IgG4-related orbital inflammation

Key Points at a Glance

Key Points of This Disease

• IgG4-related ophthalmic disease (IgG4-ROD) is an ocular manifestation of a systemic disease in which fibroinflammatory lesions rich in IgG4-positive plasma cells occur in the orbit.
• Painless swelling of the lacrimal gland is the most common lesion (62–88%), often bilateral.
• First reported in Japan in 2001, it has been found that 17–60% of idiopathic orbital inflammations are IgG4-ROD.
• Histological proof of IgG4-positive plasma cells is essential for definitive diagnosis, and differentiation from MALT lymphoma is particularly important.
• First-line treatment is oral steroid tapering (prednisolone 0.6 mg/kg/day), but the recurrence rate is as high as 70%.
• Rituximab is the most effective disease-modifying drug, with a response rate of 93% and a recurrence rate of 9%.
• Systemic IgG4-RD coexists in 68% of cases, requiring multidisciplinary collaboration.

1. What is IgG4-related orbital inflammation?

IgG4-related ophthalmic disease (IgG4-ROD) is a fibroinflammatory lesion rich in IgG4-positive plasma cells that occurs in the eye and orbit, and is the orbital localized form of systemic IgG4-related disease (IgG4-RD).

IgG4-RD was first reported in Japan in 2001 as autoimmune pancreatitis with elevated serum IgG4. The orbit was the first extra-pancreatic site reported, and IgG4-related Mikulicz disease was first described in 2004.

In Japan, the most common primary orbital tumors are lymphoproliferative diseases, which include malignant lymphoma, reactive lymphoid hyperplasia, IgG4-ROD, and idiopathic orbital inflammation. Lymphoproliferative diseases alone account for 50–60% of all orbital tumors. It has been revealed that 17–60% of cases diagnosed as idiopathic orbital inflammation are actually IgG4-ROD.

IgG4-ROD shows no gender difference, the average age is approximately 55–60 years, and cases under 20 years of age are rare.

Sites of involvement in IgG4-ROD

• Lacrimal gland: 62–88%. Most common.
• Orbital fat: 28.6–40%.
• Extraocular muscles: 19–25%.
• Peritrigeminal nerve: 9.5–39%.
• Eyelids: 12%.
• Nasolacrimal system: 1.5–9.5%.

2. Main symptoms and clinical findings

Subjective symptoms

• Eyelid swelling: Due to lacrimal gland enlargement. Typically painless and slowly progressive. Often bilateral and accompanied by salivary gland swelling (Mikulicz disease).
• Proptosis: Due to swelling of extraocular muscles or orbital soft tissues.
• Diplopia: May cause restrictive strabismus due to extraocular muscle involvement. The inferior rectus is most frequently affected.
• Decreased vision and visual field defects: Due to compressive optic neuropathy.

Clinical findings (findings confirmed by physician examination)

• Lacrimal gland enlargement: Eyelid swelling with S-shaped deformity. MRI shows bilateral lacrimal gland enlargement.
• Trigeminal nerve enlargement: Mass around the supraorbital and infraorbital nerves.
• Extraocular muscle enlargement: Requires differentiation from thyroid eye disease.
• Perioptic nerve lesions: May cause optic neuropathy. Cases with high serum IgG4 (2,090 mg/dL) have been reported to cause vision loss due to optic neuropathy.

Systemic involvement is found in 68% of patients with IgG4-ROD. The most common sites are salivary glands (43%), lymph nodes (27%), and pancreas (20%).

Q How to differentiate IgG4-ROD from thyroid eye disease?

A

Both can present with extraocular muscle enlargement and proptosis. Serum IgG4 levels, thyroid function tests (T3, T4, TSH), MRI findings (T2 hypointensity in IgG4-ROD), and tissue biopsy are important for differentiation. IgG4-ROD is more likely to involve lacrimal gland enlargement, while thyroid eye disease predominantly involves enlargement of the inferior and medial rectus muscles.

3. Causes and Risk Factors

The etiology of IgG4-ROD is unknown, but abnormalities in humoral and cellular immunity are thought to be involved.

• B-cell abnormalities: The efficacy of rituximab (anti-CD20) suggests B-cell involvement.
• Th2 cytokines: Increased production of IL-4, IL-5, and IL-13 has been reported, accompanied by eosinophilia and elevated IgE.
• Antigenic stimulation: Somatic hypermutation in the lacrimal gland suggests a local immune response.

Reported risk factors include older age in men (systemic type), atopic predisposition, asthma, and allergic rhinitis. Patients with IgG4-ROD may have an increased risk of non-Hodgkin lymphoma.

Expert Supplement

Cases of IgG4-ROD developing after SARS-CoV-2 infection or vaccination have been reported, suggesting that immune dysregulation may trigger onset ²⁾.

4. Diagnosis and Examination Methods

2023 Revised Diagnostic Criteria for IgG4-ROD ¹⁾

Diagnosis is based on the following three items.

1. Imaging findings: Enlargement of the lacrimal gland, trigeminal nerve, or extraocular muscles; or mass or thickening of ocular tissues.
2. Histopathological findings: Marked lymphoplasmacytic infiltration; IgG4/IgG-positive cell ratio ≥40%, or >50 IgG4-positive cells per high-power field ¹⁾.
3. Serum IgG4: ≥135 mg/dL.

Cases meeting all three criteria are classified as “definitive,” those meeting 1 and 2 as “probable,” and those meeting 1 and 3 as “suspected” ¹⁾.

Imaging Tests

• MRI: Isointense on T1-weighted images, hypointense on T2-weighted images. Homogeneous enhancement with gadolinium.
• FDG-PET/CT: Useful for detecting distant and asymptomatic lesions.

Laboratory Tests

Serum IgG4 levels serve as a marker of treatment response, but 40% of patients with definitive IgG4-RD have normal serum IgG4. Elevated IgG4 levels can also be seen in pancreatic cancer, lymphoma, and ANCA-associated vasculitis, so specificity is limited.

Differential Diagnosis

Differentiation from MALT lymphoma is particularly important. MALT lymphoma is usually negative for IgG4 staining, but some cases are positive. IgH gene rearrangement testing is useful for differentiation.

Differential Diagnosis	Key Points for Differentiation
MALT lymphoma	IgH gene rearrangement testing
Sjögren’s syndrome	Anti-Ro/La antibodies
Sarcoidosis	ACE level, chest imaging
Granulomatosis with polyangiitis	ANCA serology
Thyroid eye disease	Thyroid function tests

5. Standard Treatment

Tissue diagnosis to exclude malignancy is mandatory before treatment.

Oral corticosteroid tapering therapy (first-line)

Prednisolone 0.6 mg/kg/day (or 30 mg/day) for 2–4 weeks induction, then taper by 10% every 2 weeks. Maintain at 10 mg/day for at least 3 months.

Initial response is excellent at 89–100%, but relapse rate during or after treatment reaches up to 70%. Continuing maintenance at 5 mg/day reduces relapse rate from 92% to 23% over 3 years.

Corticosteroid pulse therapy

Indicated when visual acuity loss or visual field defect due to optic neuropathy is severe. Solu-Cortef 500 mg/day for 3 days constitutes one course, administered for 1–3 courses.

Rituximab

Rituximab (anti-CD20 antibody) is the most effective disease-modifying drug with a response rate of 93% and relapse rate of 9%. Two 1 g intravenous infusions 14 days apart are recommended. It is not covered by insurance in Japan.

Other immunosuppressive drugs

Methotrexate, azathioprine, mycophenolate mofetil, etc. are used, but evidence is limited.

Surgical Biopsy and Decompression

Noda et al. (2021) reported a case of IgG4-ROD with intraocular pressure of 31 mmHg and visual loss, in which they performed a transcranial biopsy and orbital wall decompression, resulting in dramatic visual improvement three days postoperatively ⁴⁾. When symptoms threaten vision, surgical decompression before steroid administration is also an option.

Treatment Considerations

For lesions confined to the lacrimal gland or when systemic administration is not desirable, lacrimal gland excision or local steroid injection are options. However, leaving the lacrimal gland untreated may lead to irreversible damage and lifelong dry eye. In cases with high IgG4 levels exceeding 500 mg/dL, special attention should be paid to concurrent systemic involvement.

Q What to do if relapse occurs after steroid therapy?

A

Relapse often occurs during tapering (when prednisolone is reduced to less than 10 mg/day) or after discontinuation of steroids. Management of relapse includes re-administration of oral steroids (for 6–10 weeks) or addition of disease-modifying drugs such as rituximab. Rituximab has the lowest relapse rate at 9%.

6. Pathophysiology and Detailed Pathogenesis

The three main pathological features of IgG4-RD are as follows:

1. Dense lymphoplasmacytic infiltration
2. Storiform fibrosis
3. Obliterative phlebitis

If two of these (most commonly a combination of 1 and 2) are present, a diagnosis of IgG4-RD is made. In IgG4-ROD, T lymphocytes are observed, and storiform fibrosis may be absent in lacrimal gland lesions.

Immunohistochemistry requires IgG4-positive plasma cells ≥10/HPF (≥100/HPF for lacrimal gland disease) and an IgG4/IgG-positive cell ratio ≥40% ¹⁾.

At the center of the pathogenesis is B cell abnormality, with overproduction of Th2 cytokines (IL-4, IL-5, IL-13) leading to elevated IgG4 and IgE, and eosinophilia. Evidence of somatic hypermutation in the lacrimal gland suggests the presence of a local antigen-driven response.

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7. Latest Research and Future Perspectives (Investigational Reports)

For Patients: Please Read Carefully

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

IgG4-ROD After SARS-CoV-2 Vaccination

Zhang et al. (2024) reported cases of IgG4-ROD developing after SARS-CoV-2 vaccination. A literature review collected 9 cases, of which 5 occurred after vaccination and 4 after infection ²⁾. It is suggested that immune dysregulation may be involved in the pathogenesis of IgG4-RD.

Association with SAPHO Syndrome

Liu et al. (2025) reported a case of IgG4-ROD complicated with SAPHO syndrome. It was proposed that modulation of the TNF-α pathway may be useful for treating both diseases ³⁾.

Orbital Decompression via Transcranial Approach

Noda et al. (2021) performed transcranial biopsy via the pterygoid process and external orbital decompression in a 63-year-old man with a serum IgG4 level of 1,255 mg/dL. Visual acuity improved from 0.7 LogMAR to −0.1 LogMAR 3 days postoperatively, and intraocular pressure normalized from 31 mmHg to 15 mmHg ⁴⁾. This is noted as a new surgical option for cases with high risk of steroid therapy.

2023 Revised Diagnostic Criteria

Takahira et al. (2023) revised the diagnostic criteria for IgG4-ROD, presenting a system that classifies cases as definite, probable, or possible based on three axes: imaging findings, histopathological findings, and serum IgG4 levels ¹⁾. Strict criteria requiring 100 or more IgG4-positive cells/HPF are adopted for lacrimal gland lesions.

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8. References

1. Takahira M, Goto H, Azumi A. The 2023 revised diagnostic criteria for IgG4-related ophthalmic disease. Jpn J Ophthalmol. 2024;68:572-576.
2. Zhang P, Wu Q, Xu X, et al. A case of IgG4-related ophthalmic disease after SARS-CoV-2 vaccination: case report and literature review. Front Immunol. 2024;15:1303589.
3. Liu C, Chen T, Wang Y, et al. SAPHO syndrome complicated by IgG4-related ophthalmic disease: a case report and literature review. Front Immunol. 2025;16:1563542.
4. Noda R, Inoue T, Tsunoda S, et al. Surgical management for IgG4-related ophthalmic disease by a transcranial biopsy combined with extraorbital decompression: illustrative case. J Neurosurg Case Lessons. 2021;1(8):CASE20170.