Retinal Vasculitis

Key points at a glance

Key Points at a Glance

• Retinal vasculitis is a condition characterized by inflammation of retinal blood vessels and is associated with various systemic diseases.
• It occurs in about 15% of patients with uveitis and is more common in young people under 40 years of age.
• Both veins and arteries can be affected, but phlebitis is more common.
• Up to one-third of patients may develop severe visual impairment (worse than 20/200).
• Differentiating between infectious and non-infectious causes is most important for determining treatment strategy.
• For non-infectious cases, systemic corticosteroids are the mainstay, and immunosuppressants or biologics are added stepwise in refractory cases.
• Early diagnosis and appropriate management of systemic disease lead to improved visual prognosis.

1. What is Retinal Vasculitis?

Retinal vasculitis is a condition characterized by inflammatory cell infiltration into the walls of retinal blood vessels. It can occur alone or as an ocular complication of systemic diseases.

The annual incidence is estimated at about 1–2 per 10,000 people. It occurs in about 15% of patients with uveitis, is more common in those under 40, and slightly more frequent in women. The mean age at diagnosis is reported to be around 34 years. It is usually bilateral, and in severe cases, up to one-third of patients may develop severe visual impairment (corrected visual acuity worse than 20/200).

The terminology varies depending on the affected vessels. Inflammation of the venous wall is called “phlebitis,” and inflammation of the arterial wall is called “arteriolitis.” Unlike systemic vasculitis, it is characterized by the absence of vascular necrosis.

The disease course is generally divided into four stages.

• ① Inflammatory stage: Predominantly perivascular inflammatory cell infiltration
• ② Ischemic stage: Appearance of vascular occlusion and non-perfusion areas
• ③ Neovascular stage: Retinal neovascularization due to ischemia
• ④ Complication stage: Vitreous hemorrhage, tractional retinal detachment

Approximately 50% of patients with granulomatosis with polyangiitis develop ocular symptoms, and in about 15%, the eye is the initial site. Occlusive retinal vasculitis is seen in less than 5% of patients with granulomatosis with polyangiitis⁶⁾. About 10% of SLE patients develop lupus retinopathy, and approximately 77% of SLE patients with lupus disease of retina/optic nerve have elevated antiphospholipid antibodies (APL)¹⁾.

Age of onset

Common age: Most common under 40 years. Mean age at diagnosis is about 34 years.

Sex difference: Slightly more common in women.

Bilaterality

Usually bilateral: Even if it starts in one eye, it may spread to the other eye over time.

Visual prognosis: Up to one-third may develop severe visual impairment (less than 20/200).

Frequency of association

Uveitis association rate: Occurs in about 15% of uveitis patients.

SLE association rate: About 10% of SLE patients develop lupus retinopathy¹⁾.

Q How rare is retinal vasculitis?

A

The annual incidence is about 1–2 per 10,000 people, making it a relatively rare disease. However, because it occurs in about 15% of uveitis patients, it is frequently encountered in uveitis specialty clinics.

2. Main symptoms and clinical findings

Subjective Symptoms

In mild cases, the condition may remain asymptomatic ¹⁾. When symptoms appear, the following are common.

• Blurred vision: The most common subjective symptom. Caused by inflammation or vitreous opacity.
• Floaters: Due to inflammation spreading to the vitreous or vitreous hemorrhage.
• Decreased vision: Caused by cystoid macular edema (CME), vitreous hemorrhage, or ischemia.

Clinical Findings

Perivascular sheathing (sheath-like changes) is a classic finding of retinal vasculitis. The following findings are observed in combination.

Main findings are organized by disease.

Finding	Characteristic	Representative Disease
Sheathing, perivascular exudation	Classic finding	Many causative diseases
Cotton-wool spots	Nerve fiber layer infarction	SLE, granulomatosis with polyangiitis
Segmental leakage from large and small vessels	Confirmed by fluorescein angiography	Cryoglobulin 2)
Arteriovenous fistula, global ischemia	Evidence of severe ischemia	Granulomatosis with polyangiitis 6)

• SLE: Characterized by bilateral cotton-wool spots, dot/blot hemorrhages, and cystoid macular edema ¹⁾. Neovascularization is present in 72% of eyes with SLE retinopathy ¹⁾.
• Cryoglobulinemia: Segmental fluorescein leakage from large and small vessels ²⁾.
• Granulomatosis with polyangiitis: Presents with anterior chamber inflammation (2+ cells), arteriovenous fistula, and extensive retinal ischemia (global ischemia) ⁶⁾.
• Pseudorabies virus (PRV): White sheathing of retinal vessels and vitreous opacity ⁵⁾.
• CREST syndrome: Cotton-wool spots and white membranous changes extending from the optic disc ⁴⁾.
• Cystoid macular edema (CME): Complicates many underlying diseases and is a major cause of vision loss.

3. Causes and Risk Factors

Causes of retinal vasculitis are broadly classified into non-infectious, infectious, and drug-induced.

Non-infectious Causes

Autoimmune diseases are the most common cause.

• SLE: Immune complex deposition is the main pathology. In cases complicated by antiphospholipid antibody syndrome (APS), the risk of thrombosis increases¹⁾.
• Behçet’s disease: Prone to occlusive vasculitis, with poor visual prognosis.
• Sarcoidosis: Often associated with periphlebitis due to granulomatous uveitis.
• Granulomatosis with polyangiitis (GPA): ANCA-associated neutrophil degranulation is central to the pathology. c-ANCA (PR3-ANCA) positivity rate is 80–95%⁶⁾.
• CREST syndrome: Intraocular surgery can trigger an inflammatory cascade⁴⁾.
• Cryoglobulinemia: Associated with hepatitis C and lymphoproliferative disorders²⁾.
• Multiple sclerosis (MS): Often associated with intermediate uveitis.
• Eales disease: Idiopathic occlusive vasculitis in young men.

Infectious causes

For infectious causes, treatment targeting the causative pathogen is prioritized.

• Tuberculosis and syphilis: Appear as ocular complications of systemic infections.
• Toxoplasma and herpes viruses: High risk in immunocompromised patients.
• Pseudorabies virus (PRV): Occupational infection risk in occupations involving contact with pigs (e.g., pig farmers)⁵⁾.

Drug-induced and other causes

• Immune checkpoint inhibitors (ICIs): Increasing with the spread of cancer immunotherapy.
• Idiopathic: Some cases remain unexplained even after all investigations.

Prevention and Daily Care

• If you have been diagnosed with a systemic autoimmune disease such as SLE, Behçet’s disease, or sarcoidosis, we recommend regular eye examinations.
• If symptoms such as floaters, blurred vision, or decreased vision appear, promptly see an ophthalmologist.
• If you are receiving treatment with immune checkpoint inhibitors, watch for eye symptoms and consult your primary care physician.

Q Can retinal vasculitis occur without an identifiable cause?

A

There are cases of “idiopathic” retinal vasculitis where the cause cannot be identified despite all tests. Eales disease is known as an idiopathic occlusive retinal vasculitis occurring in young men. Even in cases with unknown cause, ophthalmologic management and regular systemic evaluation are important.

4. Diagnosis and Examination Methods

Ophthalmic Examinations

• Fluorescein angiography (FA): Detects leakage from vessel walls, vascular occlusion, non-perfusion areas, and neovascularization. It is the most important test for assessing activity. Ultra-widefield FA reveals findings not detected by conventional imaging in more than half of patients, leading to changes in diagnosis and treatment.
• Optical coherence tomography (OCT): Useful for detecting and quantitatively monitoring cystoid macular edema.
• OCT angiography (OCTA): Allows non-invasive assessment of non-perfusion areas.

Systemic Examinations

In many cases, identifying the underlying cause is difficult based on ocular findings alone, and systematic systemic evaluation is necessary.

• Basic tests: CBC, CRP, ESR, complement (C3/C4), coagulation tests
• Autoimmune disease screening: ANA, ANCA, RF, anti-centromere antibody

Additional tests when disease is suspected are as follows:

• Suspected SLE: ANA (≥1:320), anti-dsDNA (≥1:80), lupus anticoagulant. In an actual case, ESR 90, ANA>1:320, anti-dsDNA 1:80, C3 0.76 were shown¹⁾.
• Suspected granulomatosis with polyangiitis: c-ANCA (PR3-ANCA), renal biopsy⁶⁾.
• Suspected cryoglobulinemia: Serum cryoglobulin measurement, hepatitis C virus test, bone marrow biopsy²⁾.
• Suspected CREST syndrome: Anti-centromere antibody (≥1:640)⁴⁾.
• Suspected PRV: Detection of viral nucleic acid in vitreous fluid by next-generation sequencing (NGS). In PRV-infected eyes, IL-6 (1247.1 pg/mL), IL-8 (214.7 pg/mL), and VCAM (7598.0 ng/mL) in intraocular fluid are markedly elevated⁵⁾.

Q Is fluorescein angiography always necessary?

A

Fluorescein angiography (FA) is the most important test for assessing activity. It is essential for determining the extent of vasculitis, the presence of non-perfusion areas, and neovascularization. Using ultra-widefield FA further improves diagnostic accuracy.

5. Standard treatment

Treatment differs greatly between non-infectious and infectious cases. In infectious retinal vasculitis, priority is given to identifying and eliminating the causative pathogen, and administration of steroids without excluding infection is contraindicated.

Non-infectious retinal vasculitis

A stepwise approach is fundamental.

Step	Treatment options	Remarks
First-line	Systemic steroid therapy	PSL 0.5-1 mg/kg/day, then taper
Severe cases	mPSL pulse → oral PSL	mPSL 1 g/day × 3 days → PSL 40-60 mg
Second-line	MMF, MTX, AZA	Steroid-resistant or steroid-dependent cases
Third-line	Biologic agents	Adalimumab, rituximab

Treatment of SLE-associated retinal vasculitis in practice:

Kuthyar et al. (2022) introduced adalimumab 40 mg subcutaneously every other week for a case of SLE-associated retinal vasculitis that was refractory to MMF. Remission was maintained over a 27-month observation period³⁾. The therapeutic rationale is that TNF-α plays an important role in the immune pathogenesis of SLE, and involvement of NF-κB activation has been suggested³⁾. Rituximab has also been used, but severe infections have been reported in approximately 7% and infusion reactions in approximately 4% of cases³⁾.

For anticoagulation therapy in SLE complicated by APS, warfarin 2-5 mg/day (PT-INR 1.5-2) is used¹⁾. A combination of IV methylprednisolone 1 g × 5 days → oral PSL 1 mg/kg → hydroxychloroquine (HCQ) 400 mg + MMF 1 g + warfarin 5 mg has been reported¹⁾.

Cryoglobulin-associated vasculitis: A stepwise approach with steroids → antimetabolites → biologics (rituximab) is useful ²⁾.

Granulomatosis with polyangiitis: The basic treatment is a combination of steroids + CPA/MTX/AZA, and rituximab is also an option ⁶⁾.

Local Treatment

• Dexamethasone intravitreal implant (Ozurdex): Used to control local inflammation and treat cystoid macular edema ¹⁾.
• Anti-VEGF agents: Useful as local treatment for neovascularization and macular edema ¹⁾.
• Panretinal photocoagulation (PRP): Performed for extensive non-perfusion areas to promote regression of neovascularization.

Infectious Retinal Vasculitis

Anti-infective treatment is given according to the causative pathogen.

Ying et al. (2021) reported a case of vitritis and retinal vasculitis due to PRV infection treated with systemic antiviral drugs and intravitreal ganciclovir 3.0 mg + foscarnet 2.4 mg, with visual acuity improving from 0.1 to 0.3 ⁵⁾.

Surgical Treatment

Vitrectomy is indicated in cases with vitreous hemorrhage or tractional retinal detachment.

Precautions in Treatment

• Steroids should not be administered without excluding infectious retinal vasculitis, as there is a risk of exacerbating the infection.
• When using hydroxychloroquine (HCQ), retinal toxicity screening (baseline examination and regular OCT/visual field testing) is necessary ¹⁾.
• During immunosuppressive therapy, careful attention to opportunistic infections is required.

Q What to do if steroids are not effective?

A

In cases of steroid resistance or dependence, immunosuppressive drugs such as MMF, MTX, and AZA are added. If further resistance occurs, biologic agents such as adalimumab and rituximab become options. Long-term remission for 27 months with adalimumab has been reported in a SLE-related case ³⁾. Treatment selection is determined considering the underlying disease and systemic condition.

6. Pathophysiology and Detailed Pathogenesis

The central pathology of retinal vasculitis is disruption of the blood-retinal barrier (BRB).

Inflammatory cells (mainly lymphoplasmacytic cells centered on CD4+ T cells) infiltrate around blood vessels and damage the vessel wall. Expression of adhesion molecules such as E-selectin, soluble ICAM (s-ICAM), and integrins is increased, promoting leukocyte extravasation. Elevated serum levels of type I interferon-beta (IFN-β) are also observed.

Characteristic pathologies by disease are shown below.

• SLE: Deposition of immune complexes in the vessel wall → complement activation → vascular endothelial damage. TNF-α and NF-κB activation contribute to amplification of inflammation ³⁾. In cases with APS, thrombotic mechanisms are added, leading to occlusive lesions ¹⁾.
• Granulomatosis with polyangiitis: ANCA (c-ANCA/PR3-ANCA)-associated neutrophil degranulation → destructive inflammation of the vessel wall ⁶⁾.
• Infectious: Molecular mimicry (cross-reaction between pathogen antigens and self-antigens) is suggested to cause abnormal immune activation. In PRV-infected eyes, IL-6, IL-8, and VCAM in intraocular fluid are markedly elevated, reflecting the intensity of local inflammation ⁵⁾.

Occlusive vasculitis is more likely to cause severe complications such as ischemia, neovascularization, and vitreous hemorrhage compared to non-occlusive vasculitis, and has a poorer visual prognosis.

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

For patients: Please read carefully

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

Expanded Application of Biologic Agents

Kuthyar et al. (2022) reported the efficacy of adalimumab 40 mg every other week in a case of SLE-related retinal vasculitis refractory to MMF ³⁾. They demonstrated long-term remission for 27 months and noted that rituximab may also be a useful option, but careful assessment of indications is required considering the risks of serious infections (approximately 7%) and infusion reactions (approximately 4%) ³⁾.

Thomas et al. (2024) demonstrated the usefulness of a stepwise approach—steroids, antimetabolites, then biologics—in a case series of cryoglobulin-associated retinal vasculitis ²⁾. Rituximab is gaining attention as an option for refractory cases ²⁾.

Identification and treatment of rare infectious causes

Ying et al. (2021) reported a case in which PRV was identified in vitreous fluid by next-generation sequencing (NGS) ⁵⁾. NGS is powerful for detecting rare pathogens that are difficult to identify by culture or conventional PCR. They also suggested that cytokines such as IL-8 in intraocular fluid could be used as treatment monitoring markers ⁵⁾.

Advances in imaging diagnostic technology

The widespread use of ultra-widefield fluorescein angiography (UWF-FA) and OCT angiography (OCTA) has improved the early detection of peripheral retinal nonperfusion areas and the accuracy of treatment monitoring. Ultra-widefield FA has been shown to detect nonperfusion areas in more than half of patients that were not detected by conventional imaging, potentially leading to more aggressive photocoagulation therapy decisions.

ICI-associated retinal vasculitis

With the increasing use of immune checkpoint inhibitors (ICIs), case reports of ICI-associated retinal vasculitis are rising. Establishing an optimal protocol to manage ocular symptoms while maintaining the benefits of cancer treatment is a future challenge.

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8. References

1. Aldhefeery N, Alhadhood N, Alkadi A. Bilateral retinal vasculitis as initial presentation of systemic lupus erythematosus with secondary antiphospholipid syndrome. Am J Case Rep. 2023;24:e942085.
2. Thomas C, Zubair T, Monteagudo L, Lotfi-Emran S, Yamanuha J. Cryoglobulin-associated retinal vasculitis: retrospective case series. J VitreoRetinal Dis. 2024;8(2):181-185.
3. Kuthyar S, Barnes AC, Bhawal J, et al. Systemic lupus erythematosus-associated retinal vasculitis treated with adalimumab. Ocul Immunol Inflamm. 2022;30(4):981-985.
4. Rahman EZ, Beck KD, Waldman CW, Sohn JH. Unusual presentation of CREST retinal vasculitis. Am J Ophthalmol Case Rep. 2021;23:101172.
5. Ying M, Hu X, Wang M, et al. Vitritis and retinal vasculitis caused by pseudorabies virus. J Int Med Res. 2021;49(11):1-7.
6. D’Aquila ML, John VJ. Granulomatosis with polyangiitis presenting as occlusive retinal vasculitis. J VitreoRetinal Dis. 2022;6(6):467-469.