BASICS

DESCRIPTION

• Sarcoidosis is an idiopathic systemic inflammatory disease.

• It most commonly affects eyes, lungs, and skin.

• Up to 80% of patients have ophthalmic involvement.

• Sarcoidosis can affect any part of the eye, orbit, and adnexa.

– Sarcoidosis may only affect the eye or may affect the eye before or after systemic involvement.

– Within the eye, the anterior segment is most commonly involved (up to 70%).

– Within the orbit, the lacrimal gland is most commonly involved (up to 61%).

– Within the lungs, bilateral symmetric hilar adenopathy is the most common radiographic finding.

– Skin lesions commonly include erythema nodosum (erythematous tender subdermal nodules) and lupus pernio (purple rash on face).

EPIDEMIOLOGY

• Varies widely with geography

• Can occur in any age, but most common between 20 and 40 years, and rare after 50 years

• More prevalent in women than in men

– In North America, highest prevalence amongst African Americans: 35.5 cases per 100,000

– In World, highest prevalence amongst Northern Europeans: up to 60 cases per 100,000

– Bimodal peaks in Scandinavia: (25–29 years of age and 65–69 years of age)

RISK FACTORS

• African or Northern European extraction

• Although not definitive, environmental triggers such as pesticides and pollutants have been postulated.

Genetics

• May be familial, often minimal concordance

• Association with various HLAs and gene products is a current area of research.

• Two genomewide scans for sarcoidosis loci:

– White Germans—chromosomes 3p and 6p

– African Americans—chromosomes 5p and 5q

– Genes uncovered may be biased by populations studied.

GENERAL PREVENTION

None available

PATHOPHYSIOLOGY

• See pathological findings.

• Impetus of noncaseating granuloma formation remains unknown; likely that some nidus of inflammation, once cleared, triggers an uncontrolled inflammatory cascade.

ETIOLOGY

Unknown, see pathophysiology.

COMMONLY ASSOCIATED CONDITIONS

• Löfgren’s syndrome—arthritis, erythema nodosum, and bilateral hilar adenopathy

• Sjögren-like syndrome—keratoconjunctivitis sicca, parotid dysfunction, and lacrimal gland dysfunction

• Erythema nodosum—mostly in women

• Arthritis—rheumatoid or juvenile rheumatoid

• Heerfordt’s syndrome—parotid enlargement, anterior uveitis, and cranial nerve palsies

• Blau’s syndrome (familial juvenile systemic granulomatosis)—children may present with granulomatous arthritis, skin and eye pathology.

• Hepatitis C—it is possible interferon therapy, and not hepatitis C, is associated with sarcoidosis.

DIAGNOSIS

HISTORY

• Systemic symptoms such as fevers, chills, sweats, and weight loss

• Sarcoidosis most commonly affects the lungs, eyes, and skin. A focused history is therefore targeted toward but not limited to

– Coughing, wheezing, dyspnea, tachypnea, rashes, skin lesions, and arthritis are common systemic symptoms.

– Anterior, intermediate, or posterior uveitis: pain, photophobia, floaters, redness, and decreased vision

– Conjunctival or scleral involvement: pain, redness, pain with motility, and tearing

– Lid or skin involvement: dry and itchy eyes, and scaling skin

– Orbital muscle or soft tissue involvement: pain with motility, proptosis, diplopia, decreased vision, and ptosis

– Lacrimal gland involvement: adnexal tenderness, enlargement, and dry eyes

PHYSICAL EXAM

• Physical exam should be a thorough ophthalmologic evaluation of all aforementioned ocular anatomy.

• Visual acuity, intraocular pressure, visual fields, and extraocular motility should be documented in all patients.

• Anterior slit lamp exam includes evaluation of conjunctival nodules, conjunctivitis, episcleritis, scleritis, lacrimal gland enlargement, dry eyes, corneal edema, keratic precipitates (may be granulomatous, particularly in a triangular distribution on the inferior corneal endothelium), anterior chamber cell and flare, peripheral anterior synechiae, and posterior synechiae.

• Posterior slit lamp and indirect fundus exam should evaluate for peripheral retinal neovascularization, periphlebitis and peripheral retinal vein sheathing (candle-wax drippings), intermediate uveitis, vitritis, cystoid macular edema, optic nerve edema, and Dalen–Fuchs nodules.

• All cranial nerves should be evaluated, particularly cranial nerve VII.

• Glaucoma and cataracts may result and should be followed.

• Optic nerve infiltration should be evaluated with visual acuity, visual fields, color plates, pupillary examination, and neurology consultation to evaluate for neurosarcoidosis.

• Full physical exam should evaluate for tachypnea, arthritis, lymphadenopathy, hepatosplenomegaly, erythema nodosum (most commonly found over shins), and lupus pernio.

• Imaging and further evaluation as below.

DIAGNOSTIC TESTS & INTERPRETATION

Lab

Initial lab tests

• ACE: elevated in 60–90% of patients with active sarcoidosis. Rates tend to be higher in those with active signs and symptoms. ACE may be normal in more than 9% of subjects with active sarcoidosis, and is typically unreliable in children. Furthermore, 17% of normal patients may have elevated ACE levels, and ACE levels may be decreased in those on ACE inhibitors. Sensitivity and specificity of ACE for ophthalmic sarcoidosis range from 70% to 90% in most studies. Although widely used, the sensitivity and specificity therefore make ACE levels a less than ideal screening test.

• Kveim test: splenic tissue from sarcoidosis patient injected into skin of the subject. If granulomas result several weeks later, test is positive (rarely used any longer due to lack of sensitivity/specificity and inherent health risks).

• Thorough workup to evaluate differential diagnosis of above presenting symptoms and signs (see Differential Diagnosis: HLA-B27, rapid plasma reagin (RPR), antinuclear antibody (ANA), Lyme antibodies, rheumatoid factor (RF), ESR, and other target laboratory values may be obtained.

– Purified protein derivative (PPD) and anergy panel

– Serum and urine calcium levels, liver function tests, and serum lysozymes are of variable utility without radiographic or histologic evidence of sarcoidosis (see below), although some authors advocate their use.

Follow-up & special considerations

Pulmonary, dermatologic, or neurologic involvement should involve internal medicine, pulmonology, dermatology, and neurologic referral. Further evaluation and treatment, as below, is often performed in conjunction with healthcare practitioners in those fields.

Imaging

Initial approach

Chest X-ray: evaluate for bilateral hilar adenopathy or infiltrates.

Follow-up & special considerations

• Chest CT if X-ray irregular or nonconclusive

• MRI to evaluate neurosarcoidosis if warranted

• Visual fields obtained for optic nerve involvement

• Consider fluorescein angiogram, B-scan ultrasonography, and optical coherence tomography to further evaluate ophthalmic findings (e.g., retinal vasculitis, neovascularization, ischemia, macular edema, vitreitis, scleritis).

• Whole-body gallium scan, when combined with positive ACE, is up to 73% sensitive and 100% specific for sarcoidosis. It has been shown positive in 90% of lacrimal glands of sarcoidosis patients even without clinical changes. A “panda sign” indicates involvement of the lacrimal, parotid, and submandibular glands, and a “lambda sign” connotes perihilar and paratracheal node involvement.

Diagnostic Procedures/Other

• Biopsy is considered if lesions are accessible, and all samples should be examined for typical granulomas with negative special stains (methenamine-silver to rule out tuberculosis and fungal infections, and acid-fast to look for mycobacteria).

• Conjunctiva may be biopsied: yield of blind conjunctival biopsy is 66% in sarcoidosis patients and 80% in those with conjunctival involvement.

• Lacrimal gland biopsy in patients suspected of having lacrimal gland involvement has around a 60% yield.

• Skin lesions may be biopsied: the edges of lesions should be sampled. Erythema nodosum does not contain pathologic changes.

• Bronchoscopy with pulmonary biopsy may be performed with consideration from a pulmonologist and/or cardiothoracic surgeon. See Issues for Referral.

Pathological Findings

Noncaseating granulomas, or congregations of epithelioid cells and macrophages, with negative special stains as above.

DIFFERENTIAL DIAGNOSIS

• May entail any potential etiology of symptoms listed in history

• May entail other causes of granulomatous inflammation including mycobacterial infection as diagnosed by biopsy with special stains

– Other causes of granulomatous anterior uveitis include syphilis, tuberculosis, sympathetic ophthalmia, trauma, lens-induced iritis, and rarer autoimmune pathologies.

– Multiple sclerosis, idiopathic cases, Lyme disease, inflammatory bowel disease, toxocariasis, cat scratch disease, and tubulointerstitial nephritis and uveitis syndrome may cause intermediate uveitis.

Posterior uveitis may be secondary to white dot syndromes, syphilis, lymphoma, sympathetic ophthalmia, and Vogt–Koyanagi–Harada syndrome.

TREATMENT

MEDICATION

First Line

• Anterior uveitis: topical steroids (e.g., prednisolone acetate 1% q.i.d.), cycloplegics (e.g., atropine 1% b.i.d.) to prevent synechiae

• Posterior uveitis: systemic steroids (e.g., prednisone 20–100 mg p.o. daily) with a histamine type 2 receptor blocker or proton pump inhibitor for gastrointestinal prophylaxis. Periocular steroid injections (e.g., 1–4 mg of sub-tenon triamcinolone 40 mg/mL)

• Orbital/neurologic involvement: systemic immunosuppression, usually with corticosteroids initially

– Majority of sarcoidosis cases regress spontaneously but observation recommended.

Second Line

• High-dose NSAIDs (standard of care in the U.K.).

• Systemic immunomodulators (e.g., methotrexate, cyclosporine, hydroxychloroquine) if steroids failed or poorly tolerated, and referral to uveitis specialist is often necessary.

• Surgical debulking or radiation therapy.

• Cystoid macular edema may be treated with topical NSAIDs (e.g., ketorolac q.i.d.), topical or periocular steroids as above, or systemic immunomodulators as above.

• Orbital and central nervous system disease usually requires systemic steroids or immunomodulators as above.

• Glaucoma should be managed with topical therapy (e.g., alpha agonists such as brimonidine 0.1% or beta blockers such as timolol 0.5%), when possible, with care to avoid prostaglandin analogues (e.g., latanoprost), as they may worsen inflammation.

• Retinal neovascularization may require panretinal photocoagulation.

ADDITIONAL TREATMENT

Issues for Referral

• Referral to an internist is warranted to evaluate possible systemic involvement: studies show between 50% and 91% of patients with primary ophthalmic sarcoidosis manifest systemic signs, and that systemic sarcoidosis may often present with ophthalmic changes.

• Referral to a pulmonologist for bronchoscopy, pulmonary function testing, and biopsy may be warranted, often with the guidance of an internist.

• Immunosuppression, as indicated above, is often coordinated with a primary care practitioner.

• Optic nerve or central nervous system involvement warrants prompt neurology and neuroophthalmology consultation.

SURGERY/OTHER PROCEDURES

See second-line therapy

ONGOING CARE

FOLLOW-UP RECOMMENDATIONS

• Manage appropriately to resolution of presenting issue.

• Follow-up intervals depend on severity of inflammation, and patients are usually followed every 1–7 days.

• Steroid doses, whether topical or oral, are adjusted according to response to treatment and are tapered as clinical progress allows.

• Patients treated with oral steroids should be seen by their primary care physicians every 3–6 weeks for general exams and blood work to evaluate blood pressures and blood sugars.

• Quiescent disease is reevaluated every 3–6 months.

ADDITIONAL READING

• Iannuzz MC, Rybicki B, Teirstein AS. Sarcoidosis. N Engl J Med 2007;357:2153–2165.

• Obenauf CD, Shaw HE, Sydnor CF, Klintworth GK. Sarcoidosis and its ophthalmic manifestations. Am J Ophthalmol 1978;86(5):648–655.

• Bradley D, Baughman RP, Raymond L, Kaufman AH. Ocular manifestations of sarcoidosis. Semin Respir Crit Care Med 2002;23(6):543–548.

CODES

ICD9

• 135 Sarcoidosis

• 364.11 Chronic iridocyclitis in diseases classified elsewhere

CLINICAL PEARLS

• Sarcoidosis may affect any part of the eye and orbit and should therefore be considered in the differential of many orbital and ocular conditions.

• Anterior uveitis is the most common ophthalmic sign.

• Lacrimal gland involvement is the most common orbital sign.

• Many patients have no previous history of sarcoidosis.

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