- Clinical science
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. A chest x-ray is the most appropriate initial test in a patient with suspected sarcoidosis. An x-ray may show parenchymal disease with bilateral hilar lymphadenopathy, but these features are not always evident. A 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.
- Bimodal distribution: 25–35 years old with a second peak for females 45–65 years old
- Sex: ♀ > ♂ (2:1)
- Prevalence: 10 times higher among African Americans than whites in the US. African Americans are also more likely to have chronic and more severe disease courses.
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.
- Environmental agent exposure
- Infectious agents
Sarcoidosis is a systemic disorder characterized by widespread, immune-mediated formation of .
- T-cell dysfunction and increased B-cell activity result in local immune hyperactivity and inflammation.
Formation of within the lungs and the lymphatic system (see 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-α hydroxylase → ↑ 1,25 hydroxyvitamin D (hypervitaminosis D) → hyperphosphatemia, hypercalcemia, and possibly renal failure
Acute sarcoidosis (approx. ⅓ of cases)
- 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, ,
Chronic sarcoidosis (approx. ⅔ of cases)
- In rare cases, preceded by acute sarcoidosis
- Gradual disease course; may be recurrent or progressive
Pulmonary (most common)
- Often asymptomatic in the early stages
- Dry cough, exertional dyspnea
- Mild rales on pulmonary auscultation
- Peripheral lymph nodes are the most frequent site of extrapulmonary manifestation (40%).
- Eyes (25%): granulomatous uveitis; blurred vision (ocular sarcoidosis)
- Skin (25%)
- Other manifestations
Highly acute clinical presentation with fever and the following triad of symptoms
- Migratory polyarthritis: symmetrical arthritis that primarily affects the ankles
- : primarily affects the extensor surface of the lower legs
- Bilateral hilar lymphadenopathy
|Chronic sarcoidosis||Chest x-ray findings|
|Stage 0|| |
|Stage I|| |
Bilateral hilar lymphadenopathy (reversible)*
|Stage II|| |
Bilateral reticular or ground-glass opacities with hilar lymphadenopathy → disseminated, reticulonodular infiltrates
|Stage III|| |
Bilateral reticular or ground-glass opacities without hilar lymphadenopathy
|* In most cases, the disease resolves spontaneously at this stage.|
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.
- 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!
- Acute sarcoidosis
- ↑ Calcium due to elevated levels of 1,25-(OH)2-vitamin D3
- ↓ CD4+ T cells; : T helper cells are consumed during granuloma formation → CD4+ levels are low in serum and high in bronchoalveolar lavage.
- ↑ IgG (approx. 50% of patients)
- ↑ Angiotensin-converting enzyme (ACE) blood levels; may be used to monitor disease activity and therapy
- ↑ Inflammatory markers, possible lymphopenia
- Urine analysis: hypercalciuria
- Biopsy: the gold standard for diagnosis
- Bronchoalveolar lavage (BAL): : increased CD4+/CD8+ ratio
- Restrictive or obstructive pattern (see and )
|Differential diagnosis of granulomatous disease|
|Risk factors||Clinical presentation||Biopsy||Other laboratory findings|
| || || |
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
- First line: glucocorticoids
- Second line: alternative immunosuppressive therapy (e.g., methotrexate or azathioprine), possibly in combination with glucocorticoids
- Antimalarial drugs (e.g., , )
- 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
- (see “Clinical features” above)
We list the most important complications. The selection is not exhaustive.
- Increased calcium is associated with a poorer prognosis
- Acute sarcoidosis: spontaneous remission > 95%
Chronic sarcoidosis (% remission rate)
- Type IV: Life expectancy is limited because of severely impaired lung function.
- Type III: approx. 20%
- Type II: approx. 50%
- Type I: approx. 70%