Sarcoidosis

Sarcoidosis is a multisystem disorder characterized by noncaseating granulomatous inflammation. It is classified as either acute or chronic; chronic sarcoidosis is not necessarily preceded by acute sarcoidosis. Acute sarcoidosis has an abrupt onset with constitutional symptoms (e.g., fever, malaise) as well as cough, dyspnea, anterior uveitis, erythema nodosum, and arthralgia, and it is self-limiting after a few years. Chronic sarcoidosis has an insidious onset and is often asymptomatic in its early stages. It primarily affects the lungs, although other systemic manifestations are also possible. The first symptoms of chronic sarcoidosis usually include exertional dyspnea and a dry cough with mild rales on pulmonary examination. Chest x-ray is the most appropriate initial test in a patient with suspected sarcoidosis. A chest x-ray may show parenchymal disease with bilateral hilar lymphadenopathy, but these features are not always evident. Biopsy is the gold standard for diagnosis. The most common histopathological finding is noncaseating granulomas with giant cells. Glucocorticoid therapy is indicated with disease progression or if certain organs, such as the eyes or heart, are affected. While spontaneous remission rates are high during the early stages of sarcoidosis, irreversible lung fibrosis may develop as the disease recurs or progresses.

• Peak incidence: 25–35 years old; with a second peak for females 50–65 years old ^[1]
• Sex: : ♀ > ♂ (2:1)
• Prevalence: ∼ 10 times higher among African Americans than whites ^[2]

Sarcoidosis most frequently affects young African American women in the US.

Epidemiological data refers to the US, unless otherwise specified.

The cause of sarcoidosis is still unknown. Current hypotheses suggest that the etiology is multifactorial. ^[3]

• Genetic
• Environmental agent exposure (e.g., beryllium and its salts may cause granulomas)
• Infectious agents (e.g., mycobacteria are seen as potential etiologic agents)

Sarcoidosis is a systemic disorder characterized by widespread, immune-mediated formation of noncaseating granulomas.

• T-cell dysfunction and increased B-cell activity result in local immune hyperactivity and inflammation.
• Formation of noncaseating granulomas within the lungs and the lymphatic system (see “Granulomatous inflammation” for details)
  • Macrophages activate Th1 cells.
  • Th1 cells stimulate the formation of epithelioid cells and multinucleated giant cells by releasing IFN-γ.
  • Epithelioid cells produce angiotensin-converting enzyme (ACE) and release cytokines, which recruit more immune cells.
  • A mature granuloma is composed of epithelioid cells and macrophages in the center, which are surrounded by lymphocytes and fibroblasts.
• Fibrosis and subsequent damage of organs and tissue: Epithelioid cells secrete cytokines to recruit fibroblasts, which cause fibrosis.
• Calcium dysregulation: activated macrophages produce 1-alpha hydroxylase → ↑ 1,25-dihydroxyvitamin D (hypervitaminosis D) → hyperphosphatemia, hypercalcemia, and possibly renal failure

References:^[4][5]

Acute sarcoidosis and chronic sarcoidosis are two distinct manifestations of the disease, where acute sarcoidosis does not necessarily precede chronic sarcoidosis.

Acute sarcoidosis (approx. ⅓ of cases) ^[6]

• Typically has a sudden onset and remits spontaneously within approx. 2 years
• Progression to chronic sarcoidosis is rare.
• General: fever, malaise, lack of appetite, weight loss
• Pulmonary: dyspnea, cough, chest pain
• Extrapulmonary: arthritis, anterior uveitis, erythema nodosum

Chronic sarcoidosis (approx. ⅔ of cases) ^[6]

• In rare cases, preceded by acute sarcoidosis
• Gradual disease course; may be recurrent or progressive

Pulmonary (most common) ^[7]

• Often asymptomatic in the early stages
• Interstitial fibrosis
  • Cough, exertional dyspnea
  • Mild rales on pulmonary auscultation

Extrapulmonary ^[8]

• Peripheral lymph nodes involvement: the most frequent site of extrapulmonary manifestation (∼ 40%)
• Ocular findings (∼ 25%)
  • Granulomatous uveitis
  • Blurred vision (ocular sarcoidosis)
• Skin findings (∼ 25%) ^[9]
  • Lupus pernio
    • Pathognomonic, extensive, purple skin lesions (violaceous skin plaques) on the nose, cheeks, chin, and/or ears; also referred to as epithelioid granulomas of the dermis
    • Facial rash similar to that seen in lupus
  • Scar sarcoidosis: inflamed, purple skin infiltration and elevation of old scars or tattoos
• Other manifestations
  • Musculoskeletal
    • Arthralgias/arthritis: resembles rheumatoid arthritis; usually bilateral involvement of the ankle joints
    • Bone lesions
  • Nervous system (neurosarcoidosis)
    • Cranial nerve palsy (facial nerve palsy is the most common)
    • Diabetes insipidus
    • Meningitis
    • Hypopituitarism
    • Peripheral neuropathy
    • Myopathy
  • Heart: restrictive cardiomyopathy, pericardial effusion, AV block, or even sudden cardiac death
  • Liver: hepatic granulomas; hepatomegaly in ∼ 30% of cases
  • Kidneys: most commonly related to calcium metabolism (e.g., nephrocalcinosis, nephrolithiasis)
  • Spleen: splenomegaly in ∼ 30% of cases

Features of sarcoidosis are GRUELING: Granulomas, aRthritis, Uveitis, Erythema nodosum, Lymphadenopathy, Interstitial fibrosis, Negative TB test, and Gammaglobulinemia.

Lofgren syndrome ^[10]

• Highly acute clinical presentation with fever and the following triad of symptoms
  • Migratory polyarthritis: symmetrical arthritis that primarily affects the ankles
  • Erythema nodosum: primarily affects the extensor surface of the lower legs
  • Bilateral hilar lymphadenopathy

Heerfordt syndrome ^[11]

• An atypical clinical presentation with fever and the following triad of symptoms
  • Parotitis
  • Uveitis (iridocyclitis)
  • Facial palsy

Jungling disease ^[12]

• A special form of chronic sarcoidosis
• Cystic bone lesions of the acral regions (fingers)

References:^[8][13]

A chest x-ray (which may reveal parenchymal disease with hilar lymphadenopathy) is the most appropriate initial test for a patient with suspected sarcoidosis. Laboratory tests may support the diagnosis of sarcoidosis, but a biopsy is the gold standard. Additional tests can help determine the severity of the disease, possible complications, and prognosis.

Chest x-ray

• Best initial test
• Sarcoidosis is frequently an incidental finding detected on chest x-ray
• Findings: hilar lymphadenopathy with or without bilateral reticular opacities
• Chronic sarcoidosis is categorized according to chest x-ray findings (see “Stages” above).

Patients with chronic sarcoidosis often have moderate clinical manifestations but radiographic findings of extensive disease.

High-resolution CT (HRCT) ^[14]

• Next diagnostic test if chest x-ray is suspicious or normal
• HRCT can detect parenchymal and mediastinal abnormalities such as:
  • Extensive hilar and mediastinal lymphadenopathy
  • Parenchymal masses or nodules
  • Irregular thickening of the bronchial wall and bronchovascular bundles
  • Fibrosis with traction bronchiectasis

Laboratory tests

• Acute sarcoidosis
  • ↑ Inflammatory markers
  • Findings typical for sarcoidosis are absent (e.g., ↑ ACE, ↑ IgG, ↑ calcium)
• Chronic sarcoidosis
  • ↑ Calcium due to elevated levels of 1,25-(OH)₂-vitamin D₃ (see “Pathophysiology” for mechanism)
  • ↑ ACE blood levels; : may be used to monitor disease activity and therapy
  • ↑ Inflammatory markers, possible lymphopenia
  • Soluble interleukin-2 receptor (S-IL-2R), neopterin: parameters that also correlate with disease activity ^[15]
  • ↑ Alkaline phosphatase ^[16]
  • ↓ CD4⁺ T cells: T helper cells are consumed during granuloma formation → low CD4⁺ levels in serum and high in bronchoalveolar lavage.
  • ↑ IgG (approx. 50% of patients)
  • Urine analysis: hypercalciuria

Bronchoscopy ^[8][17]

• Biopsy: the gold standard for diagnosis
  • Origin of specimen: lung tissue and lymph nodes
  • Findings
    • Noncaseating granulomas with giant cells
    • Asteroid bodies, Schaumann bodies
  • Specimens should be used for histology and culture with special stains for fungus and mycobacteria

• Bronchoalveolar lavage (BAL): increased CD4/CD8 ratio

Pulmonary function tests

• Restrictive or obstructive pattern (see “Restrictive lung disease” and “Obstructive lung disease”)

The differential diagnoses listed here are not exhaustive.

• Isolated pulmonary sarcoidosis: In most cases, no treatment is required. The disease is often asymptomatic, non‑progressive, and has a high rate of spontaneous remission.
• Symptomatic or extrapulmonary sarcoidosis ^[13]
  • First line: glucocorticoids
  • Second line: alternative immunosuppressive therapy (e.g., methotrexate or azathioprine), possibly in combination with glucocorticoids
  • Antimalarial drugs (e.g., chloroquine, hydroxychloroquine)
  • Last resort in severe pulmonary disease: lung transplantation
  • NSAIDs are always indicated for symptom relief.

• Patients with sarcoidosis have an increased risk of malignancy (especially lung cancer and malignant lymphomas)
• Pulmonary complications
  • Bronchiectasis
  • Lung fibrosis: Irreversible fibrotic remodeling together with compression of large pulmonary arteries due to bilateral hilar lymphadenopathy may increase pulmonary vascular resistance, resulting in pulmonary hypertension (PH).
• Chronic renal failure (see “Clinical features” above)

References:^[6]

We list the most important complications. The selection is not exhaustive.

• Increased calcium is associated with a poorer prognosis .
• Acute sarcoidosis: spontaneous remission in 60–70% of cases ^[21]
• 10–30% of cases may progress to chronic sarcoidosis. ^[22]
• Chronic sarcoidosis (% remission rate) ^[13]
  • Type IV: Life expectancy is limited because of severely impaired lung function.
  • Type III: approx. 20%
  • Type II: approx. 50%
  • Type I: approx. 70%

The spontaneous remission rates in acute sarcoidosis are extremely high. In chronic sarcoidosis, the remission rates vary depending on the type.