Sarcoidosis

UveaGranulomatous inflammationHigh YieldAlso: Besnier-Boeck-Schaumann Disease

Key Points

•Sarcoidosis is the 'great mimicker' in uveitis — the classic finding of mutton-fat KPs with Koeppe/Busacca iris nodules strongly suggests granulomatous uveitis, with sarcoidosis being the most common non-infectious cause
•Serum ACE is elevated in 60-80% of active sarcoidosis but is neither sensitive nor specific enough to confirm or exclude the diagnosis alone
•Candle-wax drippings (taches de bougie) — segmental retinal periphlebitis — are highly characteristic of ocular sarcoidosis
•Conjunctival biopsy of visible granulomas has a high diagnostic yield and avoids the need for more invasive tissue sampling
•Lofgren syndrome (erythema nodosum + bilateral hilar lymphadenopathy + polyarthralgia) has an excellent prognosis with >95% spontaneous resolution

Hallmark Features(Granulomatous inflammation)

Non-caseating epithelioid granulomas

Bilateral hilar lymphadenopathy

Granulomatous anterior uveitis with mutton-fat KPs

Finder Clues

Granulomatous anterior uveitis (mutton-fat KPs)Iris nodules (Busacca and Koeppe)Vitritis (snowballs / string of pearls)Retinal periphlebitis (candle-wax drippings)Bilateral hilar lymphadenopathyErythema nodosumLupus pernio / skin plaques / papulesFacial nerve palsy (CN VII)

1. Definition

Sarcoidosis is a multisystem granulomatous disease of unknown etiology, characterized by the formation of non-caseating epithelioid granulomas in affected tissues. The lungs and lymph nodes are most commonly involved, but ocular involvement occurs in 25-50% of patients and may be the presenting feature. It is the great mimicker in uveitis.

2. Genetics

Genetic susceptibility:

HLA-DRB1*1101 — associated with disease susceptibility across multiple ethnicities
HLA-DRB1*0301 (HLA-DR3) — associated with acute sarcoidosis (Lofgren syndrome)
HLA-DRB1*1501 — associated with chronic disease
BTNL2 gene polymorphisms — independent risk factor
Familial clustering — first-degree relatives have a 5-fold increased risk

Epidemiological genetics:

Higher prevalence in African Americans (3x more common and more severe than Caucasians)
Scandinavian populations also have higher prevalence
Peak onset: 20-40 years; bimodal peak in women (25-35 and 45-65)

3. Pathogenesis

Sarcoidosis results from an exaggerated granulomatous immune response in genetically susceptible individuals:

Unknown antigenic trigger (proposed: mycobacterial antigens, propionibacteria, environmental agents)
Th1-dominant immune response with macrophage activation
CD4+ T-cell accumulation at sites of disease with oligoclonal expansion
Macrophages differentiate into epithelioid cells and fuse to form multinucleated giant cells
Organized into non-caseating granulomas (key distinguishing feature from tuberculosis)
Granuloma macrophages produce ACE (angiotensin-converting enzyme) — hence elevated serum ACE
TNF-alpha, IL-12, and interferon-gamma are key cytokines driving granuloma formation
Chronic disease may develop granuloma-associated fibrosis

Ocular pathogenesis:

Granulomatous infiltration of the uveal tract, lacrimal gland, conjunctiva, and optic nerve
Mutton-fat keratic precipitates represent aggregates of epithelioid cells and macrophages on the corneal endothelium

4. Clinical Features

Pulmonary (>90%):

Bilateral hilar lymphadenopathy (BHL) — hallmark finding on chest X-ray
Pulmonary infiltrates and fibrosis
Staging: Stage 0 (normal) → Stage I (BHL) → Stage II (BHL + infiltrates) → Stage III (infiltrates only) → Stage IV (fibrosis)

Ocular (25-50%):

Anterior uveitis — most common ocular manifestation
Can involve any ocular structure

Cutaneous (25-35%):

Erythema nodosum — painful red nodules on shins (marker of acute, self-limiting sarcoidosis)
Lupus pernio — violaceous plaques on nose, cheeks, ears (marker of chronic disease)
Papules, plaques, scar infiltration

Hepatic (60-80% on biopsy):

Usually subclinical; elevated alkaline phosphatase

Neurological (5-10%):

Facial nerve palsy (CN VII) — most common neurological manifestation
Optic neuropathy, aseptic meningitis, hypothalamic involvement (diabetes insipidus)

Other:

Parotid gland enlargement — Heerfordt syndrome (parotid + uveitis + facial palsy + fever)
Cardiac — conduction abnormalities, cardiomyopathy (2-5%)
Hypercalcemia — granulomas produce 1,25-dihydroxyvitamin D
Joint — acute polyarthralgia (Lofgren syndrome: BHL + erythema nodosum + polyarthralgia + fever)

5. Ocular Manifestations

Ocular involvement occurs in 25-50% of sarcoidosis patients and may be the first manifestation in up to 20%.

Anterior segment (most common):

Granulomatous anterior uveitis — mutton-fat keratic precipitates (large, greasy, yellow-white deposits on inferior corneal endothelium)
Iris nodules: Koeppe nodules (pupillary margin) and Busacca nodules (iris stroma)
Trabecular meshwork nodules (Berlin nodules)
Tent-shaped peripheral anterior synechiae (PAS)
Band keratopathy — chronic calcium deposition (from chronic uveitis and hypercalcemia)
Secondary glaucoma — from trabecular granulomas, PAS, or steroid-induced

Posterior segment:

Vitritis — snowball opacities and string of pearls vitreous organization
Retinal periphlebitis — candle-wax drippings (taches de bougie) representing segmental perivascular granulomatous infiltration
Choroidal granulomas (Dalen-Fuchs-like nodules)
Cystoid macular edema — most common cause of visual loss
Optic disc granuloma or papillitis
Retinal neovascularization (from chronic ischemia)

Adnexal:

Lacrimal gland enlargement — painless, bilateral (25%)
Conjunctival granulomas — yellowish nodules, useful biopsy target
Orbital granulomas (rare)

Neuro-ophthalmic:

Optic neuropathy — granulomatous infiltration or raised ICP
Cranial nerve palsies (III, IV, VI, VII)

6. Systemic Manifestations

Pulmonary:

Bilateral hilar lymphadenopathy — present in 50-80% at diagnosis
Progressive pulmonary fibrosis in 20%

Cutaneous:

Erythema nodosum (acute) vs. lupus pernio (chronic)
Papules, plaques, annular lesions, scar infiltration

Hepatic:

Granulomatous hepatitis in 60-80% on biopsy, but clinically evident in <10%

Neurological:

Facial nerve palsy (most common), multiple cranial neuropathies
Aseptic meningitis, mass lesions, hydrocephalus

Cardiac:

Conduction blocks (heart block), arrhythmias
Dilated cardiomyopathy — leading cause of sarcoidosis-related death in some series

Metabolic:

Hypercalcemia (10-13%) and hypercalciuria (40%)
From extrarenal production of 1,25-dihydroxyvitamin D by granulomas

Musculoskeletal:

Acute polyarthralgia (Lofgren syndrome)
Chronic arthropathy, bone cysts (dactylitis)

Heerfordt syndrome (uveoparotid fever):

Parotid enlargement + anterior uveitis + facial nerve palsy + fever

7. Diagnosis

Diagnosis requires a compatible clinical picture + histological demonstration of non-caseating granulomas + exclusion of other causes (especially tuberculosis and lymphoma).

Laboratory:

Serum ACE — elevated in 60-80% of active sarcoidosis (produced by granuloma macrophages); sensitivity 60%, specificity 70%
Serum lysozyme — elevated (less specific)
Calcium — hypercalcemia in 10-13%
24-hour urine calcium — hypercalciuria in 40%
ESR/CRP — elevated in active disease
Liver function tests — elevated ALP

Imaging:

Chest X-ray/CT — bilateral hilar lymphadenopathy, pulmonary infiltrates
Gallium-67 scan — lambda sign (bilateral hilar uptake) and panda sign (parotid/lacrimal uptake)
FDG-PET — increasingly used to assess disease activity

Histology:

Non-caseating epithelioid granulomas with Langhans giant cells
No caseation (distinguishes from TB)
Biopsy sources: conjunctival nodule, skin lesion, transbronchial biopsy, lacrimal gland, lymph node

International Workshop on Ocular Sarcoidosis (IWOS) 2009 criteria:

Definite: biopsy-proven with compatible uveitis
Presumed: BHL on chest imaging with compatible uveitis
Probable: ≥3 intraocular signs + ≥2 supportive investigations

7 suggestive intraocular signs (IWOS):

Mutton-fat KPs / iris nodules
Trabecular meshwork nodules / tent-shaped PAS
Snowball / string-of-pearls vitreous opacities
Multiple chorioretinal peripheral lesions
Nodular / segmental periphlebitis (candle-wax drippings)
Optic disc nodule / granuloma
Bilaterality

8. Differential Diagnosis

Granulomatous uveitis:

Tuberculosis — caseating granulomas (vs. non-caseating in sarcoidosis); positive tuberculin skin test/IGRA; choroidal tubercles
Syphilis — the great imitator; positive treponemal serology
VKH syndrome — bilateral granulomatous panuveitis with exudative retinal detachment; no BHL
Sympathetic ophthalmia — history of penetrating trauma to fellow eye
Lens-induced uveitis — follows cataract surgery or lens disruption

Systemic granulomatous diseases:

Tuberculosis — caseating granulomas, positive AFB, endemic exposure
Fungal infections (histoplasmosis, coccidioidomycosis)
Berylliosis — occupational exposure
Crohn disease — GI symptoms predominate

Bilateral hilar lymphadenopathy:

Lymphoma — most important differential
Tuberculosis
Fungal infections
Metastatic disease

9. Management

Ocular management:

Topical corticosteroids (prednisolone acetate 1%) — first-line for anterior uveitis
Cycloplegics — prevent posterior synechiae
Periocular/intravitreal corticosteroids — for intermediate/posterior uveitis, CME
Dexamethasone intravitreal implant (Ozurdex) — sustained release for posterior segment inflammation

Systemic immunosuppression (for chronic, bilateral, or sight-threatening disease):

Oral corticosteroids — prednisolone 0.5-1 mg/kg, then taper
Methotrexate — first-line steroid-sparing agent for ocular sarcoidosis
Mycophenolate mofetil — alternative steroid-sparing agent
Azathioprine — for maintenance
Anti-TNF agents (adalimumab, infliximab) — for refractory disease; particularly effective for posterior uveitis and neurosarcoidosis

Pulmonary/systemic:

Indications for systemic treatment: progressive pulmonary disease, cardiac sarcoidosis, neurosarcoidosis, hypercalcemia, disfiguring skin disease
Same steroid-sparing ladder as ocular disease

Monitoring:

Regular slit-lamp examination with IOP
OCT for CME monitoring
Pulmonary function tests
ECG / cardiac MRI if cardiac involvement suspected

10. Prognosis

Overall:

Two-thirds of patients have a self-limiting course resolving within 2 years
One-third develop chronic progressive disease
Mortality rate 1-5% (mainly from pulmonary fibrosis and cardiac sarcoidosis)

Ocular prognosis:

Acute anterior uveitis — generally good prognosis with prompt treatment
Chronic posterior uveitis and CME are the major causes of visual morbidity
Complications: cataract (from chronic uveitis or steroid use), glaucoma, band keratopathy, CME, optic atrophy
20-25% of patients with ocular sarcoidosis develop significant visual impairment

Prognostic patterns:

Lofgren syndrome (erythema nodosum + BHL + acute polyarthralgia) — excellent prognosis, >95% spontaneous resolution
Lupus pernio — marker of chronic, multisystem disease with poor prognosis
African American patients — tend to have more severe and chronic disease
Cardiac and neurological involvement — most serious prognostic implications

Clinical Pearls

Always examine the conjunctiva carefully in suspected sarcoidosis — conjunctival granulomas may be visible as yellowish nodules and provide an easily accessible biopsy target with high diagnostic yield

Tent-shaped peripheral anterior synechiae are highly suggestive of sarcoidosis — they form when granulomatous material in the trabecular meshwork organizes and pulls the iris forward focally

In any patient with bilateral granulomatous uveitis, order a chest X-ray as the first investigation — bilateral hilar lymphadenopathy clinches the presumed diagnosis without biopsy (IWOS criteria)

Band keratopathy in a uveitis patient should raise suspicion for sarcoidosis — it results from chronic inflammation and sarcoidosis-associated hypercalcemia

Mnemonics

SARCOID — Key Features

S—Skin lesions (erythema nodosum, lupus pernio)

A—ACE elevated / Anterior uveitis (granulomatous)

R—Restrictive lung disease / bilateral hilaR adenopathy

C—Calcium elevated (hypercalcemia)

O—Ocular granulomas (KPs, iris nodules, periphlebitis)

I—Insidious onset / Immune granulomas (non-caseating)

D—Diagnosis of exclusion (biopsy + exclude TB)

Key systemic and ocular features of sarcoidosis

GRUELS — Granulomatous Uveitis Causes

G—Granulomatosis with polyangiitis

R—(he)Rpes (HSV/VZV)

U—Uveitis (lens-induced)

E—Endophthalmitis (chronic)

L—Lyme / Leprosy

S—Sarcoidosis / Syphilis / TB

Differential diagnosis for granulomatous uveitis — sarcoidosis is the most common non-infectious cause