HLA-B27, sarcoidosis, Behçet disease and VKH

HLA-B27-Associated Anterior Uveitis

Human Leukocyte Antigen B27 (HLA-B27) is a major histocompatibility complex (MHC) class I surface glycoprotein encoded on chromosome 6. Approximately 50% of all acute non-granulomatous anterior uveitis presentations are HLA-B27 positive, making it the single most common endogenous uveitic syndrome in populations of European descent.

Clinical Phenotype and Presentation

• Epidemiology: Typically presents in young adults (second to fourth decades), with a slight male preponderance among individuals with axial spondyloarthritis.
• Ocular Hallmarks:
  • Acute, explosive onset: Rapid development of severe periocular pain, intense ciliary injection, marked photophobia, lacrimation, and blurred vision.
  • Unilateral and alternating: The inflammation affects usually one eye at a time, but frequently alternates to the contralateral eye during future recurrences. Simultaneous, bilateral acute onset is exceedingly rare ($<2\%$) and should prompt immediate consideration of an alternative etiology (e.g., tubulointerstitial nephritis and uveitis [TINU] syndrome, sarcoidosis, or syphilis).
  • Heavy Fibrinous Exudate: Pronounced breakdown of the blood-aqueous barrier generates a dense, proteinaceous exudate within the anterior chamber, forming a thick fibrin coagulum across the pupil (plastic aqueous).
  • Hypopyon Formation: Present in 15% to 20% of severe attacks. Unlike the mobile hypopyon of Behçet disease, the HLA-B27 hypopyon is dense, sticky, gelatinous, and relatively fixed due to its high fibrin content.
  • Posterior Synechiae: High propensity for rapid formation of extensive 360-degree posterior synechiae, predisposing to iris bombé and acute pupillary block glaucoma.
  • Intraocular Pressure (IOP) Dynamics: IOP is characteristically subnormal initially due to severe ciliary body hyposecretion ("ciliary shock"). As inflammation resolves or if heavy fibrin clogs the trabecular meshwork, IOP may dramatically spike.

Systemic Spondyloarthropathies (SpA)

Approximately 50% of patients with HLA-B27 anterior uveitis have an underlying seronegative spondyloarthropathy:

1. Ankylosing Spondylitis (AS): The strongest association. Hallmarked by inflammatory back pain (worse at rest and early morning, improves with exercise, nocturnal waking), peripheral enthesitis (Achilles tendonitis, plantar fasciitis), progressive spinal rigidity, and bilateral sacroiliitis visible on pelvic radiography (New York criteria) or early bone marrow oedema on sacroiliac MRI.
2. Reactive Arthritis: Classically characterized by the clinical triad of urethritis/cervicitis, conjunctivitis/uveitis, and asymmetric oligoarthritis (predominantly involving weight-bearing joints of the lower extremities). Triggered by mucosal gastrointestinal (Salmonella, Shigella, Campylobacter, Yersinia) or genitourinary (Chlamydia trachomatis) infections. Mucocutaneous signs include circinate balanitis, keratoderma blennorrhagica, and painless oral aphthae.
3. Psoriatic Arthritis: Associated with cutaneous plaque psoriasis, nail dystrophies (pitting, oil-drop discoloration, onycholysis), and dactylitis ("sausage digits"). Uveitis may be insidious, bilateral, and chronic.
4. Inflammatory Bowel Disease (IBD): Associated with Crohn disease and Ulcerative Colitis. The activity of anterior uveitis frequently parallels peripheral articular arthritis flares rather than active gastrointestinal colitis flares.

Ocular Sarcoidosis

Sarcoidosis is a multisystem, idiopathic inflammatory disorder characterized pathologically by the formation of non-caseating epithelioid cell granulomas. Ocular involvement occurs in 25% to 50% of patients with systemic sarcoidosis and can affect every structure of the eye and ocular adnexa.

International Workshop on Ocular Sarcoidosis (IWOS) Diagnostic Criteria

The 2019 revised IWOS criteria use three categories after excluding other granulomatous causes:

1. Definite: Biopsy-supported sarcoidosis with compatible uveitis.
2. Presumed: No biopsy support, but bilateral hilar lymphadenopathy and at least two specified ocular signs.
3. Probable: No bilateral hilar lymphadenopathy or biopsy support, with at least three specified ocular signs and two qualifying systemic investigations.

The former possible category is not retained in the revised criteria.

Ocular Signs of Sarcoidosis (IWOS Consensus Signs)

• Anterior Segment:
  • Large, greasy, waxy "mutton-fat" keratic precipitates and/or iris nodules (Koeppe nodules at pupillary border, Busacca nodules on iris stroma).
  • Trabecular meshwork nodules and/or tent-shaped peripheral anterior synechiae (PAS).
• Intermediate and Posterior Segments:
  • Vitreous opacities presenting as inferior "snowballs" (cellular clumps) or linear aggregations resembling a "string of pearls".
  • Snowbanking over the inferior pars plana.
  • Multiple, discrete, punched-out peripheral chorioretinal lesions.
  • Retinal Periphlebitis: Segmental perivascular sheathing with nodular, yellowish-white exudates resembling candle-wax drippings ("en taches de bougie").
  • Optic disc granuloma or solitary/multiple choroidal granulomas (yellow-white, subretinal, hypofluorescent on early and late indocyanine green angiography [ICGA]).
  • Bilateral ocular involvement (present in $>80\%$ of cases).

Diagnostic Investigations in Ocular Sarcoidosis

• High-Resolution Chest CT (HRCT): Superior sensitivity to plain radiography for detecting symmetrical bilateral hilar lymphadenopathy (BHL) and subpleural micronodules.
• Serum ACE & Lysozyme: Both enzymes are secreted by activated epithelioid macrophages within granulomas; elevated in 60% to 80% of active cases. ACE activity is falsely suppressed by ACE-inhibitor anti-hypertensives.
• Tuberculin Skin Test (TST) / IGRA: Demonstrates cutaneous anergy (negative TST in $>80\%$ of sarcoidosis patients despite high population exposure) with a negative IGRA.
• Bronchoalveolar Lavage (BAL): Elevated $\text{CD4}^+:\text{CD8}^+$ T-cell ratio $>3.5$ strongly supports pulmonary sarcoidosis.

Behçet Disease

Behçet disease is a systemic, recurrent, obliterative occlusive vasculitis affecting blood vessels of all sizes (arteries and veins) with a high prevalence along the ancient "Silk Road" (Eastern Mediterranean, Middle East, Central Asia, and Japan). It is strongly genetically linked to the HLA-B51 allele (MHC Class I).

Diagnostic Criteria (International Study Group [ISG] & ICBD)

The historical 1990 International Study Group (ISG) classification requires:

• Mandatory Criterion: Recurrent oral aphthous ulcerations (observed by physician or reliably reported by patient $\ge 3\text{ times}$ within a 12-month period).
• Plus at least TWO of the following:
  1. Recurrent Genital Ulcerations: Painful, discrete aphthous ulcers occurring on the scrotum, penis, or vulva; characteristically heal with cicatricial scarring.
  2. Characteristic Eye Lesions: Anterior uveitis, posterior uveitis, retinal vasculitis, or cellular vitritis confirmed by an ophthalmologist.
  3. Characteristic Skin Lesions: Erythema nodosum-like lesions, pseudofolliculitis, papulopustular eruptions, or acneiform nodules in post-adolescent patients not receiving corticosteroids.
  4. Positive Pathergy Test: Formation of a sterile erythematous papule or pustule ($\ge 2\text{ mm}$ in diameter) 24 to 48 hours following oblique intracutaneous puncture of the forearm with a sterile 20-gauge needle.

Ocular Manifestations

The 2014 ICBD system differs: ocular lesions, oral aphthosis and genital aphthosis each score two points; skin, neurological and vascular manifestations each score one, with one additional point for a positive pathergy test when performed. A score of at least four meets the classification threshold. Oral ulceration is therefore not compulsory in that system. For example, genital aphthosis plus characteristic ocular disease totals four points without oral aphthosis. Classification supports research and clinical assessment; exclude mimics and judge the entire presentation rather than diagnosing from an isolated score. See the original international criteria study.

Ocular involvement develops in 60% to 80% of Behçet patients, typically 2 to 4 years following the onset of oral aphthae, and exhibits a significantly more aggressive and vision-threatening course in young males:

• Bilateral Non-Granulomatous Panuveitis: Explosive, recurrent attacks characterized by intense intraocular inflammation.
• The "Cold" Hypopyon: A characteristic, sometimes mobile, cellular, highly fluid and mobile hypopyon that shifts rapidly with head repositioning. It is termed "cold" because it can arise in an eye with deceptively minimal conjunctival or ciliary injection, and typically resolves spontaneously within several days.
• Occlusive Retinal Vasculitis: Affects both retinal veins and retinal arteries (diffuse obliterative arteriolitis and phlebitis):
  • Retinal branch vein and artery occlusions.
  • Diffuse retinal capillary non-perfusion, severe ischaemia, cotton-wool spots, and flame haemorrhages.
  • Optic disc and retinal neovascularisation leading to non-clearing vitreous haemorrhage and tractional retinal detachment.
  • Recurrent uncontrolled vascular inflammation can cause irreversible ischaemic macular and optic-nerve damage; early coordinated treatment and surveillance are essential.

Vogt-Koyanagi-Harada (VKH) Disease

VKH disease is a severe, bilateral, granulomatous autoimmune panuveitis targeting melanocyte-associated antigens (including tyrosinase, tyrosinase-related proteins TRP-1 and TRP-2, and MART-1/Melan-A). It characteristically affects darkly pigmented individuals (Asians, Hispanics, Native Americans, and Middle Easterners) and is strongly associated with HLA-DR4 and HLA-DRB1*0405.

The Four Clinical Phases of VKH

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Assess activity and prevent complications

In Behçet disease, recurrent occlusive retinal vasculitis requires activity assessment and systemic coordination; acuity alone can miss active peripheral disease. In VKH, choroidal activity and recurrence may require imaging even after serous fluid improves. Monitor pressure, cataract, macular oedema and steroid toxicity in both disorders. Immunomodulatory selection and monitoring are taught with posterior inflammatory patterns, and should follow the phenotype rather than a fixed escalation ladder for all patients.