What is uveitis, how is it classified, and what are the recommended workup and treatment for a patient presenting with ocular redness, pain, photophobia, decreased vision, or floaters?

Uveitis: Definition, Classification, Workup, and Treatment

What is Uveitis?

Uveitis is inflammation of the uveal tract (iris, ciliary body, and choroid) and adjacent intraocular structures including the retina, vitreous, and optic nerve, presenting with eye redness, pain, photophobia, floaters, and blurred vision that requires urgent ophthalmologic evaluation to prevent permanent vision loss. 1, 2, 3

• The condition is a significant cause of blindness worldwide, accounting for more than 10% of severe visual handicaps in the United States 4
• Untreated uveitis leads to sight-threatening complications including cataracts, glaucoma, macular edema, retinal detachment, and optic nerve damage 3
• Uveitis predominantly affects individuals aged 20 to 50 years 3

Classification of Uveitis

Anatomic Classification

Uveitis is classified by anatomic location, which directly determines treatment approach and prognosis: 3, 5

• Anterior uveitis (41-60% of cases): Involves the iris and ciliary body 3
• Intermediate uveitis (9-15% of cases): Affects the pars plana and peripheral retina 3
• Posterior uveitis (17-23% of cases): Involves the choroid and/or retina 3
• Panuveitis (7-32% of cases): Affects all uveal layers 3

Etiologic Classification

Uveitis is divided into infectious versus noninfectious causes, with geographic variation in prevalence: 3

• In high-income countries: 11-21% are infectious (toxoplasmosis, herpes, tuberculosis, HIV) 3
• In low- and middle-income countries: 50% are infectious 3
• In the US and Europe: 27-51% are idiopathic, 37-49% are associated with systemic disease 3

Special Subtypes

Chronic anterior uveitis (CAU) in children with JIA is typically asymptomatic and insidious, requiring scheduled screening rather than symptom-based evaluation: 6, 1

• CAU develops in 10-20% of children with JIA and is usually asymptomatic with no external evidence of inflammation 6
• Acute anterior uveitis (AAU) is distinctly different: episodic, unilateral, HLA-B27 associated, with sudden onset of erythema, pain, and photophobia, and generally does not require systemic treatment 6, 5

Clinical Presentation and When to Refer

Red Flag Symptoms Requiring Urgent Ophthalmologic Referral

Visual disturbance, photophobia, or moderate to severe pain require immediate ophthalmologic referral to prevent permanent vision loss: 1, 2

• Eye pain, blurred vision, photophobia, headache, and eye redness are classical presenting features 2
• Floaters and tearing may also be present 2, 3
• When related to systemic inflammatory conditions, uveitis is frequently bilateral and insidious in onset 2

Distinguishing Uveitis from Less Serious Conditions

Episcleritis must be differentiated from uveitis as it is relatively painless with hyperemic sclera and conjunctiva, itching and burning, and no visual changes, unlike uveitis which causes true pain and visual symptoms: 1, 2

Diagnostic Workup

Initial Clinical Assessment

Document onset characteristics, laterality, recurrence pattern, age, and systemic symptoms to guide further testing: 1

• Children require JIA screening 1
• Adults over 40 with intermediate or posterior uveitis need primary ocular lymphoma evaluation 1

Essential Ophthalmologic Examination

Slit-lamp biomicroscopy by an ophthalmologist is mandatory to characterize anatomic location, inflammation type, anterior chamber cell grade, and complications such as synechiae, keratic precipitates, cataract, glaucoma, and macular edema: 1

• Disease activity is graded using Standardization of Uveitis Nomenclature (SUN) Working Group criteria for anterior chamber cells and flare 6
• Adequately controlled CAU is defined as: ≤0.5+ AC cells, topical steroids ≤2 drops/day, not on systemic steroids, and no new ocular complications for ≥3 months 6
• Uncontrolled uveitis is defined as: ≥1+ AC cells (6-15 cells/high-power field) 6

Laboratory Testing Algorithm

All patients with uveitis require syphilis serologic screening regardless of presentation due to severe consequences of missing ocular syphilis: 1

Further testing should be guided by anatomic classification: 1

• For unilateral acute anterior non-granulomatous uveitis: HLA-B27 testing 1
• For chronic uveitis: Serum angiotensin-converting enzyme and interferon-gamma release assay 1
• Complete blood count and inflammatory markers (ESR, CRP) for suspected Behçet's disease 7

Critical Pitfalls to Avoid

Avoid extensive autoimmune panels without clinical guidance, as investigations ordered without anatomic or clinical orientation are almost always unhelpful and lead to false-positive results: 1

Do not delay ophthalmologic referral for laboratory results, as permanent vision loss can occur rapidly, particularly with infectious causes or highly inflammatory disease: 1

Screen for infectious causes before initiating immunosuppressive therapy to prevent catastrophic worsening: 1

Treatment Approach

Anterior Uveitis

Topical corticosteroids are first-line treatment for anterior uveitis, with cycloplegics as adjunctive therapy: 6, 7, 3

Systemic therapy is indicated when: 6

1. Ongoing uveitis activity despite topical steroids
2. Worsening uveitis activity while on topical steroids
3. Recurrent uncontrolled disease (≥1+ AC cells) with taper of topical steroids to twice daily or less
4. Development of new ocular complications (increased intraocular pressure, hypotony, cataracts, posterior synechiae, band keratopathy, cystoid macular edema)
5. Intolerance or inability to adhere to topical corticosteroid therapy

Intermediate, Posterior, and Panuveitis

Mild intermediate uveitis may be monitored without initial treatment, but moderate to severe intermediate uveitis, posterior uveitis, and panuveitis require systemic and/or intravitreal corticosteroids and immunosuppressive agents due to high risk of sight-threatening complications: 3

Systemic Immunosuppressive Therapy Algorithm

For noninfectious uveitis requiring systemic therapy, methotrexate is first-line disease-modifying therapy: 6, 3

• Methotrexate dosing: 0.5-1 mg/kg/week (maximum 30 mg/week), with doses closer to 1 mg/kg/week preferred 6
• Both oral and subcutaneous routes are acceptable, though subcutaneous has higher bioavailability 6
• Assess efficacy after 3 months of treatment 6
• Methotrexate achieved remission in 52.1% (95% CI, 38.6%-67.1%) of patients with posterior uveitis 3

For patients who fail methotrexate after 3 months, transition to TNF inhibitor therapy (adalimumab or infliximab): 6

• For patients not intolerant of methotrexate, TNF inhibitors should be added to, rather than replace, methotrexate 6
• Adalimumab extended time to treatment failure to 24 weeks versus 13 weeks with placebo and reduced frequency of treatment failure from 78.5% to 54.5% 3

Alternative first-line option: Mycophenolate mofetil controlled inflammation in 70.9% (95% CI, 57.1%-83.5%) of patients with posterior uveitis: 3

Dose Escalation and Treatment Failure

Before changing therapy, consider treatment nonadherence, infections, and masquerade syndromes (malignancy, retinal degeneration): 6

If initial immunosuppressive therapy is inadequate, dose escalation to maximum tolerated therapeutic dose may be considered before introducing an alternative medication: 6

Treatment choice must be individualized based on patient history (e.g., hepatitis), underlying cause of uveitis, patient preference, cost, and convenience: 6

Special Considerations for JIA-Associated Uveitis

All children with JIA require ophthalmologic screening even before arthritis diagnosis is confirmed, with screening protocol based on risk factors including oligoarticular or polyarticular JIA, ANA-positive status, age, and disease duration: 1

For JIA patients who develop new uveitis while on methotrexate for arthritis, this is considered methotrexate failure and TNF inhibitor therapy should be initiated: 6

Infectious Uveitis

Infectious uveitis requires systemic antimicrobial treatment specific to the causative organism: 3

• Local or systemic steroids may be used depending on severity and specific microorganism 3
• Active inflammatory disorders associated with uveitis should be treated by the appropriate specialist (e.g., rheumatologist) 3