Practice Essentials
Sarcoidosis is a multisystem inflammatory disease of unknown etiology that predominantly affects the lungs and intrathoracic lymph nodes and is manifested by the presence of noncaseating granulomas (NCGs) in affected organ tissues. It is characterized by a seemingly exaggerated immune response against a difficult–to-discern antigen. [1] The age-adjusted incidence is 11 cases per 100,000 population in whites but 34 cases per 100,000 population in African Americans.
Signs and symptoms
The presentation in sarcoidosis varies with the extent and severity of organ involvement, as follows:
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Asymptomatic (incidentally detected on chest imaging): Approximately 5% of cases
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Systemic complaints (fever, anorexia): 45% of cases
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Pulmonary complaints (dyspnea on exertion, cough, chest pain, and hemoptysis [rare]): 50% of cases
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Neurosarcoidosis (cranial neuropathies, leptomeningeal disease, intraparenchymal lesions, and myelitis): 5-10% of cases [2]
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Löfgren syndrome (fever, bilateral hilar lymphadenopathy, and polyarthralgias): Common in Scandinavian patients, but uncommon in African-American and Japanese patients
Pulmonary findings on physical examination are as follows:
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Usually normal
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Crackles may be audible
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Exertional oxygen desaturation may be present
Dermatologic manifestations may include the following:
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Erythema nodosum
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A lower-extremity panniculitis with painful, erythematous nodules (often with Löfgren syndrome)
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Lupus pernio (the most specific associated cutaneous lesion)
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Violaceous rash on the cheeks or nose (common)
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Maculopapular plaques (uncommon)
Ocular involvement, which
Pathophysiology
T cells play a central role in the development of sarcoidosis, as they likely propagate an excessive cellular immune reaction. For example, there is an accumulation of CD4 cells accompanied by the release of interleukin (IL)–2 at sites of disease activity. This may manifest clinically by an inverted CD4/CD8 ratio. Pulmonary sarcoidosis is frequently characterized by a CD4+/CD8+ ratio of at least 3.5 in bronchoalveolar lavage fluid (BALF), although up to 40% of the cases present a normal or even decreased ratio, thus limiting its diagnostic value. [18] Increased production of TH1 cytokines, such as interferon, is also a feature.
Moreover, both tumor necrosis factor (TNF) and TNF receptors are increased in this disease. The importance of TNF in propagating inflammation in sarcoidosis has been demonstrated by the efficacy of anti-TNF agents, such as pentoxifylline [19] and infliximab, [12, 13] in treating this disease.
In addition to T cells, B cells also play a role. There is evidence of B cell hyperreactivity with immunoglobulin production.
Soluble HLA class I antigens levels in serum and BALF are higher in patients with sarcoidosis. These levels tend to be significantly higher in active than in inactive stages and correlate with angiotensin-converting enzyme (ACE) levels. [20]
Active sarcoidosis has also been associated with plasmatic hypergammaglobulinemia. [21] B-cell accumulation has been shown in pulmonary lesions, and a beneficial effect with anti-CD20 monoclonal antibody therapy has been reported in select patients.
Glycoprotein KL-6 and surfactant protein D (SP-D) derived from alveolar type II cells and bronchiolar epithelial cells are significantly increased in pulmonary sarcoidosis and correlate with the percentage of lymphocytes in BALF, reflecting an inflammatory response in sarcoidosis. However, there is no significant correlation between KL-6 or SP-D levels and chest radiography findings, ACE levels, or CD4/CD8 ratio in BALF. [22] KL-6 has been shown to be predictive of increased pulmonary parenchymal infiltration. [23]
A study by Facco et al suggests that Th17 cells may play a role in the pathogenesis and progression of sarcoidosis; these cells were noted to be present in the blood, BALF samples, and lung tissue from patients with sarcoidosis, particularly in those with the active form of the disease. [24]
Etiology
The cause of the disease is not known; however, both genetic and environmental factors seem to play a role. [25] As yet, no bacterial, fungal, or viral antigen has been consistently isolated from the sarcoidosis lesions. Sarcoidosis is neither a malignant nor an autoimmune disease.
Epidemiology
Frequency
United States
Incidence ranges from 5-40 cases per 100,000 population. The age-adjusted incidence for whites is 11 cases per 100,000 population. The incidence is considerably higher for African Americans, at 34 cases per 100,000 population. The prevalence is 10 times greater for African Americans than for whites. Approximately 20% of patients who are African American reported an affected family member, while only 5% of whites in the United States who have sarcoidosis state they have family members also diagnosed with sarcoidosis. African Americans seem to experience more severe and chronic disease. [26] In African Americans, siblings and parents of sarcoidosis cases have about a 2.5-fold increased risk for developing the disease.
Working on the World Trade Center (WTC) debris pile after the September 11, 2001 terrorist attacks was associated with sarcoidosis [27] (odds ratio, 9.1; 95% confidence interval, 1.1-74.0), but WTC dust cloud exposure was not (odds ratio, 1.0; 95% confidence interval, 0.4-2.8).
International
Incidence is 20 cases per 100,000 population in Sweden and 1.3 cases per 100,000 population in Japan. Sarcoidosis occurs in China, Africa, India, and other developing countries. Although its incidence may be low, the disease remains hidden and often is misdiagnosed as tuberculosis.
Race
See Frequency, United States and Mortality/Morbidity.
Sex
Male-to-female ratio is approximately 1:2. Morbidity, mortality, and extrapulmonary involvement are higher in affected females. [28]
Age
Incidence peaks in persons aged 25-35 years. A second peak occurs for women aged 45-65 years.
Prognosis
Many patients do not require therapy, and their conditions spontaneously improve. Markers for a poor prognosis include advanced chest radiography stage, extrapulmonary disease (predominantly cardiac and neurologic), and evidence of pulmonary hypertension. Multiple studies have demonstrated that the most important marker for prognosis is the initial chest radiography stage (see Table 2 below).
In one study of patients with radiographic stage IV sarcoidosis, during an average follow-up of 7 years, pulmonary hypertension was observed in 30% of cases. Long-term oxygen therapy was required in 12%. Survival was 84% at 10 yrs. Cause of death in 11% patients included refractory pulmonary hypertension, acute and chronic respiratory insufficiency, and heart sarcoidosis. Seventy-five percent of fatalities are directly attributable to respiratory causes. [29]
Table 1. Prognosis (Open Table in a new window)
Stage |
Remission (%) |
Asymptomatic at 5 y (%) |
Chest Radiograph Clearing (%) |
Mortality (%) |
Stage I |
60-90 |
95 |
54 |
0 |
Stage II |
40-70 |
58 |
31 |
11 |
Stage III |
10-20 |
25 |
10 |
18 |
Stage IV |
0 |
N/A |
0 |
N/A |
Although the rate of spontaneous remission without serious outcome has been reported as high as 82%, progression of pulmonary disease occurs in more than 10% of patients and is associated with a mortality rate of 12% to 18% within 5 years. Sarcoidosis has an overall mortality rate of approximately 7% within a 5-year follow-up period with the majority (approximately 60%) of deaths due to advanced pulmonary sarcoidosis. [30]
Functional impairment occurs in only 15-20% of patients and often resolves spontaneously. The overall mortality rate is less than 5% for untreated patients.
The likelihood of regression for pulmonary disease correlates with the extent of parenchymal disease, as noted by chest radiography stage.
According to a study by Swigris et al, the rate of sarcoidosis-related mortality in the United States appears to have increased significantly from 1988-2007, particularly in black females aged 55 years or older. This study also confirmed findings from prior reports, indicating that the underlying cause of death in most patients with sarcoidosis was the disease itself. [31]
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Stage I sarcoidosis.
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Stage II sarcoidosis.
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Stage III sarcoidosis.
Tables
Stage |
Remission (%) |
Asymptomatic at 5 y (%) |
Chest Radiograph Clearing (%) |
Mortality (%) |
Stage I |
60-90 |
95 |
54 |
0 |
Stage II |
40-70 |
58 |
31 |
11 |
Stage III |
10-20 |
25 |
10 |
18 |
Stage IV |
0 |
N/A |
0 |
N/A |
Characteristics |
Group La |
Group Sb |
P |
Dyspnea score (range 1-4) |
0.24 |
0.47 |
NS |
Fibrosis score (range 0-16) |
0.83 |
1.47 |
NS |
FEV1c (% predicted) |
95.9 |
86.9 |
0.05 |
VCd (% predicted) |
99.8 |
90.8 |
0.02 |
DLCOe (% predicted) |
84.3 |
77.7 |
NS |
Weight gain (kg) |
+3.26 |
+0.99 |
0.02 |
a Long-term steroids. b Short bursts of steroids. c Forced expiratory volume in 1 second. d Ventilatory capacity. e Diffusing capacity of lung for carbon monoxide. |
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