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Because the etiology of sarcoidosis is unknown, the diagnosis remains one of exclusion. As such, there is no one test to confirm the diagnosis. Indeed, sarcoidosis' clinical hetero geneity probably reflects multiple disease etiologies. CS may represent a final common clinical and histopathologic presentation for several pathologic sequences. Acknowledging the limitations of our understanding, it is worthwhile summarizing the major studies in epidemiology and immunogenetics in systemic sarcoidosis. Few data exist for isolated cardiac disease, and these are noted when available.

Boeck used the term "sarkoid" in 1899 to describe cutaneous lesions because he thought the lesions resembled sarcoma (reviewed in reference 17). Associations with malignant neoplasms have been described since, suggesting that sarcoidosis might be a form of or a marker for malignancy. Epithelioid granulomas were observed in the regional lymph nodes of a small percentage of patients with carcinomas or in association with non-Hodgkin lymphoma;20'21 however, a large well-controlled study of 555 sarcoidosis cases in Denmark failed to demonstrate an excess rate of malignancy in sarcoid patients.22 Currently, the trend of investigation is away from malignancy associations and toward identification of environmental triggers in genetically susceptible individuals.

Infectious and environmental agents have been considered in the search for a cause. Early investigators thought that sarcoidosis could be a variant of tuberculosis.23 Other putative infectious agents include Borrelia burgdorferi, Propionibacterium acnes, Mycoplasma, and several viruses (Table 18-1). Environmental agents that could induce a granulomatous response include aluminum, zirconium, and talc. An epidemiologic report suggested that

Table 18-1

Examples of Agents Suggested to Be Involved in the Etiology of Sarcoidosis*

Type of agent

Infectious agents

Viruses (herpes, Epstein-Barr, retrovirus, coxsackie B

virus, cytomegalovirus) Borrelia burgdorferi Propionibacterium acnes

Mycobacterium tuberculosis and other mycobacteria Mycoplasma Inorganic agents Aluminum Zirconium Talc Organic agents Pine tree pollen Clay

*This table does not include beryllium, which causes berylliosis and not sarcoidosis. From Hunninghake et al.17 By permission of PCA Publishing.

exposure to wood stoves and fireplaces, both rurally linked risk factors, was associated with the development of sarcoidosis.24 The argument for a transmissible agent is supported by the development of sarcoidosis in a transplant recipient who received tissue from a donor with sarcoidosis.25

The argument for an environmental cause or person-to-person transmission is further strengthened by the observation that sarcoidosis cases cluster temporally. Clustering has been observed in the Isle of Man,26'27 and among firefighters and health care workers. 9 Furthermore, some cases occur in families,30-32 and there is evidence to suggest a seasonal clustering in the winter and early spring.33 Taken together these data suggest that an environmental or infectious trigger(s) may play a role in some cases of sarcoidosis.

Arguments for a genetic predisposition come from familial clustering, race as a risk factor, and studies of the major histocompatibility complex genes. The most common genotype frequencies in sarcoidosis are class I human leukocyte antigen (HLA)-A1 and B8 and class II HLA-DR.34-36 The polymorph ism for tumor necrosis factor (TNF)-beta (TNFB*1) is associated with good prognosis in pulmonary sarcoidosis.37 Genetic studies demonstrated an association of certain alleles for angiotensin-converting enzyme (ACE) genotype, interferon (IFN) regulatory factor 4, and interleukin (IL)-1 alpha in certain groups with systemic sarcoidosis.38,39 The data for cardiac involvement are limited to a report by Takashige et al.40 that demonstrated a TNF-alpha (A2) gene polymorphism was more common in Japanese patients with CS than in normal controls (RR 11.51, P = 0.001). These associations of allelic polymorphisms with phenotype and prognosis may explain some individual differences in susceptibility to disease.

The cellular pathophysiology of sarcoidosis is an area of active research. Studies of pulmonary sarcoidosis suggest that CD4+ T lymphocytes accumulate at sites of inflammation. These cells release cytokines, including IFN-gamma and IL-2,41 suggesting a TH1-type T-cell response. Alveolar macrophages are also active, secreting cytokines and growth factors. A T^-type response seems to favor the formation of granulomas in the lung.42 The pathway that leads to granuloma resolution and fibrosis is not well understood. Knowledge of these cellular mechanisms of disease may guide rational, targeted therapeutic trials; however, at the present time, neither the antigenic stimulus nor the mechanism of persistent inflammation and fibrosis is known.

To better define the causes of sarcoidosis, the National Heart, Lung, and Blood Institute sponsored a case-control study of sarcoidosis (ACCESS).43 This multicenter, observational study includes a comprehensive investigation of genetic, environmental, infectious, and primary immune factors in sarcoidosis. The study has the power to permit testing of multiple hypotheses; 720 cases will be compared with an equal number of matched controls. Enrollment in this study is ongoing.

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