Evaluating Non-Infectious Uveitis: A Rheumatology Perspective

Dr Neeraj Manikath , claude.ai

Abstract

Non-infectious uveitis represents a significant diagnostic and therapeutic challenge for rheumatologists and ophthalmologists alike. As a manifestation of numerous systemic autoimmune and inflammatory disorders, non-infectious uveitis requires a comprehensive approach to evaluation, diagnosis, and management. This review provides an evidence-based framework for rheumatologists to effectively assess patients with non-infectious uveitis, highlighting the importance of interdisciplinary collaboration, recent advances in diagnostic modalities, and current classification criteria. The review emphasizes a systematic approach to identify underlying systemic diseases and discusses the complexities of differentiating between various etiologies of non-infectious uveitis to guide appropriate therapeutic interventions.

Introduction

Uveitis, defined as inflammation of the uveal tract (iris, ciliary body, and choroid), represents a heterogeneous group of inflammatory ocular disorders that can lead to significant visual morbidity. While infectious etiologies account for a proportion of uveitis cases, non-infectious uveitis poses unique challenges in diagnosis and management due to its associations with systemic inflammatory disorders often falling within the rheumatologist's domain of expertise.

Non-infectious uveitis may be idiopathic or associated with systemic autoimmune conditions, including spondyloarthropathies, juvenile idiopathic arthritis, Behçet's disease, sarcoidosis, and systemic vasculitides. Given these associations, rheumatologists play a pivotal role in the evaluation and management of these patients, often working collaboratively with ophthalmologists to achieve optimal outcomes.

This review presents a comprehensive approach to evaluating non-infectious uveitis from a rheumatological perspective, emphasizing the importance of a structured assessment to identify underlying systemic inflammatory disorders and guide appropriate therapeutic interventions.

Epidemiology and Classification

Non-infectious uveitis accounts for approximately 70-90% of all uveitis cases in developed countries, with an estimated annual incidence of 17-52 cases per 100,000 person-years and a prevalence of 38-714 per 100,000 persons. The epidemiological variation reflects differences in geographic, environmental, and genetic factors influencing disease expression.

The Standardization of Uveitis Nomenclature (SUN) working group has established a classification system based on:

1. Anatomical location:

   • Anterior uveitis (iris and ciliary body)
   • Intermediate uveitis (vitreous and peripheral retina)
   • Posterior uveitis (choroid and retina)
   • Panuveitis (all three segments)

2. Disease course:

   • Acute (sudden onset, limited duration)
   • Recurrent (repeated episodes separated by periods of inactivity without treatment)
   • Chronic (persistent inflammation for >3 months despite therapy)

3. Laterality:

   • Unilateral
   • Bilateral

Understanding this classification is essential for rheumatologists, as different anatomical locations and patterns correlate with specific systemic disorders. For instance, HLA-B27-associated diseases typically present with acute anterior uveitis, while sarcoidosis more commonly manifests as granulomatous anterior, intermediate, or panuveitis.

Clinical Approach to Non-Infectious Uveitis: The Rheumatologist's Perspective

Initial Assessment

When evaluating a patient with suspected or confirmed non-infectious uveitis, rheumatologists should follow a structured approach:

1. Comprehensive history:

   • Demographics (age, sex, race, ethnicity)
   • Ocular symptoms (pain, redness, photophobia, visual changes)
   • Systemic symptoms (joint pain, back pain, skin manifestations, gastrointestinal symptoms)
   • Previous episodes of uveitis and response to treatment
   • Family history of autoimmune diseases or uveitis
   • Recent infections or travel history

2. Detailed physical examination:

   • Complete musculoskeletal examination
   • Dermatological assessment (psoriasis, erythema nodosum, etc.)
   • Oral and genital mucosal examination
   • Cardiovascular and respiratory evaluation
   • Neurological examination when indicated

3. Ophthalmological examination findings review:

   • Anterior segment findings (keratic precipitates, cells, flare)
   • Posterior segment involvement (vitritis, retinal lesions, choroiditis)
   • Complications (cataract, glaucoma, macular edema)

Laboratory and Imaging Investigations

Laboratory workup should be guided by clinical suspicion rather than employing a shotgun approach. Common investigations include:

1. Basic laboratory tests:

   • Complete blood count
   • Inflammatory markers (ESR, CRP)
   • Comprehensive metabolic panel
   • Urinalysis

2. Targeted serological testing:

   • HLA-B27 typing (when spondyloarthropathies are suspected)
   • Antinuclear antibodies and specific autoantibodies (anti-dsDNA, anti-Ro/La)
   • Complement levels
   • Angiotensin-converting enzyme (ACE) and lysozyme (for sarcoidosis)
   • Antineutrophil cytoplasmic antibodies (for vasculitis)

3. Infectious disease screening:

   • Tuberculosis screening (interferon-gamma release assay or tuberculin skin test)
   • Syphilis serology
   • Lyme disease serology in endemic areas
   • Viral hepatitis serology

4. Imaging studies:

   • Chest radiography or CT (for sarcoidosis, tuberculosis)
   • Sacroiliac joint imaging (for spondyloarthropathies)
   • MRI when neurological involvement is suspected

5. Advanced ocular imaging:

   • Optical coherence tomography (OCT)
   • Fluorescein angiography
   • Indocyanine green angiography
   • Ultrasound biomicroscopy

Specific Disease Associations and Their Ocular Manifestations

Spondyloarthropathies

Acute anterior uveitis (AAU) is the most common extra-articular manifestation of spondyloarthropathies, particularly in HLA-B27-positive individuals. Approximately 30-40% of patients with ankylosing spondylitis develop AAU during their disease course. Typical features include:

• Unilateral, sudden-onset, recurrent episodes
• Significant anterior chamber inflammation with fibrin deposition
• Alternating eye involvement between episodes
• Strong association with HLA-B27 positivity (>50% of cases)

The diagnosis of underlying spondyloarthropathy should be considered in patients with AAU, particularly when accompanied by inflammatory back pain, enthesitis, or inflammatory bowel disease. The Assessment of SpondyloArthritis International Society (ASAS) criteria should be utilized for classification.

Juvenile Idiopathic Arthritis (JIA)

Chronic anterior uveitis is a significant complication of JIA, particularly in young females with oligoarticular JIA who are antinuclear antibody (ANA)-positive. Key features include:

• Bilateral, asymptomatic, chronic anterior uveitis
• Insidious onset often preceding or occurring simultaneously with arthritis
• High risk of complications (band keratopathy, posterior synechiae, cataract)
• Requires regular ophthalmological screening according to risk stratification

Early detection through regular ophthalmological screening is crucial for preventing vision-threatening complications. Risk factors for uveitis in JIA include oligoarticular subtype, early age of onset, ANA positivity, and female gender.

Behçet's Disease

Behçet's disease can manifest with severe, recurrent panuveitis or retinal vasculitis. Ocular involvement occurs in 50-70% of patients and is characterized by:

• Bilateral, recurrent, non-granulomatous panuveitis
• Retinal vasculitis (predominantly venous)
• Hypopyon (sterile collection of neutrophils in anterior chamber)
• Retinal infiltrates and occlusive vasculitis

The diagnosis is primarily clinical, based on the International Criteria for Behçet's Disease (ICBD), which include oral aphthosis, genital aphthosis, skin lesions, ocular manifestations, vascular involvement, and positive pathergy test.

Sarcoidosis

Ocular sarcoidosis can affect any segment of the eye but commonly presents as granulomatous anterior uveitis or panuveitis. Characteristic features include:

• Bilateral, granulomatous anterior uveitis with "mutton-fat" keratic precipitates
• Iris nodules (Koeppe and Busacca nodules)
• Snowball or string-of-pearls vitreous opacities
• Segmental periphlebitis or "candle wax drippings"
• Chorioretinal granulomas

The International Workshop on Ocular Sarcoidosis (IWOS) has established diagnostic criteria including clinical signs, laboratory investigations (elevated ACE, lysozyme), chest imaging, and histopathological confirmation when possible.

Inflammatory Bowel Disease (IBD)

Uveitis in IBD (Crohn's disease and ulcerative colitis) may present as:

• Anterior uveitis (more common in Crohn's disease)
• Intermediate or panuveitis (more common in ulcerative colitis)
• Can occur independent of bowel disease activity

A comprehensive gastrointestinal assessment is warranted in patients with recurrent non-infectious uveitis, particularly when accompanied by abdominal pain, diarrhea, rectal bleeding, or unexplained weight loss.

Systemic Vasculitides

Several vasculitides can manifest with ocular inflammation:

• ANCA-associated vasculitis: scleritis, peripheral ulcerative keratitis, retinal vasculitis
• Giant cell arteritis: anterior ischemic optic neuropathy, retinal artery occlusion
• Polyarteritis nodosa: retinal vasculitis, choroiditis
• Kawasaki disease: conjunctivitis, anterior uveitis

Systemic Lupus Erythematosus (SLE)

While frank uveitis is less common in SLE, retinal vasculitis and choroidopathy can occur. The presence of antiphospholipid antibodies increases the risk of retinal vaso-occlusive disease.

Diagnostic Challenges and Approach to Undifferentiated Uveitis

Despite comprehensive evaluation, approximately 30-40% of non-infectious uveitis cases remain idiopathic. In these undifferentiated cases, a systematic approach includes:

1. Pattern recognition:

   • Correlating specific uveitis patterns with potential underlying diseases
   • Using anatomical classification to narrow differential diagnoses

2. Biomarker assessment:

   • Novel biomarkers (cytokine profiles, autoantibody panels)
   • Genetic testing in selected cases

3. Advanced imaging techniques:

   • Multimodal imaging to identify disease-specific patterns
   • OCT angiography for detailed assessment of retinal vasculature

4. Interdisciplinary consultation:

   • Close collaboration with ophthalmologists, immunologists, and infectious disease specialists
   • Multidisciplinary uveitis clinics for complex cases

Therapeutic Considerations for Rheumatologists

While detailed treatment protocols are beyond this review's scope, therapeutic decision-making should consider:

1. Treatment of underlying systemic disease:

   • Control of systemic inflammation often improves ocular manifestations
   • Disease-modifying antirheumatic drugs (DMARDs) may prevent recurrence

2. Corticosteroid therapy:

   • Topical for anterior uveitis
   • Periocular or intravitreal for intermediate or posterior uveitis
   • Systemic for bilateral, sight-threatening, or treatment-resistant disease

3. Conventional immunosuppressive agents:

   • Methotrexate, azathioprine, mycophenolate mofetil
   • Calcineurin inhibitors (cyclosporine, tacrolimus)
   • Cyclophosphamide for severe, refractory cases

4. Biologic therapy:

   • TNF-α inhibitors (adalimumab, infliximab)
   • IL-6 receptor antagonists (tocilizumab)
   • IL-1 inhibitors (anakinra, canakinumab)
   • JAK inhibitors (tofacitinib, baricitinib)

5. Collaborative monitoring:

   • Regular ophthalmological assessments
   • Monitoring for drug toxicity
   • Objective measures of treatment response (SUN criteria)

Emerging Concepts and Future Directions

Recent advances in understanding non-infectious uveitis include:

1. Immunogenetics and precision medicine:

   • HLA associations beyond HLA-B27
   • Non-HLA genetic factors (IL23R, ERAP1)
   • Pharmacogenetic markers predicting treatment response

2. Novel imaging biomarkers:

   • Quantitative assessment of choroidal thickness
   • OCT angiography for subclinical retinal vasculitis
   • Advanced image analysis with artificial intelligence

3. Targeted therapeutics:

   • Selective JAK inhibition
   • T-cell targeted therapies
   • Local drug delivery systems

4. Predictive models:

   • Risk stratification tools for uveitis development in rheumatic diseases
   • Predictors of treatment response and recurrence

Conclusion

Non-infectious uveitis represents a significant diagnostic and therapeutic challenge requiring close collaboration between rheumatologists and ophthalmologists. A systematic approach to evaluation, focusing on identifying underlying systemic inflammatory disorders, enables appropriate therapeutic interventions and improved visual outcomes.

Rheumatologists play a crucial role in this interdisciplinary approach, applying their expertise in systemic inflammatory diseases to guide diagnosis and management. As our understanding of the immunopathogenesis of non-infectious uveitis evolves, more targeted therapeutic approaches will emerge, potentially transforming the management paradigm from symptom control to disease modification and perhaps eventual cure.

Future research should focus on developing validated classification criteria for uveitis subtypes, identifying reliable biomarkers for disease activity monitoring, and establishing evidence-based treatment algorithms through randomized controlled trials comparing different immunomodulatory strategies.

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