Granulomatous lung disease occurring during etanercept treatment

Abstract

Introduction Tumor necrosis factor (TNF ) is an important mediator of the molecular cascade that leads to chronic inflammation. It induces chemokine production, which results in the recruitment of leukocytes into the local environment, and upregulates adhesion molecules on vascular endothelial cells, which also promotes the localization of leukocytes into the inflamed tissue. Animal models suggest that TNF also plays an important role in the formation and maintenance of granulomas (1). Granulomas form in response to either infection or an inflammatory stimulus, and are composed of organized aggregations of activated macrophages surrounded by lymphocytes and fibroblasts (2). Fibroblasts surrounding the granuloma produce a fibrous capsule, and this tissue reaction may help protect the host from an inciting agent by maintaining containment and reducing the nutrient availability to potential infectious agents. Sensitized CD4 T cells with a Th1 pattern of cytokine production help initiate and maintain the structure, and cross-talk between T lymphocytes and macrophages is also important for maintenance. Both interferon gamma and TNF inhibit microbial growth, and have a synergistic effect on macrophage activation. Blockade of TNF results in down regulation of many adhesion molecules, and decreases circulating inflammatory cytokines. Etanercept is an anti–TNF therapy developed for the treatment of inflammatory arthritis. It is a fusion protein that consists of the extracellular ligandbinding domain of the TNF receptor coupled to the Fc portion of human IgG. It is thought to work by binding TNF and blocking its interaction with TNF receptors, thereby rendering TNF inactive. Chronic TNF inhibition has been rarely associated with reactivation of selected infections such as mycobacterial infections, which require granuloma formation for host response. Previous studies have suggested that anti–TNF therapy may result in diminished granuloma formation (3). For this reason anti–TNF therapy is being evaluated in sarcoidosis, a disease characterized by the formation of granulomas (4). Although much is known about the mediators involved in cytokine production in granulomatous diseases, the exact role of TNF remains unclear, as the following case illustrates. We report a patient who developed a pulmonary granulomatosis reaction (culture negative) while receiving etanercept therapy for psoriatic arthritis.