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 keratoconjunctivitis sicca (dry eye), often associated with Sjögren syndrome.
• Scleritis is characterized by deep injection and eye pain; necrotizing scleritis has a poor visual prognosis.
• Peripheral corneal ulcer can rapidly progress to corneal thinning and perforation; control of RA is fundamental to treatment.
• When necrotizing scleritis or peripheral corneal ulcer is present, systemic malignant rheumatoid arthritis should be suspected, and steroid pulse therapy or immunosuppressive agents may be required.
• Close collaboration between ophthalmology and internal medicine (rheumatology) directly improves the prognosis of ocular involvement.
• Biologic agents (e.g., anti-TNF-α antibodies) show high efficacy, but attention must be paid to serious side effects such as infections and tuberculosis.

1. What is 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 including the lungs, skin, and eyes, and is the most common collagen disease.

It commonly occurs in women aged 30–60 years, with a male-to-female ratio of approximately 1:3. The proportion of males increases in elderly-onset cases. 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 symptoms ¹⁾. The frequency of ocular complications is related to the duration of RA, disease activity, and the presence of extra-articular symptoms ²⁾.

Classification of Ocular Complications

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

Ocular Complication	Frequency	Main Features
Keratoconjunctivitis sicca (dry eye)	Most common	Often associated with Sjögren’s syndrome
Scleritis	Relatively common	Eye pain, deep congestion, necrotizing form possible
Episcleritis	Relatively common	Superficial inflammation, tendency 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 form 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 linked to visual prognosis.

2. Main Symptoms and Clinical Findings

Anterior segment photograph. Anterior diffuse scleritis showing extensive hyperemia and edema in the temporal sclera of the left eye

Seidel G, et al. Anterior segment picture of diffuse scleritis of the temporal part of the left eye. J Clin Med. 2023;12(14):4825. Figure 1. PMCID: PMC10381547. License: CC BY.

Anterior segment photograph of anterior diffuse scleritis with hyperemia and edema spreading over the entire sclera, mainly on the temporal side of the left eye. The dark red deep hyperemia is 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.

• Keratoconjunctivitis sicca: 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: Sectoral redness, mild pain, tendency to resolve spontaneously
• Peripheral corneal ulcer: Redness, decreased vision, sudden severe pain upon perforation

Clinical Findings (Ophthalmic Findings)

Keratoconjunctivitis Sicca

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

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

Fluorescein staining: Punctate epithelial erosions on inferior cornea and conjunctiva.

Scleritis

Anterior diffuse: Diffuse redness and edema over the entire sclera.

Anterior nodular: Nodule formation on the sclera.

Necrotizing: Central yellowish-white ischemic area with avascular appearance.

Posterior scleritis: Fundus edema, T-sign (on ultrasound).

Episcleritis

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

Diffuse type: Widespread hyperemia. Often associated with RA.

Course: May resolve spontaneously but can recur.

Peripheral Corneal Ulcer

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

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

Fluorescein staining: Positive fluorescein in epithelial defects.

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 scleritis patients have a systemic autoimmune disease, with RA being the most common ⁵⁾.

Q If the eye is red and painful, how is scleritis different 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). The redness is dark red and does not easily blanch with pressure. Conjunctivitis involves superficial redness that is bright red, with mild pain or burning sensation, and the redness easily blanches with pressure. If scleritis is suspected, prompt ophthalmologic evaluation is necessary.

3. Causes and Risk Factors

Ocular involvement in RA results from autoimmune-mediated systemic vasculitis and granulomatous inflammation spreading to the scleral and limbal vessels ¹¹⁾.

RA Pathophysiology and Ocular Involvement

• 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 periphery: Type III allergic reaction in the limbal vascular network → MMP (matrix metalloproteinase) production → degradation of corneal stromal collagen
• Lacrimal gland dysfunction: In cases with Sjögren’s syndrome, lymphocytic infiltration leads to decreased secretion of lacrimal and salivary glands

Risk factors for ocular involvement

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

AS-OCT image of peripheral corneal ulcer (PUK). High-magnification image showing three stages: active, healing, and healed

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 corneal ulcer (PUK) showing temporal changes in corneal stromal thinning and epithelial defect in three stages: active, healing, and healed. This corresponds to the examination findings and course evaluation of peripheral corneal ulcer discussed in the section “Diagnosis and examination methods.”

Systemic diagnosis

The diagnosis of RA is based on the 2010 ACR/EULAR classification criteria ⁹⁾. Four domains are scored: number of swollen joints, serological tests (RF, anti-CCP antibody), 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 antibody, 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

Ocular complications are evaluated by the following tests.

Test	Evaluation Target	Finding Criteria
Schirmer test	Tear secretion volume	≤5 mm/5 min indicates decreased secretion
Tear break-up time (BUT)	Tear film stability	≤5 seconds indicates instability
Slit-lamp microscopy	Sclera, cornea, anterior segment	Check for necrotic changes and corneal thinning
Intraocular pressure measurement	Glaucoma, steroid response	Mandatory when using steroids
Fundus examination	Posterior scleritis, papilledema	Exclude posterior lesions
B-scan ultrasound	Posterior scleritis	T-sign (Tenon’s capsule edema)
Orbital MRI	Evaluate extent of posterior scleritis	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’s corneal ulcer (idiopathic)

In patients with scleritis, systematic evaluation including RF, ANA, ANCA, complement, and chest X-ray is recommended to screen for systemic diseases⁵⁾.

Q Should patients with rheumatoid arthritis also have regular eye examinations?

A

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

5. Standard Treatment

Anterior segment photograph of necrotizing scleritis. Severe case showing conjunctival injection, scleral melting, and uveal exposure.

Krishnamurthy R, et al. Coloured anterior segment photograph showing conjunctival hyperemia, scleral melting, and exposed uveal tissue. Cureus. 2024;16(4):e58652. Figure 1. PMCID: PMC11104700. License: CC BY.

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

Treatment of ocular manifestations of RA involves both local ophthalmic therapy and systemic treatment by a rheumatologist.

Keratoconjunctivitis Sicca

For mild to moderate keratoconjunctivitis sicca, the following are applied stepwise:

• Artificial tears: Choose preservative-free formulations (to avoid corneal toxicity from preservatives with 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 ophthalmic solution: Enhances mucin production. Useful in cases with Sjögren’s syndrome.

In cases with Sjögren’s syndrome, dry eye tends to be more severe, and adding cyclosporine ophthalmic solution may be considered.

Episcleritis

• NSAIDs eye drops and oral: Flurbiprofen eye drops, diclofenac eye drops. First-line for mild cases.
• Most cases of sectoral episcleritis resolve spontaneously, but in recurrent cases, 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 for 3 days + immunosuppressant
Indication for immunosuppressants	Cyclophosphamide (2 mg/kg/day) or azathioprine (2 mg/kg/day)
Refractory	Biologics such as rituximab and tocilizumab
Scleral perforation	Lamellar keratoplasty or scleral graft 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 ocular treatment alone is insufficient. Collaboration with rheumatology is essential.
• Corneal protection: Preservative-free eye drops and therapeutic soft contact lenses (for corneal protection).
• Surgical treatment: For corneal perforation, lamellar keratoplasty using preserved cornea is performed.
• Early intensification of systemic immunosuppressive therapy is important to prevent perforation¹⁰⁾.

Coordination with systemic treatment

The following systemic treatments are applied for RA⁴⁾.

DMARDs (disease-modifying antirheumatic drugs):

• Methotrexate (MTX) 6–16 mg/week is the basic drug. Folic acid is used concomitantly to reduce side effects.
• Sulfasalazine, bucillamine (Rimatil): Used for patients intolerant to MTX.
• Used aggressively from an early stage, 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 for refractory scleritis).
• Caution for serious infections and tuberculosis reactivation risk. Screening is mandatory before administration¹²⁾.

JAK inhibitors:

• Tofacitinib, baricitinib, upadacitinib.
• Use has increased in recent years. Reports show efficacy comparable to biologic agents.

Q How do rheumatoid arthritis medications affect the eyes?

A

Steroids (prednisolone, etc.) carry risks of cataract (posterior subcapsular cataract), increased intraocular pressure, and glaucoma with long-term use, so regular ophthalmologic examinations are necessary. Some biologic agents such as anti-TNF-α antibodies have rarely been reported to cause paradoxical uveitis. 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 Pathophysiology of RA

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

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 leading to cartilage destruction and bone erosion

Mechanisms of Ocular Involvement

Ocular manifestations are local expressions 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, giant cells) destroys the scleral stroma
• Degradation of scleral collagen by MMP-1 and MMP-3

Mechanism of marginal corneal ulcer:

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

Mechanism of keratoconjunctivitis sicca (associated with Sjögren’s syndrome):

• Infiltration of lymphocytes, predominantly CD4-positive T cells, into the lacrimal gland and conjunctival goblet cells
• Decreased tear secretion → corneal and conjunctival 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 breakup time

Relationship between disease activity and ocular complications

Scleritis and peripheral corneal ulcer are extra-articular manifestations of RA, and their exacerbation and remission parallel systemic vasculitis activity. Suppression of RA disease activity with biologics or immunosuppressants also contributes to improvement of ocular lesions¹⁾.

7. Latest research and future perspectives

For patients: Please read

The following content is based on reports from research or clinical trial stages 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 ulcer has been reported in case reports and small studies. Intensification of systemic RA treatment with biologics may contribute to improvement and prevention of recurrence of ocular complications.

Uveitis Induced by Anti-TNF-α Antibodies

Cases of paradoxical uveitis (demyelinating uveitis-like reaction) occurring during anti-TNF-α antibody administration have been reported ⁴⁾. Ophthalmologic monitoring before and after administration is necessary, and when inflammation worsens, the continuation of 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 on their effects on ocular inflammation such as scleritis is progressing. 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 cases of severe peripheral corneal ulcer perforation, cell engineering approaches such as amniotic membrane transplantation, artificial cornea, and cultured corneal stromal cell transplantation have been attempted. Evaluation of long-term outcomes remains a challenge.

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8. References

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3. Artifoni M, Rothschild PR, Brézin A, et al. Ocular inflammatory diseases associated with rheumatoid arthritis. Nat Rev Rheumatol. 2014;10(2):108-116.

4. 日本リウマチ学会 編. 関節リウマチ診療ガイドライン2020. メディカルレビュー社; 2021.

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12. Bongartz T, Sutton AJ, Sweeting MJ, et al. Anti-TNF antibody therapy in rheumatoid arthritis and the risk of serious infections and malignancies. JAMA. 2006;295(19):2275-2285.