Sarcoidosis: Evolving Concepts and Controversies

Marc A. Judson, M.D. Michael C. Iannuzzi, M.D.

Sarcoidosis has fascinated clinicians and scientists since it was first discovered in 1877. Nearly one and one half centuries later the etiology remains unknown, the pathogenesis unclear, and the treatment often unsatisfying.

Sarcoidosis is thought to result from the events triggered when a genetically susceptible individual is exposed to an environmental or occupational antigen. The immunologic response involves an interplay of lymphocytes and mononuclear cells and their associated cytokines and chemokines. Granulomas form and accumulate and may result in organ dysfunction. The process, however, does not terminate at this point because most clinically relevant disease hinges on whether the granulomas resolve or fibrosis occurs.

The incidence and severity of sarcoidosis are not uniform throughout the world, supporting the concept that various environmental and genetic factors are likely involved in etiology and phenotypic expression. Epidemiological and genetic studies of sarcoidosis have and continue to provide insights into its mechanisms. First-degree relatives of sarcoidosis patients have an increased risk for developing sarcoidosis. Certain human leukocyte antigen (HLA) genes play roles in susceptibility and disease phenotype. Association studies have evaluated key immune response genes. Two genome scans searching for sarcoidosis susceptibility genes have identified attractive candidate genes.

The variable phenotypic expression of sarcoidosis coupled with the lack of controlled clinical trials presents challenges for the practitioner. The decision to administer therapy must be weighed against the possibility that the disease may remit spontaneously, particularly given that therapy is often associated with significant side effects. Constitutional symptoms such as fatigue, malaise, depression, and pain frequently occur and adversely affect quality of life. This may account for the reported discordance in disease assessment between physician and patient.

Liver, heart, and lung transplantation for end-stage sarcoidosis presents special issues for consideration. Pulmonary hypertension, which often accompanies end-stage lung disease, and extrapulmonary involvement must be searched for and may preclude transplant. Aspergilloma, if present, must be completely resected to prevent potential tissue invasion. Recurrent disease can occur in any transplanted organ despite immunosuppression regimens.

We hope that this issue of Seminars in Respiratory and Critical Care Medicine will serve as a stimulus for thought aimed at solving the many mysteries in sarcoidosis as well as providing guidance for clinicians who care for these challenging patients.