Sarcoidosis is an inflammatory disease characterized by the presence of noncaseating granulomas. The disease is often multisystem and requires the presence of involvement in two or more organs for a specific diagnosis. The finding of granulomas is not specific for sarcoidosis, and other conditions known to cause granulomas must be ruled out. These conditions include mycobacterial and fungal infections, malignancy, and environmental agents such as beryllium. While sarcoidosis can affect virtually every organ of the body, the lung is most commonly affected. Other organs commonly affected are the liver, skin, and eye. The clinical outcome of sarcoidosis varies, with remission occurring in over one-half of the patients within a few years of diagnosis; however, the remaining patients may develop a chronic disease that lasts for decades.
Despite multiple investigations, the cause of sarcoidosis remains unknown. Currently, the most likely etiology is an infectious or noninfectious environmental agent that triggers an inflammatory response in a genetically susceptible host. Among the possible infectious agents, careful studies have shown a much higher incidence of Propionibacter acnes in the lymph nodes of sarcoidosis patients compared to controls. An animal model has shown that P. acnes can induce a granulomatous response in mice similar to sarcoidosis. Others have demonstrated the presence of a mycobacterial protein [Mycobacterium tuberculosis catalase-peroxidase (mKatG)] in the granulomas of some sarcoidosis patients. This protein is very resistant to degradation and may represent the persistent antigen in sarcoidosis. Immune response to this and other mycobacterial proteins has been documented by another laboratory. These studies suggest that a mycobacterium similar to M. tuberculosis could be responsible for sarcoidosis. The mechanism exposure/infection with such agents has been the focus of other studies. Environmental exposures to insecticides and mold have been associated with an increased risk for disease. In addition, health care workers appear to have an increased risk. Also, sarcoidosis in a donor organ has occurred after transplantation into a sarcoidosis patient. Some authors have suggested that sarcoidosis is not due to a single agent but represents a particular host response to multiple agents. Some studies have been able to correlate the environmental exposures to genetic markers. These studies have supported the hypothesis that a genetically susceptible host is a key factor in the disease.
Sarcoidosis is seen worldwide, with the highest prevalence reported in the Nordic population. In the United States, the disease has been reported more commonly in African Americans than whites, with the ratio of African Americans to whites ranging from 3:1 to 17:0. Women appear to be slightly more susceptible than men. The lower estimate is from a large health maintenance organization in Detroit. The earlier American studies finding the higher incidence in African Americans may have been influenced by the fact that African Americans seem to develop more extensive and chronic pulmonary disease. Since most sarcoidosis clinics are run by pulmonologists, a selection bias may have occurred. Worldwide, the prevalence of the disease varies from 20–60 per 100,000 for many groups such as Japanese, Italians, and American whites. Higher rate occurs in Ireland and Nordic countries. In one closely observed community in Sweden, the lifetime risk for developing sarcoidosis was 3%.
Sarcoidosis often occurs in young, otherwise healthy adults. It is uncommon to diagnose the disease in someone under age 18. However, it has become clear that a second peak in incidence develops around age 60. In a study of >700 newly diagnosed sarcoidosis patients in the United States, one-half of the patients were ≥40 years at the time of diagnosis.
Although most cases of sarcoidosis are sporadic, a familial form of the disease exists. At least 5% of patients with sarcoidosis will have a family member with sarcoidosis. Sarcoidosis patients who are Irish or African American seem to have a two to three times higher rate of familial disease.
The granuloma is the pathologic hallmark of sarcoidosis. A distinct feature of sarcoidosis is the local accumulation of inflammatory cells. Extensive studies in the lung using bronchoalveolar lavage (BAL) have demonstrated that the initial inflammatory response is an influx of T helper cells. In addition, there is an accumulation of activated monocytes. Figure 329-1 is a proposed model for sarcoidosis. Using the HLA-CD4 complex, antigen-presenting cells present an unknown antigen to the helper T cell. Studies have clarified that specific HLA haplotypes such as HLA-DRB1*1101 are associated with an increased risk for developing sarcoidosis. In addition, different HLA haplotypes are associated with different clinical outcomes.
Schematic representation of initial events of sarcoidosis. The antigen-presenting cell and helper T cell complex leads to the release of multiple cytokines. This forms a granuloma. Over time, the granuloma may resolve or lead to chronic disease, including fibrosis. APC, antigen-presenting cell; HLA, human leukocyte antigen; IFN, interferon; IL, interleukin; TNF, tumor necrosis factor.
The macrophage/helper T cell cluster leads to activation with the increased release of several cytokines. These include interleukin (IL)-2 released from the T cell and interferon γ and tumor necrosis factor (TNF) released by the macrophage. The T cell is a necessary part of the initial inflammatory response. In advanced, untreated HIV infection, patients who lack helper T cells rarely develop sarcoidosis. In contrast, several reports confirm that sarcoidosis becomes unmasked as HIV-infected individuals receive antiretroviral therapy, with subsequent restoration of their immune system. In contrast, treatment of established pulmonary sarcoidosis with cyclosporine, a drug that downregulates helper T cell responses, seems to have little impact on sarcoidosis.
The granulomatous response of sarcoidosis can resolve with or without therapy. However, in at least 20% of patients with sarcoidosis, a chronic form of the disease develops. This persistent form of the disease is associated with the secretion of high levels of IL-8. Also, studies have reported that in patients with this chronic form of disease excessive amounts ...