Epidemiology

Sarcoidosis occurs worldwide and may affect any person at any age, although more than 80% of patients are diagnosed between ages 20 and 50 years. In the United States, African Americans are three and a half times more commonly affected, with an age-adjusted incidence of 35.5 per 100,000 persons, compared with 10.9 per 100,000 in whites. African American women are most commonly affected, with a lifetime risk of approximately 2.7%. African Americans tend to have a more severe form of the disease with greater extrapulmonary involvement. The incidence in most European nations has been reported at less than 1 case per 100,000. In Scandinavian countries such as Sweden and Finland, incidence ranges from 11 to 64 per 100,000. Sarcoidosis is uncommon in Chinese and Southeast Asians; the Japanese, however, have a particular susceptibility to cardiac involvement.

Etiology and Risk Factors

No single environmental sarcoidosis trigger has been identified. Recently, the multicenter ACCESS (A Case Controlled Etiologic Sarcoidosis Study) report found modestly increased risk with exposure to pesticides or moldy environments or working with building materials, hardware, or industrial organic dusts. Sarcoidosis was not associated with rural living conditions or exposure to wood dusts or heavy metals.

Several microorganisms and viruses have been suggested as potential sarcoid antigens. Mycobacterial catalase protein MkatG is the most promising agent thus far and has been found in tissue obtained from more than 50% of patients with sarcoidosis. A possible explanation for the difficulty in identifying an infectious cause for sarcoidosis is that an insoluble bacterial protein serves as antigen long after the infecting organism has been cleared.

Occupational clustering of sarcoidosis cases has been reported in ship workers, fire fighters, and rescue workers who were involved in the response to the World Trade Center attacks in the United States.

Genetic Factors

Racial differences in incidence rates and disease clustering in families support the hypothesis that heredity contributes to sarcoidosis etiology. Having a first-degree relative with sarcoidosis increases the risk for the disease approximately five-fold. Screening for sarcoidosis among relatives is not recommended, because less than 1% will be found to have the disease. Several human leukocyte antigen (HLA) associations with sarcoidosis have been reported (Table 48-1), but HLA seems more likely to influence phenotype than susceptibility. The major histocompatibility complex (MHC) class I allele HLA-B8 is associated with acute sarcoidosis. HLA-DQB1*0201 and HLA-DRB1*0301 are strongly associated with acute disease and good prognosis.

Table 48-1 Summary of Human Leukocyte Antigen (HLA) Association Studies of Sarcoidosis

Investigators have studied non-HLA candidate genes that influence antigen processing, antigen presentation, macrophage and T cell activation, and cell recruitment. Table 48-2 lists non-HLA candidate genes studied to date. Although these candidates are logical on the basis of function, their associations with sarcoidosis have not been consistently reproduced.

Table 48-2 Non-HLA Candidate Genes Evaluated in Sarcoidosis

To date, two genome scans for sarcoidosis have been reported: one in German whites, with the strongest linkage signals localized to chromosomal short arms 3p and 6p, and the other in African Americans with signals at 5p and 5q. Thus far, two candidate genes from linked regions have been identified: BTNL2, located on 6p, encoding butyrophilin-like protein 2, a B7 family member that functions as a negative costimulatory molecule, and ANXA11, at chromosomal locus 10q22.2, encoding annexin A11, which may affect apoptosis.

Pathophysiology

Sarcoidosis is a multisystem inflammatory disease characterized by T lymphocyte infiltration, granuloma formation, and microarchitecture distortion. The events leading to granuloma formation probably begin with antigen presented to T lymphocytes by way of MHC class II peptide in a genetically predisposed host (Figure 48-1). Serum amyloid A may have a role in the immune response in sarcoidosis and is capable of eliciting immune responses and triggering cytokine release through interaction with Toll-like receptors (TLRs). The oligoclonal T cell repertoire in sarcoidosis (α/β and δ/γ receptors) suggests that triggering antigens favor progressive accumulation and activation of selective T cell clones. Initially, macrophages process the antigens, which are then presented to CD4⁺ T cells by class II MHC molecules. T cell activation occurs by means of T cell receptor (TCR), TLR, or cytokine or chemokine receptors. This leads to signal transduction and activation of transcription factors that promote gene expression controlling T cell proliferation, differentiation, and apoptosis and produce proinflammatory cytokines and chemokines. T cell signal transduction pathways are potential therapeutic targets in sarcoidosis. Macrophages, in the face of chronic cytokine stimulation, differentiate into epithelioid cells, gain secretory and bactericidal capability, lose some phagocytic capacity, and fuse to form multinucleate giant cells. In more mature granulomas, fibroblasts and collagen encase the ball-like cell cluster. As granulomas accumulate, alterations in organ architecture and function occur.

Figure 48-1 Noncaseating granulomatous inflammation in sarcoidosis. A, Closeup of epithelioid granuloma with giant cells and mononuclear cell infiltration. B, Open lung biopsy specimen showing granulomas, giant cells, and lymphocytic infiltrates in lung parenchyma and within interlobular septal and subpleural regions. C, Lymph node biopsy specimen showing extensive replacement with typical sarcoid-type epithelioid granulomas. Fibrinoid necrosis, but not overt caseation, may be seen in the center of granulomas. D, Myocardial biopsy specimen showing patchy granulomatous inflammation with giant cells.

Granulomas can resolve with little clinical consequence or may progress to fibrosis. Acute granulomatous and chronic fibrotic sarcoidosis probably represent different immunopathogenic processes, which remain to be defined (Figure 48-2). A switch from T_H1 to T_H2 cytokine profile, along with other mediators such as interleukin-6 (IL-6), transforming growth factor-β (TGF-β), osteopontin, and insulin growth factors (IGFs), is suggested to result in fibrosis. Sarcoidosis may develop or worsen in patients with immune reconstitution during treatment of HIV infection or in those undergoing treatment with interferon.

Figure 48-2 Model of the immunopathogenesis of sarcoidosis. A, Initiation of sarcoidosis involves stimulation of production of interleukins IL-12 and IL-18 from mononuclear phagocytes and dendritic cells and adaptive T cell immunity to an inciting agent. B, Maintenance of granuloma formation by a T_H1 immune response driven by IFN-γ and IL-12 and IL-18. C, Resolution of sarcoidosis after removal of stimulating antigen, suppression of T cell responses by TGF-β and other mediators, and granuloma resorption by cell apoptosis. D, Fibrotic outcome from persistent, possibly autoimmune antigenic stimulation in the presence of TGF-β and other profibrotic mediators. APC, antigen-presenting cell; GM-CSF, granulocyte-macrophage colony-stimulating factor; IFN-γ, interferon-γ; IGF-1, insulin-like growth factor-1; MCP-1, monocyte chemotactic protein-1; MIG, monokine induced by IFN-γ; MIP-1, macrophage inflammatory protein-1; PDGF, platelet-derived growth factor; TGF-β, transforming growth factor-β; TNF-α, tumor necrosis factor-α.

Clinical Features

The clinical presentation of sarcoidosis varies. In up to two thirds of the cases, the patient is asymptomatic, and sarcoidosis is diagnosed incidentally on the basis of radiographic findings of hilar lymphadenopathy. Thoracic involvement is most common (over 90% of patients), followed by skin, eyes, liver, spleen, peripheral lymph nodes, central nervous system (CNS), and heart. Two well-recognized acute, febrile presentations of sarcoidosis are Löfgren syndrome (arthritis, erythema nodosum, and bilateral hilar adenopathy) and Heerfordt syndrome (uveitis, parotid gland enlargement, and facial nerve palsy). These acute presentations portend a good prognosis, with disease resolution within 1 to 2 years. Both syndromes are uncommon in African Americans.

Pulmonary Manifestations

More than 90% of patients with sarcoidosis have pulmonary involvement. Common complaints include dry cough, vague chest discomfort, and dyspnea, particularly with exertion. Pleuritic chest pain is uncommon. Wheezing may occur with endobronchial involvement or hyperreactive airways. Sputum production and hemoptysis occur in advanced fibrocystic disease. Pleural involvement is seen in only 2% to 4% of patients and can manifest with pleural effusions, pleural thickening, pneumothorax, and chylothorax. The diagnosis of sarcoidosis often is delayed, especially in patients presenting with predominantly pulmonary symptoms.

Chest auscultation may reveal fine, late, or mid-expiratory crackles, but comparatively less than that heard in pulmonary fibrosis. In view of the marked chest radiographic abnormalities, physical examination of the lungs is surprisingly unrevealing. Clubbing is rare but when present usually is associated with advanced bronchiectasis or liver disease.

Pulmonary Hypertension

The prevalence of pulmonary arterial hypertension and right ventricular dysfunction ranges from 4% to 28%. Pulmonary hypertension is more common in patients with advanced lung disease and has been reported in up to 74% of patients with sarcoidosis who are awaiting a lung transplant. Several potential causes of pulmonary hypertension in sarcoidosis include interstitial lung disease, fibrous destruction of the pulmonary vascular bed, compression of pulmonary arteries by lymphadenopathy, pulmonary venoocclusion, portopulmonary hypertension, myocardial dysfunction, and an intrinsic sarcoid vasculopathy. Patients with pulmonary hypertension are more likely to be listed for a lung transplant and exhibit a 10-fold increase in mortality over that for patients with isolated pulmonary sarcoidosis. Prognosis is poor, with a 5-year survival rate of only 59%. The management of pulmonary hypertension involves reversal of resting hypoxia. Use of corticosteroids for pulmonary hypertension in sarcoidosis is controversial. The data supporting the benefit of endothelin receptor antagonist and phosphodiesterase-5 inhibitors are very limited.

Chest Radiology

Chest radiographs obtained in patients with sarcoidosis are classified by appearance into four patterns (Figure 48-3). Unfortunately, these radiographic patterns have been termed “stages,” leading to the erroneous assumption that they represent disease stages rather than chest x-ray patterns.

Stage 0: Absence of radiographic abnormalities

Stage I: Bilateral hilar and/or mediastinal adenopathy without pulmonary parenchymal abnormalities

Stage II: Hilar and/or mediastinal lymphadenopathy with pulmonary parenchymal abnormalities (generally a diffuse interstitial pattern)

Stage III: Diffuse parenchymal disease without nodal enlargement

Stage IV: Pulmonary fibrosis with evidence of volume loss or cystic or honeycomb changes

Figure 48-3 Chest radiography stages (patterns) of sarcoidosis. A, Stage I pattern on the chest radiograph, with bilateral hilar lymphadenopathy. B, Stage II pattern, with bilateral lymphadenopathy and reticulonodular infiltrates. C, Stage III pattern, with bilateral infiltrates without adenopathy. D, Stage IV pattern, with upward hilar retraction, large cystic and bullous changes, and fibrocystic disease.

The initial radiographic pattern at initial presentation generally predicts likelihood of radiographic resolution. Resolution of radiographic abnormalities occurs in approximately 60% to 80% of patients who present with a stage I pattern on the chest radiograph and in 50% to 60% with a stage II pattern, but in less than 30% with a stage III pattern.

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