Sarcoidosis¶

Chapter 379 | Harrison's 22e · Part 11 – Rheumatology & Immunology · Chapter 379

Key Clinical Points¶

Systemic inflammatory disease characterized by nonnecrotizing granulomatous inflammation.
Lung involvement occurs in >90% of cases; pulmonary fibrosis is the leading cause of death.
Immunopathogenesis involves a Th1 and Th17 response driven by CD4+ T cells following antigen presentation via MHC.
Diagnosis requires excluding common mimics: infections (mycobacterial, fungal), environmental exposures, and malignancy.
Glucocorticoids are the cornerstone of initial treatment for inflammation.
Steroid-sparing agents (e.g., Methotrexate, Leflunomide) or biologics (Infliximab, Adalimumab) used for refractory disease or inability to taper steroids.
High incidence in African Americans and Northern Europeans; higher risk of certain complications in women (ocular/musculoskeletal) vs men (hypercalcemia).
Risk factors include high BMI and specific occupations; smoking is associated with reduced odds of occurrence.
Clinical presentation varies widely, including cutaneous (nose/philtrum), cardiac (valvular), and pulmonary involvement.
Scadding stages are used to grade the extent of pulmonary involvement based on hilar lymphadenopathy and parenchymal involvement.

DEFINITION & CLASSIFICATION¶

• Definition: Systemic inflammatory disease of unknown cause characterized by the formation of nonnecrotizing granulomatous inflammation. • Prevalence: Affects the lung in >90% of cases; can affect almost any other organ system.

EPIDEMIOLOGY¶

• Demographics: Affects all genders, races, and ages. • Incidence & Prevalence: ◦ Varies by race, gender, geographic region, ethnicity, and season. ◦ Higher incidence in African Americans (35.5 per 100,000) and Northern Europeans (24 per 100,000). ◦ Women: Higher incidence; higher risk for erythema nodosum, ocular, musculoskeletal, and neurologic disease. ◦ Men: Earlier manifestation of disease; higher risk for hypercalcemia. • Risk Factors: ◦ Identified factors: High BMI, specific occupations, and exposures. ◦ Protective factor: Smoking is associated with reduced odds of incident sarcoidosis. • Seasonality: Predominance of diagnoses occurring in the springtime.

Mortality¶

• Rates: Vary by setting; lower in general population screenings than in referral centers. ◦ United States: Average rate 4.32 per 1,000,000 (Pulmonary fibrosis is the leading cause of death). ◦ Japan: Lower rates (~0.1 per million); mortality usually attributed to cardiac involvement.

ETIOLOGY & PATHOPHYSIOLOGY¶

• Etiology: Unknown; evidence suggests a heightened host immune response to an undetermined environmental exposure in a genetically susceptible individual. • Immunopathogenesis (Figure 379-1): 1. Antigen Presentation: APC presents unknown antigen via MHC → CD4+ T cell activation. 2. T Cell Response: Activation of CD4+ T cell leads to polarized Th1 and Th17 responses. 3. Granulomatous Inflammation: Activated lymphocytes, macrophages, and monocytes migrate to sites of inflammation → formation of tightly formed noncaseating granulomas. 4. Resolution vs. Fibrosis: Determined by the balance of pro-inflammatory signals and Regulatory Response (Treg).

Granuloma Morphology (Figure 379-2)¶

• Sarcoidosis: Tightly formed, nonnecrotizing. ◦ Differentiation: Distinct from infectious granulomas (e.g., TB/fungal) which have a necrotizing center, and hypersensitivity pneumonitis (loosely formed).

CLINICAL FEATURES¶

• Organ Involvement: ◦ Lung: >90% of cases; primary site of involvement. ◦ Skin: Cutaneous sarcoidosis (e.g., nose and philtrum involvement, Figure 379-6). ◦ Heart: Valvular heart disease (assessed via echocardiography). ◦ Musculoskeletal: Only ~1% of cases involve bones/joints/muscles (Figure 379-3). • Clinical Presentation: ◦ Highly heterogeneous; varies by clinical phenotype. ◦ Severity correlates with socioeconomic status (lower income associated with greater disability and new organ involvement).

DIFFERENTIAL DIAGNOSIS¶

Infections: ◦ Mycobacterial: Tuberculosis, Atypical mycobacteria. ◦ Fungal: Histoplasmosis, Coccidiomycosis, Blastomycosis, Aspergillosis, Cryptococcus. ◦ Parasitic: Toxoplasmosis, Schistosomiasis. ◦ Other: Herpes zoster, Tularemia (Francisella tularensis), Q fever (Coxiella burnetii), Bartonella henselae.
Environmental Exposure: ◦ Hypersensitivity pneumonitis, Aspiration pneumonitis, Chronic beryllium disease, Silicosis, Talc inhalation or injection, Local or systemic reaction to tattoo ink.
Medication-related (Sarcoid-like reactions): ◦ Immune checkpoint inhibitors, Antiretroviral therapy, Interferon, TNF-α antagonist.
Autoimmune/Inflammatory: ◦ ANCA-associated vasculitis, Granulomatous-lymphocytic interstitial lung disease (associated with common variable immunodeficiency), IgG4-related disease, Rheumatoid nodules, Inflammatory bowel disease, Bronchocentric granulomatosis.
Malignancy Related: ◦ Local granulomatous reaction surrounding tumor, Systemic sarcoid-like reaction to malignancy, Chemotherapy or immunotherapy reactions.

DIAGNOSTIC APPROACH¶

Initial Assessment: Full history, review of systems, and physical exam.
Pulmonary Function Testing (PFT): Essential for monitoring progression despite potentially normal physical exams.
Imaging: ◦ Chest imaging (e.g., Scadding stages to grade hilar lymphadenopathy/parenchymal involvement). ◦ CT: Assess subpleural distribution, bronchovascular bundle thickening, and calcified lymphadenopathy (Figure 379-5).
Specialized Exams: Eye exam (to monitor for glaucoma/cataracts) and Echocardiogram (for valvular disease).
Laboratory Studies (Table 379-2): ◦ Serum creatinine, alkaline phosphatase, calcium level. ◦ Complete blood counts. ◦ 25- and 1,25-hydroxyvitamin D levels (if assessing vitamin D metabolism).
Cardiac Assessment: Electrocardiogram.

Additional Testing¶

• Triggered Testing: Further testing is dependent upon signs or symptoms indicating potential organ involvement.

MANAGEMENT & TREATMENT¶

Initial Therapy (Table 379-3): ◦ Glucocorticoids (prednisone, prednisolone) are the cornerstone. ◦ Dosage: 20–40 mg/d initial → tapered to 7.5–15 mg/d. ◦ Considerations: Taper early based on clinical improvement; monitor bone health, weight gain, and risk of diabetes; monitor eye exams (glaucoma/cataracts).
Alternative / Steroid-Sparing Agents: ◦ Methotrexate: 7.5–20 mg/wk orally or subcutaneously. ◦ Leflunomide: 10–20 mg/d. ◦ Azathioprine: 50–200 mg/d or 1–2 mg/kg/d. ◦ Mycophenolate: 1000–3000 mg/d. ◦ Hydroxychloroquine: 200–400 mg/d.
Refractory Disease / Inability to Taper (Table 379-3): ◦ Infliximab: 3–5 mg/kg intravenously at weeks 0 and 2, then every 4–8 weeks. ◦ Adalimumab: 40 mg subcutaneous every 1–2 weeks. ◦ Precautions for Biologics: Tuberculosis screening required; avoid in heart failure; risk of demyelination syndrome and malignancy; can induce sarcoid-like reactions.

KEY PEARLS & HIGH-YIELD POINTS¶

• Key Distinction: Sarcoidosis granulomas are nonnecrotizing (unlike TB/fungal). • Primary Organ: Lung involvement >90%; pulmonary fibrosis is the leading cause of death. • Treatment Goal: Glucocorticoids for initial inflammation; use steroid-sparing agents to facilitate tapering. • Risk Factors: High BMI and specific exposures increase risk; smoking decreases risk. • Clinical Rule: Use Scadding stages to quantify pulmonary involvement via hilar lymphadenopathy.

Reference Tables¶

TABLE 379-1 Common Exclusionary Causes of Granulomatous Disease in the Diagnosis of Sarcoidosis INFECTIONS…¶

Harrison's 22e, p.2924

INFECTIONS	OTHER INFLAMMATORY DISEASES	MALIGNANCY RELATED
Mycobacterial infection • Tuberculosis • Atypical mycobacteria Fungal infection • Histoplasmosis • Coccidiomycosis • Blastomycosis • Aspergillosis • Cryptococcus Parasitic infection • Toxoplasmosis • Schistosomiasis Other bacterial and viral infection (less common) • Herpes zoster • Tularemia (Francisella tularensis) • Q fever (Coxiella burnetii) • Bartonella henselae	Environmental exposure • Hypersensitivity pneumonitis • Aspiration pneumonitis • Chronic beryllium disease • Silicosis • Talc inhalation or injection • Local or systemic reaction to tattoo ink Medication sarcoid-like reaction • Immune checkpoint inhibitors • Antiretroviral therapy • Interferon • TNF-α antagonist Autoimmune/Inflammatory • ANCA-associated vasculitis • Granulomatous-lymphocytic interstitial lung disease (associated with common variable immunodeficiency) • IgG4-related disease • Rheumatoid nodules • Inflammatory bowel disease • Bronchocentric granulomatosis	Malignancy • Local granulomatous reaction surrounding tumor • Systemic sarcoid- like reaction to malignancy Chemotherapy or immunotherapy • Sarcoid-like reaction

TABLE 379-2 Baseline Testing upon Initial Diagnosis of Sarcoidosis Full history, review of systems, physical exam…¶

Harrison's 22e, p.2924

Full history, review of systems, physical exam
Pulmonary function testing
Chest imaging
Eye exam
Serum creatinine, alkaline phosphatase, calcium level, complete blood counts
25- and 1,25-hydroxyvitamin D levels if assessing vitamin D metabolism
Electrocardiogram

TABLE 379-3 Treatments for Sarcoidosis Initial therapy¶

Harrison's 22e, p.2929

	DRUG NAME	DOSE RANGE	CONSIDERATIONS
Initial therapy	Corticosteroids (prednisone, prednisolone)	20–40 mg/d initial, tapered to 7.5–15 mg/d	Consider taper early based on clinical improvement Monitor bone health Consider implications of weight gain Assess risk of diabetes Monitor eye exams (glaucoma and cataracts)
	Methotrexate	7.5–20 mg/wk orally or subcutaneously
	Leflunomide	10–20 mg/d
	Azathioprine	50–200 mg/d or 1–2 mg/kg/d
	Mycophenolate	1000–3000 mg/d
	Hydroxychloroquine	200–400 mg/d
Refractory disease or inability to taper corticosteroids	Infliximab	3–5 mg/kg intravenously at weeks 0 and 2, and then every 4–8 weeks	Tuberculosis screening prior to use Avoid use in heart failure Allergic reactions possible with infusion Longer term association with demyelination syndrome and malignancy Can induce sarcoid-like reactions
	Adalimumab	40 mg subcutaneous every 1–2 weeks (exact dose unknown)	Similar precautions and adverse events as infliximab