., steroid-induced cataracts and glaucoma).

The main neuro-ophthalmic signs are classified into the following six categories.

• Optic neuritis: Optic nerve damage due to inflammatory demyelination or vasculitis.
• Ischemic optic neuropathy (ION): Classified into arteritic (AAION), non-arteritic (NAION), and posterior (PION) types.
• Orbital inflammatory syndrome (OIS): Nonspecific inflammation of orbital tissues.
• Retinal vasculitis: Inflammatory changes of retinal blood vessels.
• Vascular occlusive retinopathy: Retinal vein occlusion (BRVO/CRVO) or artery occlusion (CRAO/BRAO).
• Amaurosis fugax: Transient episodes of vision loss.

The associated major autoimmune diseases are diverse. They include SLE, multiple sclerosis (MS), neuromyelitis optica spectrum disorder (NMOSD), MOG antibody-associated disease (MOGAD), giant cell arteritis (GCA), Behçet’s disease, sarcoidosis, granulomatosis with polyangiitis (GPA), polyarteritis nodosa (PAN), eosinophilic granulomatosis with polyangiitis (EGPA), antiphospholipid syndrome (APLS), Sjögren’s syndrome, rheumatoid arthritis, scleroderma, dermatomyositis, and inflammatory bowel disease (IBD).

Q What eye symptoms can occur in autoimmune diseases?

A

Symptoms range from acute vision loss and eye pain due to optic neuritis, to sudden painless vision loss from ischemic optic neuropathy, proptosis and diplopia from orbital inflammation, and visual field defects from retinal vasculitis or vascular occlusion. Ocular symptoms may be the first sign of systemic disease.

2. Main Symptoms and Clinical Findings

Subjective Symptoms

Characteristic subjective symptoms for each neuro-ophthalmic sign are as follows.

• Optic neuritis: Acute vision loss worsening over days (usually unilateral). Accompanied by photopsia, color vision abnormalities (especially reduced red perception), and pain with eye movement.
• Non-arteritic anterior ischemic optic neuropathy (non-arteritic anterior ION): Sudden, unilateral, painless severe vision loss. Often noticed upon waking.
• GCA (AAION): Sudden unilateral or bilateral vision loss. Accompanied by headache, jaw claudication, scalp tenderness, joint pain, and malaise.
• Orbital inflammatory syndrome: Acute onset of deep stabbing orbital pain, diplopia, headache, progressive vision loss. Pain with eye movement suggests orbital myositis.
• Retinal vasculitis: Painless vision loss, blurred vision, scotomas, floaters, photopsia. May be asymptomatic in peripheral lesions.
• Vascular occlusive retinopathy: CRVO → acute painless blurred vision. CRAO → sudden painless severe vision loss in one eye. BRVO → asymptomatic to visual field defect with scotoma.
• Amaurosis fugax: Temporary vision loss (blurring to complete darkness) lasting seconds to minutes.

Clinical Findings

• Optic neuritis: Positive relative afferent pupillary defect (RAPD), various degrees of visual acuity loss, visual field defects (central scotoma, nerve fiber layer defect type), color vision abnormalities. Some cases show optic disc edema, but in retrobulbar optic neuritis, the optic disc is normal.
• AAION: Pale optic disc edema (chalky pallor) with peripapillary linear hemorrhages. After edema resolves, optic disc cupping appears.
• Non-arteritic anterior ischemic optic neuropathy: Hyperemic edematous optic disc with peripapillary linear hemorrhages. Cupping is rare.
• PION: At onset, the optic disc is normal, with only RAPD. Eventually leads to optic atrophy.
• Orbital inflammatory syndrome: Proptosis, conjunctival injection, ptosis, palpable orbital mass, restricted eye movements, chemosis. Enlargement at the insertion of extraocular muscles is a distinguishing feature from thyroid eye disease.
• Retinal vasculitis: Perivascular sheathing, soft exudates (cotton-wool spots), frosted branch angiitis, retinal hemorrhages, optic disc edema.
• SLE retinopathy: cotton-wool spots, retinal hemorrhages, Roth spots, retinal vein/artery occlusion, serous retinal detachment. SLE retinopathy occurs in about 10–30% of patients, is bilateral, and is more common during periods of high disease activity. The most frequent ocular symptom in SLE is dry keratoconjunctivitis (about 30%).
• Vascular occlusive retinopathy: macular edema (main cause of vision loss), intraretinal hemorrhages, venous dilation and tortuosity, cherry-red spot (CRAO).

Characteristic clinical findings of anti-AQP4 antibody-positive optic neuritis:

• Presents with acute vision loss and is resistant to steroid treatment.
• Tends to also affect the fellow eye, often becoming bilateral.
• Eye pain is present in about half of patients.
• In addition to central scotoma, visual field defects such as horizontal hemianopia, bitemporal hemianopia, and homonymous hemianopia may occur. Lesions may extend to the optic chiasm and optic tract.
• It may be the initial symptom of NMO. Inquiry about numbness, abnormal temperature/pain sensation, and hiccups is important.

Characteristic clinical findings of anti-MOG antibody-positive optic neuritis:

• Bilateral involvement, optic disc swelling, and extensive longitudinal optic nerve hyperintensity and perineuritis on MRI.
• MOG antibody positivity is high in cases diagnosed with CRION.

Q How does anti-AQP4 antibody-positive optic neuritis differ from typical optic neuritis?

A

Unlike typical optic neuritis, anti-AQP4 antibody-positive optic neuritis is often steroid-resistant and has a poor visual prognosis. It tends to be bilateral, and visual field defects are diverse, sometimes presenting as horizontal hemianopia or homonymous hemianopia. In about 10% of cases, steroid pulse therapy alone is insufficient for recovery, and blindness may occur.

3. Causes and Risk Factors

Ocular involvement patterns differ depending on the autoimmune disease. The ocular involvement of the four major diseases is shown below.

SLE

Frequency of ocular symptoms: Dry keratoconjunctivitis (about 30%) is the most common. Retinopathy occurs in 10–30%.

Characteristics of retinopathy: Bilateral, associated with disease activity. Main findings include cotton-wool spots, retinal hemorrhages, and Roth spots.

Predilection: Women in their 20s to 30s.

Multiple Sclerosis

Association with optic neuritis: Approximately 30% present with visual impairment at onset.

Risk of conversion to MS: Cumulative probability of MS conversion 15 years after optic neuritis is 72% with brain lesions, 25% without.

Other: Internuclear ophthalmoplegia (diplopia) is also a characteristic finding.

NMOSD (Anti-AQP4 Antibody)

Epidemiology: Over 90% are women, with peak onset in the late 30s to early 40s.

Features: Primarily refractory and recurrent optic neuritis and myelitis. Steroids alone may be insufficient.

Giant Cell Arteritis

Ocular effects: Vasculitis of the terminal arteries supplying the optic disc leads to AAION. Involvement of the ophthalmic artery can cause CRAO, potentially resulting in complete blindness.

AAION: The most important cause of AAION, leading to permanent vision loss.

Patterns of retinal vasculitis by autoimmune disease:

Whether autoimmune diseases tend to cause inflammation in arteries or veins differs.

Pattern	Main associated diseases
Primarily arteritis	SLE, PAN, EGPA, giant cell arteritis
Primarily phlebitis	Behçet’s disease, multiple sclerosis, sarcoidosis
Mixed type	Granulomatosis with polyangiitis, IBD

Orbital inflammatory syndrome (OIS)-associated diseases: Granulomatosis with polyangiitis, giant cell arteritis, IBD, SLE, EGPA, scleroderma, sarcoidosis, dermatomyositis, rheumatoid arthritis.

Amaurosis fugax-associated diseases: SLE, GCA, Crohn’s disease, APLS, Takayasu arteritis.

Vascular occlusive retinopathy-associated diseases: SLE, sarcoidosis, APLS, Crohn’s disease, granulomatosis with polyangiitis, EGPA, PAN.

Relationship between ocular symptoms and systemic diseases

Ocular symptoms of autoimmune diseases often correlate with systemic disease activity. In some cases, ocular symptoms precede the discovery of systemic disease. For unexplained optic neuritis or retinal vasculitis, do not forget to investigate systemic autoimmune diseases.

Q Why should systemic disease be suspected in unexplained retinal vasculitis?

A

Up to 42.5% of patients with retinal vasculitis have been reported to have undiagnosed systemic disease. Therefore, in retinal vasculitis without obvious local factors, investigation for systemic diseases such as SLE, Behçet’s disease, and sarcoidosis is essential.

4. Diagnosis and Examination Methods

Diagnosis of Optic Neuritis

• Clinical diagnosis is fundamental. Gadolinium-enhanced orbital MRI confirms optic nerve enhancement.
• MRI is also useful for assessing the risk of conversion to MS.
• Auxiliary tests include visual evoked potentials (VEP), lumbar puncture, and chest X-ray.
• OCT can detect and quantify optic nerve atrophy.

Diagnosis of anti-AQP4 antibody-positive optic neuritis:

• Detection of serum anti-AQP4 antibodies is essential.
• The ELISA method is covered by insurance, but its sensitivity and specificity are slightly inferior to the cell-based assay (CBA) method.
• Contrast-enhanced MRI: enhancement consistent with the optic nerve.
• Also confirm a decrease in critical flicker frequency (CFF).
• Differential diagnosis: Since onset often occurs at an older age than typical optic neuritis, differentiation from ischemic optic neuropathy is important. The presence or absence of lifestyle-related diseases and partial pale swelling of the optic disc are key points for differentiation.

Diagnostic criteria for NMOSD (2015):

• Positive anti-AQP4 antibody + at least one core clinical syndrome + exclusion of other diseases.
• If anti-AQP4 antibody is negative: at least two core clinical syndromes (at least one of which is optic neuritis, acute myelitis, or area postrema syndrome) plus meeting specified MRI findings are required.

Diagnostic criteria for MS:

• Use the 2010 revised McDonald diagnostic criteria.
• Demonstration of temporal and spatial dissemination in the central nervous system. MRI findings play a central role.

Diagnosis of ischemic optic neuropathy

• Fundus findings + fluorescein angiography (FA) are useful.
• MRI is used to differentiate AAION from non-arteritic anterior ischemic optic neuropathy.
• In PION, no optic nerve enhancement (differentiating from retrobulbar optic neuritis).

Diagnosis of Orbital Inflammatory Syndrome

• Dilated fundus examination (DFE), optic nerve assessment (color vision, RAPD), visual field testing.
• MRI/CT: Lacrimal gland enlargement (most common), extraocular muscle enlargement, orbital fat infiltration. MRI shows T1/T2 hypointensity and gadolinium enhancement.
• Ultrasound: Enlargement of the extraocular muscle insertion (useful for differentiation from thyroid eye disease).
• Orbital biopsy: Considered in treatment-refractory or diagnostically uncertain cases.

Diagnosis of Retinal Vasculitis

• Clinical diagnosis is based on fundus examination.
• FA: Useful for evaluating vascular leakage patterns (focal vs. diffuse). In SLE, important for assessing retinal vasculitis and vascular occlusion.
• OCT: Evaluation of retinal structure.

Detection of MOG antibodies:

• Serum MOG-IgG is detected using a live cell-based assay.
• Only antibodies that bind to MOG in its native conformational state are pathogenic.

5. Standard Treatment

Optic Neuritis (Typical Cases)

• In over 90% of cases, vision improves with systemic steroid administration or observation.
• Steroid pulse therapy is the standard (methylprednisolone).

Anti-AQP4 Antibody-Positive Optic Neuritis

Initial treatment:

• Steroid pulse therapy (methylprednisolone 1,000 mg, intravenous infusion for 3 days). Since this is not covered by insurance, explanation and consent from the patient are required.
• If visual improvement is not achieved after a 3-4 day interval, administer another course.

Steroid-resistant cases (after confirmation of anti-AQP4 antibody positivity):

• Consider plasma exchange therapy.
• Simple plasma exchange → double filtration plasmapheresis → immunoadsorption therapy have higher treatment efficacy in this order, but the burden on the body also increases in this order.
• Perform 5-6 sessions per course. Collaboration with neurologists and nephrologists is essential.
• Plasma exchange therapy for optic neuritis is not covered by insurance.
• Hospitalization period is prolonged due to reduction of IgG in the body.

Maintenance therapy:

• Combination of low-dose prednisolone (5-10 mg/day) and azathioprine (50-100 mg/day).

Prognosis: Without appropriate treatment, visual impairment becomes permanent. In about 10% of cases, steroid pulse therapy alone is insufficient, and without plasma exchange, there is a risk of blindness.

NMOSD

• Acute phase: Steroid pulse therapy (first-line). For refractory cases, plasma exchange therapy.
• Chronic phase (relapse prevention): Oral steroids (low-dose prednisolone) are recommended (first-line not established).
• Note that the treatment strategy differs significantly from optic neuritis associated with MS.

Anti-MOG antibody-positive optic neuritis

• Steroid pulse therapy tends to be effective.
• It tends to recur frequently, especially during steroid tapering.

Autoimmune optic neuritis (general)

• Steroids are often effective, but recurrence may occur with tapering, leading to steroid dependence.
• Prevention of recurrence: continue low-dose steroids. If recurrence persists, use immunosuppressants.

Optic neuritis associated with MS

• After visual improvement, consider preventive treatment for recurrence and collaborate with a neurologist.
• Options: interferon beta, glatiramer acetate, fingolimod, natalizumab.

SLE retinopathy

• Treatment is linked to systemic SLE management (steroids and immunosuppressants).
• Scleritis responds well to steroids.

Treatment precautions

• In anti-AQP4 antibody-positive optic neuritis, steroids alone may be insufficient (about 10% of cases).
• Plasmapheresis is not covered by insurance for optic neuritis, and sufficient explanation and consent from the patient are required before implementation.
• Long-term steroid use requires attention to the risk of developing cataracts and glaucoma.
• Collaboration with specialists such as neurologists and nephrologists is important before starting each treatment.

Q In what cases is plasmapheresis necessary for anti-AQP4 antibody-positive optic neuritis?

A

Plasmapheresis is considered when visual improvement is not achieved after 1-2 courses of steroid pulse therapy (methylprednisolone 1,000 mg for 3 days). In about 10% of patients, steroids alone are insufficient, and without plasmapheresis, blindness may occur. Both are not covered by insurance, and collaboration with neurologists and nephrologists is necessary.

6. Pathophysiology and Detailed Pathogenesis

The main mechanisms by which systemic autoimmune diseases cause ocular lesions are as follows.

• Vasculitis: Luminal narrowing or occlusion due to inflammatory cell infiltration of the vessel wall.
• Vasospasm: Vasoconstriction caused by inflammatory mediators.
• Immune-mediated demyelination: Destruction of myelin sheaths by autoantibodies or cell-mediated immunity.
• Immune complex deposition: Tissue damage due to deposition of immune complexes and complement in the vessel wall.
• Hypercoagulable state: Inflammation upregulates procoagulant factors and downregulates anticoagulant factors. Pathogenic antibodies such as anticardiolipin antibodies and lupus anticoagulant also contribute to hypercoagulability.

Pathophysiology of SLE:

Vasculitis with fibrinoid necrosis of small vessels and capillaries is characteristic. Fibrinoid material consists of fibrin, immune complexes, and complement.

Pathophysiology of anti-AQP4 antibody-positive optic neuritis:

Anti-AQP4 antibodies bind complement and attack astrocytes. The optic nerve and chiasm are vulnerable because astrocytes there highly express AQP4 (aquaporin-4).

Pathophysiology of optic neuritis (demyelinating):

Inflammatory demyelination causes conduction block leading to vision loss. Remyelination can occur, but persistent demyelination or axonal loss may result in incomplete recovery.

Pathophysiology of MOGAD (MOG antibody-associated disease):

It is an independent demyelinating disease distinct from MS and NMOSD. The binding of MOG-IgG to MOG in its native conformational state is considered the essence of pathogenicity.

7. Latest Research and Future Perspectives (Research-stage Reports)

For patients: Please read this

The following content is currently at the research stage or under clinical trial and is not standard treatment available at general hospitals. It is reference information for professionals regarding future medical developments.

Validation of the International Diagnostic Criteria for MOGAD (2023)

Validation of the international diagnostic criteria established in 2023 is underway.

In validation studies involving all patients, sensitivity of 96.5%, specificity of 98.9%, and accuracy of 98.5% have been reported. In children, both sensitivity and specificity were close to 100%, while in adults, sensitivity was 91.9% and specificity was 98.9%. The usefulness of the diagnostic criteria has been confirmed even when compared to the accuracy of MOG antibody testing alone.

Research Challenges in MOG-ON (MOG Antibody-Associated Optic Neuritis)

Currently unresolved issues include the following.

• Establishment of optimal acute treatment.
• Role of steroid-sparing immunotherapy for long-term relapse prevention.
• Identification of predictors for recurrent disease (persistent MOG-IgG positivity is being studied as a predictor of recurrence).
• Utility of OCT as a biomarker: application to detection of acute optic nerve swelling and chronic atrophy.

COVID-19-related reports

Cases of ION (ischemic optic neuropathy) and MOG antibody-positive optic neuritis after COVID-19 vaccination have been reported. Further research is needed to evaluate causality.

Evidence reinforcement

• The epidemiology of ocular complications in autoimmune diseases overall is comprehensively summarized in a review by Glover et al. (2021) (Reference 2), and the frequency of ocular complications in SLE (approximately 30%) is supported by this review and a systematic review in the same field (Turk et al. 2021, Reference 4).
• The frequency (10–30%) and findings (cotton-wool spots, Roth spots, vascular occlusion) of SLE retinopathy are based on the literature review by Palejwala et al. (2012) (Reference 3).
• The steroid resistance, bilateral tendency, and poor prognosis of anti-AQP4 antibody-positive optic neuritis were demonstrated by Yamagami et al. (2018) in a Japanese cohort (Reference 5).
• The description of the MOGAD international diagnostic criteria (2023) with a sensitivity of 96.5%, specificity of 98.9%, and accuracy of 98.5% is based on the validation study by Varley et al. (2024) (Reference 6).
• AAION due to giant cell arteritis and related neuro-ophthalmic signs are systematically summarized in the review by Khoury & Albreiki (2025) (Reference 7).
• The diagnostic approach of suspecting autoimmune disease from neuro-ophthalmic signs is detailed in the review by Poonja & Costello (2023) (Reference 1).

---

8. References

1. Poonja S, Costello F. Neuro-ophthalmic manifestations of autoimmune disorders: diagnostic pearls & pitfalls. Curr Opin Ophthalmol. 2023;34(6):500-513. doi:10.1097/ICU.0000000000001001. PMID: 37729661. https://pubmed.ncbi.nlm.nih.gov/37729661/

2. Glover K, Mishra D, Singh TRR. Epidemiology of Ocular Manifestations in Autoimmune Disease. Front Immunol. 2021;12:744396. doi:10.3389/fimmu.2021.744396. PMID: 34795665; PMCID: PMC8593335. https://pmc.ncbi.nlm.nih.gov/articles/PMC8593335/

3. Palejwala NV, Walia HS, Yeh S. Ocular Manifestations of Systemic Lupus Erythematosus: A Review of the Literature. Autoimmune Dis. 2012;2012:290898. doi:10.1155/2012/290898. PMID: 22811887; PMCID: PMC3395333. https://pmc.ncbi.nlm.nih.gov/articles/PMC3395333/

4. Turk MA, Hayworth JL, Nevskaya T, Pope JE. Ocular Manifestations in Rheumatoid Arthritis, Connective Tissue Disease, and Vasculitis: A Systematic Review and Metaanalysis. J Rheumatol. 2021;48(1):25-34. doi:10.3899/jrheum.190768. PMID: 32358156. https://pubmed.ncbi.nlm.nih.gov/32358156/

5. Yamagami A, Wakakura M, Inoue K, Ishikawa H, Takahashi T, Tanaka K. Clinical Characteristics of Anti-aquaporin 4 Antibody Positive Optic Neuritis in Japan. Neuroophthalmology. 2018;43(2):71-80. doi:10.1080/01658107.2018.1520905. PMID: 31312230; PMCID: PMC6619931. https://pmc.ncbi.nlm.nih.gov/articles/PMC6619931/

6. Varley JA, Champsas D, Prossor T, et al. Validation of the 2023 International Diagnostic Criteria for MOGAD in a Selected Cohort of Adults and Children. Neurology. 2024;103(1):e209321. doi:10.1212/WNL.0000000000209321. PMID: 38870448; PMCID: PMC11244737. https://pubmed.ncbi.nlm.nih.gov/38870448/

7. Khoury JA, Albreiki D. Neuro-ophthalmic Manifestations of Giant Cell Arteritis: A Review. J Ophthalmic Vis Res. 2025;20. doi:10.18502/jovr.v20.15248. PMID: 40689118; PMCID: PMC12258379. https://pmc.ncbi.nlm.nih.gov/articles/PMC12258379/