Rheumatoid Arthritis and Ocular Manifestations (Dry Eye, Scleritis)

Key points of this disease

• Rheumatoid arthritis (RA) is the most common collagen disease, and approximately 25–30% of patients have some ocular complications.
• The most common ocular complication is dry eye (keratoconjunctivitis sicca), often associated with Sjögren’s syndrome.
• Scleritis is characterized by deep injection and eye pain, and necrotizing scleritis leads to poor visual prognosis.
• Peripheral corneal ulcers can rapidly progress to corneal thinning and perforation, and control of RA is fundamental to treatment.
• If necrotizing scleritis or peripheral corneal ulcer is complicated, systemic malignant rheumatoid arthritis should be suspected, and steroid pulse therapy or immunosuppressive drugs may be required.
• Close collaboration between ophthalmology and internal medicine (rheumatology) directly improves the prognosis of ocular lesions.
• Biologic agents (e.g., anti-TNF-α antibodies) are highly effective, but attention must be paid to serious side effects such as infections and tuberculosis.

1. Rheumatoid arthritis and ocular involvement

Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disease primarily affecting the synovial membrane of joints. It presents with various systemic symptoms involving the lungs, skin, eyes, and other organs, and is the most common among collagen diseases.

It commonly occurs in women aged 30–60 years, with a male-to-female ratio of approximately 1:3. In older-onset cases, the proportion of men increases. The prevalence in Japan is estimated to be about 0.5–1% of the population (approximately 600,000 to 1.2 million people).

Approximately 25–30% of RA patients have some ocular symptoms¹⁾. The frequency of ocular complications is associated with RA duration, disease activity, and the presence of extra-articular manifestations²⁾.

Classification of Ocular Complications

Ocular complications associated with RA are classified into the following five types.

Ocular complications	Frequency	Main features
Keratoconjunctivitis sicca (dry eye)	Most common	Often associated with Sjögren’s syndrome
Scleritis	Relatively common	Eye pain, deep injection, necrotizing form possible
Episcleritis	Relatively common	Superficial inflammation, tends to resolve spontaneously
Peripheral corneal ulcer	Relatively rare	Rapid corneal thinning and risk of perforation
Iridocyclitis	Rare	Anterior uveitis

Malignant rheumatoid arthritis is a severe type accompanied by scleritis, pleuritis, interstitial pneumonia, pericarditis, myocarditis, multiple mononeuritis, mesenteric artery embolism, and fingertip ulcers, and has a poor prognosis.

Q How often do patients with rheumatoid arthritis develop eye symptoms?

A

Approximately 25–30% of patients have some ocular symptoms. The most common is dry eye (keratoconjunctivitis sicca), followed by scleritis and episcleritis. Peripheral corneal ulcers and necrotizing scleritis are relatively rare but are serious complications directly affecting visual prognosis.

2. Main Symptoms and Clinical Findings

Smeller L, Toth-Molnar E, Sohar N. Optical Coherence Tomography: Focus on the Pathology of Macula in Scleritis Patients. J Clin Med. 2023;12(14):4825. Figure 1. PMID: 37510941; PMCID: PMC10381547; DOI: 10.3390/jcm12144825. License: CC BY.

An anterior segment photograph of anterior diffuse scleritis showing hyperemia and edema spreading across the entire sclera, predominantly on the temporal side of the left eye, with deep, dark red hyperemia as a characteristic finding of scleritis. This corresponds to scleritis (anterior diffuse) discussed in the section “Main Symptoms and Clinical Findings.”

Subjective Symptoms

Subjective symptoms vary depending on the type of ocular complication.

• Dry keratoconjunctivitis: dry eye sensation, foreign body sensation, photophobia, eye fatigue, visual fluctuation
• Scleritis: Severe eye pain (deep, throbbing), redness, photophobia, tearing
• Necrotizing scleritis (scleromalacia perforans): May be painless, so careful not to overlook
• Episcleritis: Regional redness, mild pain, tendency for spontaneous resolution
• Peripheral corneal ulcer: hyperemia, decreased vision, and sudden severe eye pain upon perforation

Clinical Findings (Ophthalmological Findings)

Dry Keratoconjunctivitis

Schirmer test: ≤5 mm/5 min indicates decreased secretion.

BUT (tear break-up time): ≤5 seconds indicates unstable tear film.

Fluorescein staining: Punctate epithelial keratopathy of the inferior cornea and conjunctiva.

Scleritis

Anterior diffuse: Hyperemia and edema throughout the sclera.

Anterior nodular: Forms nodules on the sclera.

Necrotizing: Central yellowish-white ischemic focus with loss of blood vessels.

Posterior scleritis: Fundus edema and T-sign (ultrasonography).

Episcleritis

Sectoral type: Fan-shaped congestion. Improves with topical NSAIDs.

Diffuse type: Widespread congestion. Often associated with RA.

Course: It may resolve spontaneously but can recur.

Peripheral Corneal Ulcer

Location: Groove-like thinning along the corneal limbus, 1–2 mm from the edge.

Progression: It expands circumferentially in a crescent shape and may rapidly lead to perforation.

Fluorescein staining: Positive fluorescein staining in the epithelial defect area.

Scleritis is classified according to the Watson classification into anterior scleritis (diffuse, nodular, necrotizing) and posterior scleritis, with necrotizing being the most severe ⁷⁾. Approximately 30–50% of patients with scleritis have an associated systemic autoimmune disease, with RA being the most common ⁵⁾.

Q When the eye is red and painful, how does scleritis differ from conjunctivitis?

A

Scleritis involves inflammation of the blood vessels in the sclera (deep layer of the white of the eye) and is accompanied by severe eye pain (deep, throbbing pain). The redness is dark red and does not easily disappear when pressure is applied to the blood vessels. Conjunctivitis presents with superficial redness that is bright red, with mild pain or a burning sensation, and the redness easily fades with pressure. If scleritis is suspected, prompt ophthalmological consultation is necessary.

3. Causes and Risk Factors

Ocular involvement in RA results from systemic vasculitis and granulomatous inflammation due to autoimmune mechanisms spreading to the scleral and corneal limbal vessels¹¹⁾.

Pathophysiology of RA and its involvement in the eye

• Autoimmune mechanism: Lymphocyte infiltration, angiogenesis, and pannus formation in the synovium lead to cartilage destruction and bone erosion.
• Inflammatory cytokines: TNF-α, IL-1β, IL-6, and IL-17 drive tissue destruction
• Ocular involvement: Deposition of immune complexes in scleral blood vessels → complement activation and vasculitis → granulomatous necrotizing inflammation
• Corneal limbus: Type III allergic reaction in the limbal vascular network → MMP (matrix metalloproteinase) production → degradation of corneal stromal collagen
• Decreased lacrimal gland function: In cases complicated by Sjögren syndrome, lymphocyte infiltration leads to reduced secretion of the lacrimal and salivary glands.

Risk Factors for Ocular Lesions

• Long duration of RA
• High titer of rheumatoid factor (RF) and positive anti-CCP antibody
• Malignant rheumatoid arthritis with extra-articular manifestations (lung, skin, nerves)
• Complication of Sjögren’s syndrome (increased risk of keratoconjunctivitis sicca)
• High disease activity (high DAS28 score)
• Smoking

Patients who develop necrotizing scleritis or peripheral corneal ulcers have been reported to have a reduced 10-year survival rate ⁸⁾, and these ocular lesions serve as indicators of systemic vasculitis activity.

4. Diagnosis and Examination Methods

Baradaran-Rafii A, et al. High magnification of AS OCT findings in peripheral ulcerative keratitis. BMC Ophthalmol. 2020;20:205. Figure 2. PMCID: PMC7249626. License: CC BY.

Anterior segment OCT image of peripheral ulcerative keratitis (PUK) showing temporal changes in corneal stromal thinning and epithelial defects during the active, healing, and healed stages. This corresponds to the examination findings and course evaluation of peripheral corneal ulcers discussed in the section “Diagnosis and Examination Methods.”

Systemic Diagnosis

The diagnosis of RA is based on the 2010 ACR/EULAR classification criteria ⁹⁾. It scores four domains: number of swollen joints, serological tests (RF, anti-CCP antibodies), symptom duration, and acute-phase reactants (CRP, ESR).

In blood tests, elevated ESR, elevated CRP, positive RF (approximately 75%; negative in about 25%), anti-CCP antibodies, and elevated MMP-3 are useful for diagnosis ⁴⁾. On X-ray, joint erosion and bone destruction in the hands and fingers are characteristic.

Ophthalmic Examination

Evaluate ocular complications using the following tests.

Examination method	Evaluation target	Criteria for findings
Schirmer test	Tear secretion volume	Decreased secretion if ≤5 mm/5 min
Tear Break-Up Time (BUT)	Tear film stability	Unstable if ≤5 seconds
Slit-lamp microscope	Sclera, cornea, anterior segment	Confirmation of necrotic changes and corneal thinning
Intraocular pressure measurement	Glaucoma / steroid response	Essential when using steroids
Fundus examination	Posterior scleritis, papilledema	Exclusion of posterior lesions
B-scan ultrasound	Posterior scleritis	T-sign (Tenon’s capsule edema)
Orbital MRI	Assessment of posterior scleritis extent	Scleral thickening and enhancement

Posterior scleritis is easily overlooked and may present with eye pain, vision loss, proptosis, and diplopia. The T-sign on B-scan ultrasound is useful for diagnosis.

Differential Diagnosis

• Infectious scleritis (herpes zoster virus, bacteria)
• ANCA-associated vasculitis (granulomatosis with polyangiitis, microscopic polyangiitis)
• Systemic lupus erythematosus (SLE)
• Relapsing polychondritis
• Sarcoidosis
• Mooren corneal ulcer (idiopathic)

In patients with scleritis, systematic evaluation including RF, ANA, ANCA, complement, and chest X-ray is recommended as a workup for systemic diseases ⁵⁾.

Q Should patients with rheumatoid arthritis also regularly visit an ophthalmologist?

A

Regular ophthalmologic examinations are strongly recommended. Early detection and treatment of scleritis and peripheral corneal ulcers are directly linked to visual prognosis. Especially during periods of high RA disease activity or in malignant RA, ophthalmologic screening is important even in the absence of symptoms. Additionally, for patients using hydroxychloroquine, regular monitoring for retinal toxicity is necessary.

5. Standard treatment

Tanveer S, Priyatha V, Tahir A, et al. Surgically-Induced Necrotizing Scleritis After Pars Plana Vitrectomy: A Case Report. Cureus. 2024;16(4):e58652. Figure 1. PMID: 38770509; PMCID: PMC11104700; DOI: 10.7759/cureus.58652. License: CC BY.

An anterior segment photograph of necrotizing scleritis showing scleral melting and black uveal exposure against a background of conjunctival and ciliary injection and tortuous scleral vessels. This corresponds to necrotizing scleritis (the most severe type with risk of scleral perforation) discussed in the section “Standard Treatment.”

Treatment of ocular lesions in RA involves both local ophthalmic treatment and systemic treatment by internal medicine (rheumatology).

Dry Keratoconjunctivitis

For mild to moderate dry keratoconjunctivitis, the following are applied stepwise.

• Artificial tear eye drops: Choose preservative-free formulations (to avoid corneal toxicity from preservatives due to long-term use).
• Sodium hyaluronate 0.1% ophthalmic solution: 5–6 times daily (corneal protection, tear stabilization)
• Punctal plug insertion: Effective for moderate to severe cases. Placement in upper and lower puncta.
• Diquafosol sodium 3% ophthalmic solution: 6 times daily. Promotes water and mucin secretion.
• Rebamipide eye drops: enhance mucin production. Useful in cases with Sjögren’s syndrome

In patients with Sjögren syndrome, dry eye tends to become severe, and the addition of cyclosporine eye drops may be considered.

Episcleritis

• NSAIDs eye drops and oral administration: Flurbiprofen eye drops, diclofenac eye drops. First-line treatment for mild cases.
• Most regional types resolve spontaneously, but in cases with repeated recurrence, evaluation of systemic disease activity should be performed.

Scleritis

Severity	Treatment options
Mild	Oral NSAIDs (diclofenac sodium 75–100 mg/day, indomethacin 75 mg/day)
Moderate	Prednisolone 0.5–1 mg/kg/day orally. Taper after response.
Severe/necrotizing	Methylprednisolone 1 g/day IV pulse therapy for 3 days + immunosuppressant
Immunosuppressive drug indicated	Cyclophosphamide (2 mg/kg/day) or azathioprine (2 mg/kg/day)
Refractory	Biologic agents such as rituximab and tocilizumab
Scleral perforation	Superficial keratoplasty and scleral grafting using preserved cornea

Nonsteroidal anti-inflammatory drugs may be effective for nodular and diffuse scleritis, but more aggressive immunosuppressive therapy is required for necrotizing scleritis⁶⁾.

Peripheral Corneal Ulcer

• Systemic control of RA: Local eye treatment alone is insufficient. Collaboration with a rheumatology department is essential.
• Corneal protection: Preservative-free eye drops, therapeutic soft contact lenses (for corneal protection)
• Surgical treatment: In cases of corneal perforation, superficial keratoplasty using preserved cornea is performed.
• Early intensification of systemic immunosuppressive therapy is important to prevent perforation¹⁰⁾

Coordination with systemic treatment

The following are applied as systemic treatment for RA⁴⁾.

DMARDs (disease-modifying antirheumatic drugs):

• Methotrexate (MTX) 6–16 mg/week is the basic drug. Folic acid co-administration reduces side effects.
• Salazosulfapyridine, Bucillamine (Rimati): Used in cases of MTX intolerance
• Use early and aggressively, aiming for DAS28 remission with a treat-to-target strategy

Biologic DMARDs:

• Anti-TNF-α antibodies: Infliximab, Adalimumab, Certolizumab, Etanercept, Golimumab
• IL-6 inhibitors: Tocilizumab (reported efficacy for scleritis)
• T-cell costimulation inhibitor: Abatacept
• Anti-CD20 antibody: Rituximab (reported efficacy in refractory scleritis)
• Be cautious of the risk of severe infections and tuberculosis reactivation. Screening is mandatory before administration¹²⁾

JAK inhibitors:

• Tofacitinib, baricitinib, upadacitinib
• Use has increased in recent years. Some reports indicate efficacy comparable to biologics.

Q How do rheumatism medications affect the eyes?

A

Steroids (such as prednisolone) carry risks of cataracts (posterior subcapsular cataracts), increased intraocular pressure, and glaucoma with long-term use, so regular ophthalmologic examinations are necessary. Paradoxical development of uveitis has been rarely reported with some biologic agents such as anti-TNF-α antibodies. Hydroxychloroquine (HCQ) can cause retinal toxicity (hydroxychloroquine retinopathy) when exceeding a certain dose, so annual ophthalmologic monitoring is recommended.

6. Pathophysiology and Detailed Pathogenesis

Systemic pathology of RA

The onset of RA involves a combination of genetic predisposition (e.g., HLA-DR4/DR1) and environmental factors (e.g., smoking, protein citrullination by periodontal pathogens). Autoantibodies against citrullinated proteins (anti-CCP antibodies) are produced and deposited in the joints as immune complexes.

In the synovium, tissue destruction progresses through the following mechanisms.

• Infiltration of T cells, B cells, and macrophages into the synovium
• Massive production of inflammatory cytokines such as TNF-α, IL-1β, IL-6, and IL-17
• Formation of pannus (thickened synovial tissue) due to angiogenesis
• Osteoclast activation → cartilage destruction and bone erosion

Mechanism of ocular involvement

Ocular lesions are a local manifestation of systemic vasculitis and immune reactions in RA ³⁾.

Mechanism of scleritis:

• Immune complex deposition in scleral vessels → complement activation → neutrophil infiltration → necrotizing vasculitis
• Granulomatous inflammation (epithelioid cells and giant cells) destroys the scleral stroma
• Scleral collagen degradation by MMP-1 and MMP-3

Mechanism of marginal corneal ulcer:

• Immune complexes deposit in the limbal plexus
• Type III hypersensitivity reaction (Arthus reaction) → stromal melting mediated by complement and neutrophils
• Collagen degradation by MMP-1, MMP-2, and MMP-9 causes rapid thinning.

Mechanism of dry keratoconjunctivitis (associated with Sjögren syndrome):

• Lymphocytes, predominantly CD4-positive T cells, infiltrate the lacrimal glands and conjunctival goblet cells
• Decreased tear secretion → keratoconjunctival epithelial damage → local production of inflammatory cytokines (IL-1β, TNF-α) in the cornea and conjunctiva → vicious cycle of epithelial damage
• Secondary decrease in mucin production and shortened tear film breakup time

Relationship between disease activity and ocular complications

Scleritis and peripheral corneal ulcers are one of the extra-articular manifestations of RA, and they worsen and remit in parallel with systemic vasculitis activity. Suppression of RA disease activity with biologic agents or immunosuppressive drugs also contributes to improvement of ocular lesions ¹⁾.

7. Latest Research and Future Prospects

For patients: Please be sure to read

The following content is based on research-stage or clinical trial reports and is not standard treatment available at general hospitals. It is reference information for professionals regarding future medical developments.

Application of Biologics to Ocular Inflammation

The efficacy of rituximab (anti-CD20 antibody) ³⁾ and tocilizumab (anti-IL-6 receptor antibody) for refractory scleritis and peripheral corneal ulcers has been reported in case reports and small-scale studies. Intensification of systemic RA treatment with biologics may contribute to improvement and suppression of recurrence of ocular complications.

Uveitis Induction by Anti-TNF-α Antibodies

Cases have been reported in which paradoxical uveitis (demyelinating uveitis-like reaction) develops during anti-TNF-α antibody administration⁴⁾. Ophthalmologic monitoring before and after administration is necessary, and when inflammation worsens, the advisability of continuing administration should be reconsidered.

JAK inhibitors and ocular inflammation

JAK inhibitors (tofacitinib, baricitinib, etc.) are becoming widely used as systemic treatments for RA, and research is progressing on their effects on ocular inflammation such as scleritis. The JAK-STAT pathway is involved in ocular inflammation mediated by IL-6 and IFN-γ signaling, and local ocular application is expected.

Corneal Bioengineering and Cell Therapy

For perforated cases of severe peripheral corneal ulcers, cell engineering approaches such as amniotic membrane transplantation, artificial cornea, and cultured corneal stromal cell transplantation have been attempted. Evaluating long-term outcomes remains a challenge.

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8. References

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