Inhaled corticosteroids in pulmonary sarcoidosis.

Pulmonary sarcoidosis is a chronic inflammatory disease characterized histologically by granuloma formation within the lung interstitium. Clinically the disease has a variable course. In the majority of patients the inflammation resolves spontaneously, while in 15-20% of patients the granulomata persist and lead to irreversible fibrosis with significant respiratory embarrassment. Clear guidelines for treatment in this disease are absent. Despite substantial advances in the scientific understanding of the basic immune mechanisms responsible for pulmonary sarcoidosis, there is to date a lack of any clear prognostic signs in this disease. This leaves in dispute the question of who and when to treat. Usually therapy is started late, and consists of systemic corticosteroids in varying doses and regimes with variable clinical efficacy. Systemic corticosteroids have been shown to control the local inflammatory response in sarcoidosis by decreasing the CD4/CD8 T cell ratio, with consequent increase in CD8 + T-lymphocyte accumulation at the site of the granuloma. ' In addition, there is also suppression oflocal immunoglobulin production, and a reduction in the lymphocytic production of interleukin-2.2 Invariably, however, undesirable side effects occur. For this reason systemic steroid therapy is often started too late (or curtailed too soon), with many of the patients already developing pulmonary fibrosis. When this happens the lung damage is irreversible, with steroid therapy often being found to be ineffective both clinically and at the cellular level.3'4 Against such a background, there is clearly a need for a therapeutic regimen that is safe enough to commence early in disease, that can be targeted to the lung, and that can be shown (as with systemic steroids) to modulate the underlying cellular dysfunction occurring in the lungs of sarcoid patients. Inhaled corticosteroids became available 15 years ago for the treatment of patients with bronchial asthma. Early attempts to use inhaled steroids for the treatment of pulmonary sarcoidosis were unsuccessful,5 probably because the daily dose was too low and the disease too advanced to be treatable with targeted corticosteroids. With the development of newer generations of inhaled corticosteroids that possess an improved ratio between anti-inflammatory effects and systemic potency, together with a different lung pharmacokinetic profile, the idea for using such therapy in pulmonary sarcoidosis has revived. Preliminary studies6 using inhaled budesonide in a dose of 16001ig per day have shown that it produces clinical benefit with minimal side effects in patients with active pulmonary sarcoidosis. Yet these investigations have not documented whether such therapy would be effective in modulating local immune reactivity, or indeed whether the inhaled mode of administration is effective in depositing the drug at the site of the alveolitis. Essentially, all previous work on sarcoidosis has invariably focused on lymphocyte activity and its manipulation with therapy. It is now becoming increasingly recognized that both the T-cell activation and the granuloma formation occurring in sarcoidosis are mechanisms controlled by macrophage-like cells.7 In support we have conclusively shown that the immune aberrations within the sarcoid lung extend to the non-lymphoid population, involving subpopulations of macrophages with distinctive phenotype and function.8'9 In particular, we have observed the emergence of a specific population of cells with the morphological appearance of alveolar macrophages (AM), but coexpressing antigenic characteristics of both mature phagocytes and dendritic antigen-presenting cells. Experiments on the functional capacity of these macrophages with the double phenotype have shown them to suppress autologous and allogeneic peripheral blood lymphocyte reactivity. '0"' Of greater significance, such alterations have been found to reflect changes in clinical status. '2 These observations were made possible by the use of monoclonal antibody (MoAb) probes that specifically identify subpopulations of macrophages Correspondence: M.A. Spiteri, Ph.D., M.R. C.P. Received: 19 September 1990 coright.