Sarcoidosis

Xavier Soler

Sarcoidosis is a multisystem granulomatous disease of undetermined etiology with a variable clinical presentation and course that ranges from an incidental radiographic finding in an asymptomatic individual to life-threatening illness. The epidemiology of sarcoidosis remains problematic because of its variable presentation and insensitive and nonspecific diagnostic tests. In the United States, sarcoidosis has a higher prevalence among African-Americans, especially women. Several epidemiologic studies have demonstrated temporal, seasonal, and geographic clustering of sarcoidosis cases, suggesting a common etiologic origin. Possible agents have been identified as a cause for sarcoidosis, although none has been definitely confirmed. There is increasing evidence to suggest that infectious agents are involved. Genome-wide scans (GWAS) have identified candidate genes, and cytokine dysregulation has been demonstrated. However, the criteria for diagnosis have not changed. Sarcoidosis remains a diagnosis of exclusion best supported by a tissue biopsy specimen demonstrating noncaseating granulomas in a patient with compatible clinical and radiologic features.

The immunopathogenesis of sarcoidosis remains unclear. It is likely due to a complex interplay to exposure to one or more exogenous antigens, environmental conditions, and host immunologic responses. Reports of case-clustering, increased susceptibility in certain occupations and environmental exposures (e.g., work in agriculture, exposure to mold, mildew, musty odors, or pesticides), and transmission via organ transplant all support this theory. After the World Trade Center disaster, firefighters exposed to dust exhibited a higher-than-expected incidence of sarcoidosis that was clinically and phenotypically distinct from that in the general population. Reduced risk has been associated with allergic responses and tobacco use. GWAS has identified non-HLA candidate susceptibility genes commonly involved in host-immune response, such as butyrophilin-like 2 (BTNL2). It has become increasingly well recognized that polymorphisms within various chemical mediators of inflammation contribute to the immunopathogenesis of sarcoidosis. In the United States, African-Americans are affected more frequently and generally have chronic and more severe disease. Familial clustering of sarcoidosis is common.

The ACCESS (A Case Control Etiologic Study of Sarcoidosis) study collected data on 704 patients with newly diagnosed, biopsy-proven sarcoidosis and control subjects matched by age, sex, race, and geographic area and found that cases were five times more likely than control subjects to report an affected sibling or parent. Also, polymorphisms in the promoter region of tumor necrosis factor-α (TNF-α) have been associated with Löfgren syndrome, a form of sarcoidosis characterized by erythema nodosum, hilar adenopathy, uveitis, and a good prognosis. Insertion/deletions in the promoter region of angiotensin-1 converting enzyme have also been identified. The importance of TNF has been validated in studies documenting the effectiveness of biologic TNF antagonists in treating some patients with sarcoidosis. Reduced numbers of natural killer T (NKT) cells have been found in sarcoid blood and bronchoalveolar lavage (BAL) fluid.

There are data suggesting that bacteria, such as Mycobacteriun Tuberculosis or Propionibacterium acnes, may be involved in causing the disease. It is quite possible that the triggering antigen varies depending on ethnicity, geographic location, and individual genetic background. Also, strongly polarized T helper cell (TH) 1 immune responses are present more frequently. The immune response may precipitate a cascade of events leading to granuloma formation involving (1) exposure to the antigen; (2) presentation of the antigen (by macrophages via HLA class II molecules to T lymphocytes); and (3) immune effector cells promoting the development of noncaseating granulomas, the pathologic hallmark of sarcoidosis. The release of cytokines, such as interleukin-2 (IL-2) and interferon-γ, by activated CD4 T lymphocytes (indicating a TH-1 immunologic response) eventually leads to enhanced fibroblast replication and granuloma formation. Despite the increased local immunologic activity, cutaneous anergy is commonly present.

The diagnosis of sarcoidosis is never certain, although it may be established by clinical correlation of nonspecific symptoms with biochemical, radiologic, and pathologic confirmation. Sarcoidosis is usually underdiagnosed. The clinical presentation ranges from asymptomatic to life-threatening organ involvement. A common feature of this disease is its multiorgan involvement, including respiratory (cough, chest pain, and dyspnea), musculoskeletal (arthralgia and myalgia), ocular (visual changes and pain), and skin manifestations (erythema nodosum, nodules, plaques, and papules). There is no gold standard for diagnosis. Certain nonspecific clinical features are typical of sarcoidosis including bilateral hilar adenopathy, Löfgren syndrome (erythema nodosum coupled with bilateral hilar adenopathy and often fever and/or arthritis), Heerfordt syndrome (uveitis, parotitis, and fever), and gallium-67 scan uptake in the parotid and lacrimal glands (panda sign) along with right paratracheal and bilateral hilar areas (lambda sign). Unless one of the special clinical situations previously described is present, the diagnosis usually requires histologic confirmation and exclusion of alternative causes. Cough and dyspnea are the most common respiratory complaints. The heart can be affected in 1% to 4% of cases and cardiac sarcoidosis is potentially sudden and life-threatening. Erythema nodosum is seen occasionally with the typical presentation of bilateral hilar adenopathy and generally indicates a good prognosis. Pleural disease occurs uncommonly and can be associated with pleural effusions. Between 30% and 60% of patients are asymptomatic and present with incidental findings on chest radiographs.

The chest radiograph is staged as follows:

• Stage 0, normal;

• Stage 1, bilateral hilar adenopathy;

• Stage 2, bilateral hilar adenopathy with pulmonary infiltrate;

• Stage 3, pulmonary infiltrates without hilar adenopathy; and

• Stage 4, pulmonary fibrosis.

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