sarcoidosis

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Sarcoidosis

Definition

Sarcoidosis is a systemic granulomatous disease of unknown cause characterized by a variable clinical presentation and course. More than 90% of patients exhibit thoracic involvement with mediastinal and hilar lymph node enlargement or parenchymal lung disease, but any organ may be involved. The presentation ranges from asymptomatic disease with spontaneous resolution to organ failure and death.

Goldman-Cecil Medicine, Ch. 83

Epidemiology

Occurs worldwide; affects all racial and ethnic groups; usually presents before age 50, with peak incidence at 20-39 years
Highest incidence in Northern Europe: 5-40 per 100,000/year
In the United States, Black Americans have ~3.5x higher adjusted incidence than White Americans (35.5 vs. 10.9 per 100,000)
Black women have the highest lifetime risk: 2.7%
In Black patients: disease tends to occur later in life, peak in the 4th decade, and is more likely to be chronic and fatal
Women are affected more often across all racial/ethnic groups
Strong familial clustering: a Scandinavian registry study found an 80-fold increased risk in monozygotic twins
Low income and financial barriers to care are associated with more severe disease
Goldman-Cecil Medicine, Ch. 83

Immunopathogenesis

The noncaseating epithelioid granuloma is the histologic hallmark of sarcoidosis, forming via a stepwise process:

Step 1: Lymphocytic Alveolitis

A triggering antigen is taken up through Toll-like receptors and processed by antigen-presenting cells (type II alveolar epithelial cells, alveolar macrophages, dendritic cells) bearing MHC class II molecules. This activates alveolar macrophages to secrete chemoattractant cytokines (IL-15, IL-16) and chemokines (MCP1/CCL2, MIP-1/CCL3-4, RANTES/CCL5, IL-8/CXCL8, IP-10/CXCL10), coupled with TNF-α-, IL-1-, and IL-15-mediated upregulation of endothelial ICAM adhesion molecules. This drives marked accumulation and recruitment of CD4+ T cells from peripheral blood into the lung alveoli. An antigen-specific immune response is evidenced by oligoclonal expansion of αβ T cells with a restricted TCR repertoire (Vβ2, Vβ8, Vβ12, Vα2.3).

Candidate Antigens

Environmental substances, microbial remnants (Mycobacterium tuberculosis, Propionibacterium acnes proteins have been implicated), vimentin, and misfolded serum amyloid A.

Granuloma Formation

The noncaseating granuloma is formed by activated macrophages and CD4+ T cells. It is a protective response to isolate poorly degradable antigens. Granulomas are well-circumscribed, compact, noncaseating, of the epithelioid type, rimmed by hyaline collagen. Note: ~20% of sarcoidosis patients may show some minor necrosis on biopsy, which does not exclude the diagnosis.

Rheumatology, 2-Volume Set (Elsevier), p. 1611

Clinical Features

Sarcoidosis is a multisystem disease. The table below summarizes organ involvement:

Organ System	Prevalence (Cumulative)	Key Manifestations
Pulmonary	>90%	Restrictive/obstructive impairment, reduced DLCO, fibrocystic disease, pulmonary hypertension, bronchiectasis, cavitating nodules, aspergillomas, tracheal/bronchial stenosis
Constitutional	>50%	Fever, night sweats, malaise, fatigue, weight loss
Skin	20-30%	Chronic nodules/plaques, lupus pernio, erythema nodosum, scar granulomas, tattoo granulomas, alopecia
Ocular	20-30%	Anterior/posterior uveitis, chorioretinitis, optic neuritis, orbital inflammation
Hematologic	20-30%	Lymphadenopathy, splenomegaly, anemia, lymphopenia, hypergammaglobulinemia
Cardiac	5-20%	Arrhythmias, heart block, cardiomyopathy, sudden death, pericardial disease
Hepatic/Abdominal	10-20%	Hepatomegaly, jaundice, cirrhosis with portal hypertension, splenomegaly, abdominal lymphadenopathy
Musculoskeletal	10-20%	Arthralgia, polyarthritis, Achilles tendinitis, dactylitis, bone cysts, myopathy
Endocrine	10-20%	Hypercalcemia, hypercalciuria, diabetes insipidus, hypopituitarism
Neurologic	5-10%	Facial palsy (most common cranial neuropathy), basilar leptomeningitis, seizures, myelopathy, small fiber neuropathy
Upper respiratory tract	5-10%	Nasal congestion, sinusitis, saddle nose deformity, hoarseness, laryngeal obstruction
Renal	<10%	Renal calculi, nephrocalcinosis, granulomatous interstitial nephritis, renal failure

Fishman's Pulmonary Diseases and Disorders, p. 271; Rheumatology 2-Vol Set, p. 1614

Special Clinical Syndromes

Löfgren syndrome: Acute presentation with bilateral hilar adenopathy + erythema nodosum + arthritis (especially ankle periarthritis) + fever. Carries an excellent prognosis with spontaneous remission in most cases.
Heerfordt syndrome (uveoparotid fever): Uveitis + parotid enlargement + fever + facial nerve palsy.
Lupus pernio: Violaceous indurated plaques on nose, cheeks, ears, and lips - strongly associated with chronic fibrotic pulmonary disease and bone involvement.

Chest Radiology: Scadding Staging

The Scadding staging system classifies pulmonary sarcoidosis on plain chest X-ray:

Stage	Findings	Spontaneous Resolution Rate
0	Normal CXR	-
I	Bilateral hilar lymphadenopathy (BHL) only	~60-80%
II	BHL + pulmonary infiltrates	~50-60%
III	Pulmonary infiltrates without BHL	~30%
IV	Pulmonary fibrosis	Very low

Chest X-ray demonstrating bilateral hilar adenopathy in sarcoidosis (Stage I)

Chest X-ray demonstrating bilateral hilar adenopathy (Stage I sarcoidosis) - Rheumatology, 2-Vol Set

Airway disease (obstruction from endobronchial granulomas or bronchiolitis) occurs in ~50% and is a poor prognostic sign.

Diagnosis

Histology (Gold Standard)

Tissue biopsy showing noncaseating epithelioid granulomas after exclusion of other granulomatous diseases (TB, fungal infection, berylliosis, Crohn's, lymphoma).

Biopsy yield by site:

Transbronchial biopsy: 40% (normal CXR) to >90% (abnormal CXR)
Endobronchial/esophageal ultrasound-guided FNA of hilar/mediastinal nodes: 80-93%
Skin and peripheral lymph node biopsies: high yield when involved
BAL: not diagnostic alone, but CD4/CD8 ratio >3.5 is 94% specific, 52% sensitive

Key Labs and Tests

Serum ACE (sACE): elevated in 30-80% of active disease - not specific (also elevated in TB, fungal disease, cirrhosis, diabetes); useful for monitoring
Hypercalciuria (more common than hypercalcemia): due to macrophage/epithelioid cell conversion of 25(OH) vitamin D to 1,25(OH)₂ vitamin D
Hypercalcemia: can cause fatigue, constipation, polyuria, altered mental status
BAL: >30-60% lymphocytes; CD4/CD8 ratio >3.5

Recommended Initial Evaluation (all patients)

Chest radiograph + PFTs (spirometry, DLCO, lung volumes) + 6-minute walk
CBC, chemistry (calcium, LFTs, creatinine), urinalysis
25(OH) and 1,25(OH)₂ vitamin D levels
ECG (all patients, yearly)
Ophthalmologic exam (slit lamp + funduscopy + tonometry)
TB test (tuberculin skin test or IGRA)
Rheumatology, 2-Vol Set (ATS/ERS/WASOG guidelines)

Treatment

Indications

Not all patients require treatment. Observation for 3-6 months is appropriate for patients with:

Good prognostic signs (Löfgren syndrome, Stage I, asymptomatic Stage II-III)

Treatment is indicated for:

Progressive or symptomatic pulmonary disease (TLC decrease ≥10%, FVC decrease ≥15%, DLCO decrease ≥20%, or progressive radiographic changes)
Cardiac, neurologic, ocular (non-anterior), or hypercalcemia
Cosmetically disfiguring skin disease

Step 1: Corticosteroids (First-line)

Prednisone: 40 mg/day (≤1 mg/kg/day) for 4-6 weeks, then taper by 5-10 mg every 4-8 weeks to maintenance of 10-15 mg/day
Continue maintenance for 6-8 months (total ≥12 months before attempting to taper off)
70% respond favorably; however, relapse occurs in 25-50% after tapering or discontinuation

Step 2: Steroid-Sparing Agents (2nd line / chronic disease)

Drug	Dose
Methotrexate	15 mg/week
Mycophenolate mofetil	1-1.5 g twice daily
Azathioprine	2 mg/kg/day
Leflunomide	10-20 mg/day
Infliximab (anti-TNF)	3-5 mg/kg IV every 1-2 months
Rituximab	1000 mg x2, 2 weeks apart

Organ-Specific Considerations

Cardiac sarcoidosis: Antiarrhythmics, diuretics, afterload reduction + corticosteroids (prednisone 10-25 mg/day maintenance). ICD placement for serious arrhythmias. Anti-TNF agents as steroid-sparing.
Neurosarcoidosis/severe ocular: High-dose oral corticosteroids or IV pulse therapy, followed by maintenance. Steroid-sparing agents often needed for chronic disease. Anterior uveitis can be managed with topical steroid drops.
Pulmonary hypertension: May respond to sildenafil, bosentan, or epoprostenol.
Pregnancy: Corticosteroids only (other agents teratogenic). Spontaneous remission may occur during pregnancy, but exacerbation often follows delivery.

End-Stage Disease

Lung transplantation is an option; outcomes are comparable to other interstitial lung diseases.
Sarcoidosis recurs in the allograft in ~50% of cases, but this is usually asymptomatic and does not significantly affect outcomes.
Fishman's Pulmonary Diseases, p. 939; Rheumatology, 2-Vol Set, p. 3113-3121

Prognosis

~2/3 of patients experience spontaneous remission within 10 years
Stage I: ~60-80% spontaneous resolution
Stage IV: fibrosis is generally irreversible
Chronic/progressive disease is more common in Black patients, older age at onset, multi-organ involvement, and Stage III-IV disease
Mortality: ~1-5%; main causes are respiratory failure, cardiac arrhythmias/cardiomyopathy, and neurosarcoidosis

Recent Evidence (2025)

A 2025 systematic review and meta-analysis (PMID 40393718) published in Thorax evaluated the efficacy of biologic and targeted synthetic therapies in sarcoidosis, supporting the role of anti-TNF agents (especially infliximab) in refractory disease. This aligns with current guideline recommendations for steroid-sparing treatment.

Sources: Goldman-Cecil Medicine (26th ed., Ch. 83) | Fishman's Pulmonary Diseases and Disorders | Rheumatology, 2-Volume Set (Elsevier, 2022) | Firestein & Kelley's Textbook of Rheumatology

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