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Sarcoidosis is a multisystem disease of unknown etiology that is characterized
by the presence of noncaseating granulomas in various tissues. Any organ
system may be affected. Most patients are asymptomatic and come to medical attention because of unrelated respiratory symptoms. Most of
those asymptomatic patients are recognized through a chest radiograph abnormality. Fewer than 5% of patients who have
sarcoidosis have a normal chest radiograph. Furthermore, the morbidity and mortality that are
associated with sarcoidosis result most often from pulmonary involvement. Sarcoidosis is
primarily a respiratory tract disorder that may also have features of extrapulmonary
disease.
Many infectious and noninfectious conditions are associated with granuloma formation
and a histopathologic picture indistinguishable from that of sarcoidosis. Thus, diagnosis of
sarcoidoses requires the exclusion of other causes of granuloma formation. Berylliosis and
histoplasmosis, for example, can have clinicopathologic features identical to those of
sarcoidosis.
Epidemiology
Sarcoidosis occurs worldwide among all ethnic groups, but there are striking regional and
ethnic differences in its incidence and prevalence. For example, in the United States,
sarcoidosis is 10 times more common among blacks than among whites and tends to be more
severe in black patients. However, this increased prevalence is not observed among blacks in
Pathogenesis
A specific sequence of events leads to granuloma formation in sarcoidosis.
Expansion of the helper T cell population in the lungs likely occurs through the activation of
T cells by macrophages via interleuken-1 (IL-1) and the subsequent release of IL-2
(also termed T cell growth factor) by the helper T cell. IL-2 causes self-replication of the
existing T cell population. This population of helper T cells, which are greatly increased in
number and in degree of activity, recruits monocytes from peripheral blood into the lung by
Clinical Manifestations of Intrathoracic Sarcoidosis
The most common manifestations of intrathoracic sarcoidosis are bilateral hilar
lymphadenopathy and diffuse infiltrative lung disease. A staging system has been created
on the basis of the presence or absence of these two manifestations on radiography: stage I,
bilateral hilar lymphadenopathy alone; stage II, bilateral hilar lymphadenopathy and diffuse
infiltrative lung disease; and stage III, diffuse infiltrative lung disease alone.
Symptoms resulting from parenchymal lung involvement include dyspnea and cough.
Pulmonary function abnormalities are found in nearly all symptomatic patients and in some
patients who are asymptomatic. Physiologic abnormalities in patients with symptomatic
sarcoidosis typically consist of a reduction in Dlco and vital capacity without airflow
obstruction. The Dlco typically becomes abnormal before the vital capacity, but both
measurements are usually affected in persons with moderate to severe symptoms. Airflow
obstruction is relatively uncommon, except in patients with advanced disease or with
endobronchial involvement of larger airways. In rare instances, diffuse endobronchial
granulomas in small airways lead to a predominantly obstructive abnormality in patients who
present with stage I disease.
Most patients with stage I sarcoidosis are asymptomatic, and the abnormality is detected
on a routine chest radiograph. When stage I disease is symptomatic, the symptoms are
nonpulmonary in nature and consist of systemic complaints of fever, malaise, arthralgia, or
erythema nodosum. The presence of fever, bilateral hilar lymphadenopathy, arthralgia or
arthritis, and erythema nodosum is known as Löfgren’s syndrome. Approximately 10% of
The frequency of symptoms is higher in patients with stage II sarcoidosis, but
asymptomatic cases are not unusual. Symptoms may be primarily systemic, as in stage I
disease, or may arise from pulmonary involvement. A presentation of extensive radiographic
abnormalities associated with only minimal respiratory symptoms is not uncommon. Roughly
50% of patients with stage II sarcoidosis will be in remission 2 years after presentation. Stage
II disease is more likely to be progressive and to follow a chronic symptomatic course than
stage I disease.
Stage III disease is found at presentation in 5% to 15% of patients. Respiratory symptoms
are common, but as in stage II disease, the chest radiograph may make the patient appear
Clinical Manifestations of Extrathoracic Sarcoidosis
Although extrathoracic sarcoidosis is a much less common cause of morbidity than
intrathoracic disease, it can dominate the clinical picture in some patients.
Erythema nodosum, a nongranulomatous panniculitis, is the most common cutaneous
manifestation of sarcoidosis. More than 90% of patients with sarcoidosis who develop
erythema nodosum have a stage I radiograph; the other 10% have stage II radiographs. Granulomatous
skin lesions occur in 10% to 30% of patients and are especially common in African
Americans. Lupus pernio is a bluish-purple swollen lesion on the nose, cheeks, earlobes,
fingers and toes, lips, or knees that may become disfiguring. Skin plaques tend to be
violaceous, angular, and flat with a raised edge. Psoriasislike plaques may also be seen.
Nodules may be elevated or may arise in the subcutaneous tissue. As a rule, these
granulomatous skin manifestations of sarcoidosis are seen with chronic and persistent stage
III pulmonary disease.
Ocular involvement occurs in about 25% of patients with sarcoidosis. The uveal tract is
most often affected; sarcoidosis is responsible for 2% to 4% of all cases of uveitis. Anterior
uveal tract disease with iridocyclitis usually presents as tearing, photophobia, and little or no
pain. Heerfordt’s syndrome, or uveoparotid fever, is an uncommon manifestation of
sarcoidosis that consists of uveitis, parotid enlargement, cranial nerve palsies, subacute
meningitis, and systemic symptoms. Posterior uveitis (chorioretinitis) causes blurring of
vision or may be asymptomatic. Chorioretinitis may be difficult to detect when anterior
uveitis is present.
The nervous system is affected in fewer than 5% of patients with sarcoidosis. Central
Diagnosis
The diagnosis of sarcoidosis is established by demonstration of noncaseating granulomas
in tissue and exclusion of other causes of granulomas. Intrathoracic sarcoidosis
is diagnosed most easily by bronchoscopy with transbronchial lung biopsy. The yield of
transbronchial lung biopsy depends on the radiographic stage. In patients with pulmonary
infiltrates (stages II and III), transbronchial lung biopsy demonstrates noncaseating
granulomas in approximately 90% of cases. In stage I disease, the yield is 60% to 70%. If a
diagnosis is not established by transbronchial lung biopsy, mediastinoscopy is indicated
and will provide a diagnosis in 95% to 100% of cases. Biopsy of extrapulmonary tissues can
be used for diagnosis when clinically indicated (e.g., in patients with peripheral lymph node
enlargement or skin lesions).
When noncaseating granulomas are found in tissue, possible causes of granuloma
formation other than sarcoidosis must always be considered. Occasionally, lymphoma or
carcinoma is associated with granulomatous inflammation in local lymph nodes. Infectious
Management
Administration of glucocorticoids is standard therapy for symptomatic sarcoidosis, though
there is no definitive proof that such therapy influences long-term outcome. Most patients
respond very well to therapy, and often, low dosages of prednisone (e.g., 15 mg every other day)
may be effective in suppressing disease activity. A higher dosage (e.g., 40 to 60 mg/day) is
usually given for a few weeks to induce regression of disease activity. The primary indication
for glucocorticoids is symptomatic pulmonary involvement. Other indications include
significant systemic symptoms (e.g., fever or weight loss), hypercalcemia, and involvement of