Sarcoidosis is a common disease of unknown origin characterized by the inﬁltration of many organs by non-caseating epithelioid granulomas. The lung is the most common organ affected by sarcoidosis. The skin, eye, and liver are also frequently involved. Sarcoidosis may affect many other organs, many of which are detailed in the next paragraph. Although in the United States sarcoidosis is most common in African Americans, the disease is also has a high prevalence in Northern Europeans and occurs worldwide. Women appear to contract the disease more often than men. The majority of patients are younger than 40 years of age at onset, although there is a second peak of increased incidence after age 50 years in women. There is a higher incidence of the disease in ﬁrst-degree relatives (parents, siblings, and children) of sarcoidosis patients than the general population. This is in keeping with the belief that sarcoidosis represents an abnormal granulomatous response to an environmental exposure in genetically susceptible individuals. Sarcoidosis is rare in people younger than age 18 years. Sarcoidosis is often a benign condition that may run its entire course without detection. It is often discovered in asymptomatic patients on screening chest radiographs.
Sarcoidosis may present as a variety of clinical syndromes, which vary primarily depending on the distribution of granulomatous involvement of the affected organs (see Plate 4-155). These include (1) Löfgren syndrome (erythema nodosum with radiographic evidence of hilar lymph node enlargement, often with concomitant fever and joint [often ankle] arthritis); (2) cutaneous plaques and subcutaneous nodules; (3) Heer fordt syndrome (uveoparotid fever); (4) isolated uveitis; (5) salivary gland enlargement; (6) central nervous system (CNS) syndromes (usually seventh nerve palsy); (7) cardiomyopathy or cardiac arrhythmias; (8) hepatosplenomegaly (with or without hypersplenism); (9) upper airway involvement (sarcoidosis of the upper respiratory tract [SURT]); (10) hypercalcemia; (11) renal failure; (12) peripheral lymphadenopathy; and (13) various forms of pulmonary disease, including mediastinal adenopathy, interstitial lung disease, endobronchial involvement with airﬂow obstruction and wheezing, and pulmonary hypertension.
Pulmonary hypertension is a potentially life-threatening complication of sarcoidosis. Sarcoidosis associated pulmonary hypertension is classiﬁed in the miscellaneous category (class 5) according to the World Health Organization classiﬁcation scheme. This is because there are multiple mechanisms that may cause pulmonary hypertension in sarcoidosis, including pulmonary venous hypertension from myocardial involvement, pulmonary ﬁbrosis causing vascular distortion, hypoxemia from parenchymal sarcoidosis, compression of the vasculature from the thoracic lymphadenopathy of sarcoidosis, and direct granulomatous involvement of the pulmonary vasculature.
The radiographic presentations of sarcoidosis have been divided into ﬁve stages: (0) a normal chest radiograph, (I) bilateral hilar and right paratracheal lymph node enlargement, (II) persistence of lymph nodes with concomitant pulmonary inﬁltrations, (III) pulmonary inﬁltrations with no identiﬁable mediastinal adenopathy, and (IV) ﬁbrocystic changes that are usually most prominent in the upper lobes. The ﬁbrosis may be signiﬁcant, with retraction of the hilar areas upward and unilateral deviation of the trachea. Occasionally, aspergillomas may develop in these ﬁbrocystic spaces. Patients with radiographic stage I sarcoidosis are most often asymptomatic and usually have normal pulmonary function test results despite the universal presence of granulomas on lung biopsy specimens at this stage of the disease. With radiographically discernible pulmonary lesions, a restrictive pattern of dysfunction may emerge, with loss of lung volumes; decreased pulmonary compliance; hyperventilation; decreased diffusing capacity; and in the most severely afﬂicted patients, hypoxemia. In chronically scarred lungs, evidence of airway dysfunction usually appears, with decreased FEV1 (forced expiratory volume in 1 second) and diminished ﬂow rates at low lung volumes. Although dyspnea, pulmonary dysfunction, and prognosis are generally worse with higher radiographic stages, there is too much overlap for this to be useful to assess individual patients. It is clear that patients with stage IV radiographs include nearly all the patients with a very poor prognosis, although not all patients with stage IV radiographs will fare poorly.
Although chest computed tomography scanning is not required to assess the status of pulmonary sarcoidosis, it often clearly identiﬁes mediastinal adenopathy. Furthermore, it may detect parenchymal disease that is not evident on chest radiographs. Parenchymal sarcoidosis is commonly located along the bronchovascular bundles and in subpleural locations.
Noncaseating epithelioid granulomas, often accompanied by giant cells and rarely by small, calciﬁed bodies (Schaumann bodies), are the fundamental pathologic lesions in sarcoidosis but are nonspeciﬁc (see Plate 4-156). However, these granulomas often cannot be differentiated from the granulomas of fungal infections, berylliosis, leprosy, brucellosis, hypersensitivity lung diseases, the occasional instances of tuberculosis when caseation and acid-fast bacilli are not apparent, and lymph nodes draining neoplastic tumors. Therefore, the diagnosis of sarcoidosis requires a compatible clinical picture and negative smears and cultures for organisms causing the diseases. Granulomas frequently develop in several organs, accounting for the multiple modes of clinical presentation when organ structure and function are impaired. In the majority of patients with disability, the organs primarily affected are the lungs, eyes, and myocardium.
The immunopathogenesis of sarcoidosis is not completely understood. The process probably begins with the interaction of unknown antigen(s) with antigen-presenting cells (APCs) such as dendritic cells and macrophages. It is postulated that these APCs process these antigens and present them via human leukocyte antigen class II molecules to T-cell receptors attached to T lymphocytes, usually of the CD4+ class. After these events occur, T cells are stimulated to proliferate, and cytokines including interleukin-2 and interferon-, are produced. These cytokines are thought to enhance pro- duction of macrophage-derived tumor necrosis factor-(TNF-α). These cytokines and undoubtedly many others are responsible for granuloma formation.
Elevated levels of serum angiotensin-converting enzyme (ACE) have been observed in active sarcoidosis. However, the serum ACE level is thought not to be speciﬁc or sensitive enough for the diagnosis of sarcoidosis. The serum ACE level may be useful to measure disease activity in cases in which clinical methods of assessment are difﬁcult or costly.
The diagnosis of sarcoidosis rests on the demonstration of noncaseating epithelioid granulomas in tissues subjected to biopsy (skin, lymph nodes, or lung) from a patient with a compatible clinical picture. As previously mentioned, the clinician must be vigilant that alternate potential causes of granulomatous inﬂammation have been reasonably excluded.
The majority of patients with sarcoidosis can expect a benign course with complete clearing or nondisabling persistence of radiographic and other clinical abnormalities. However, a small but signiﬁcant number of patients will be disabled, and approximately 4% will die of their sarcoidosis, usually from respiratory failure. Less commonly, death occurs from sarcoid cardiomyopathy or CNS involvement. For unknown reasons, cardiac involvement is the major cause of death from sarcoidosis in Japanese individuals. Rarely, death may be the result of renal failure or from hemorrhage because of pulmonary aspergillomas that form in sarcoid bullae. African Americans tend to have more aggressive forms of sarcoidosis than whites.
Patients with active sarcoidosis usually respond well to corticosteroids. The usual course of therapy for acute pulmonary sarcoidosis is 20 to 40 mg/d prednisone equivalent for 6 to 12 months. Relapse is common after cessation of prednisone and may require reinstitution of treatment. Higher doses of corticosteroids are often required for cardiac involvement, disﬁguring facial sarcoidosis (lupus pernio), and neurosarcoidosis. Prompt treatment with corticosteroids is indicated for patients with uveitis, CNS disease, hypercalcemia, cardiomyopathy, hypersplenism, and progressive pulmonary dysfunction, but only 10% of patients with sarcoidosis require mandatory treatment of this kind. Corticosteroids are not indicated in patients with asymptomatic hilar lymphadenopathy or minor radiographic pulmonary shadows or for asymptomatic elevations in serum liver function tests. The arthritis of Löfgren syndrome can usually be managed with nonsteroidal antiinﬂammatory agents.
Because prolonged corticosteroid therapy is hazardous, alternative medications to corticosteroids are often used for chronic sarcoidosis. In these instances, corticosteroids are often still required, but the addition of alternative medicines has a corticosteroid-sparing effect such that the maintenance corticosteroid dose can be reduced. Such medications include methotrexate, hydroxychloroquine, chloroquine, azathioprine, leﬂunomide, pentoxifylline, thalidomide, the tetracyclines, and inﬂiximab.