Postgrad Med J: first published as 10.1136/pgmj.67.786.327 on 1 April 1991. Downloaded from Postgrad Med J (1991) 67, 327 - 329 ©) The Fellowship of Postgraduate Medicine, 1991

Leading Article Inhaled corticosteroids in pulmonary sarcoidosis Monica A. Spiteri The Royal Brompton andNational Heart Hospital, Fulham Road, London SW3 6HP, UK

Introduction Pulmonary sarcoidosis is a chronic inflammatory chial asthma. Early attempts to use inhaled steroids disease characterized histologically by granuloma for the treatment of pulmonary sarcoidosis were formation within the lung interstitium. Clinically unsuccessful,5 probably because the daily dose was the disease has a variable course. In the majority of too low and the disease too advanced to be patients the inflammation resolves spontaneously, treatable with targeted corticosteroids. With the while in 15-20% of patients the granulomata development of newer generations of inhaled persist and lead to irreversible fibrosis with signi- corticosteroids that possess an improved ratio ficant respiratory embarrassment. Clear guidelines between anti-inflammatory effects and systemic for treatment in this disease are absent. potency, together with a different lung pharmaco- Despite substantial advances in the scientific kinetic profile, the idea for using such therapy in understanding of the basic immune mechanisms pulmonary sarcoidosis has revived. Preliminary responsible for pulmonary sarcoidosis, there is to studies6 using inhaled budesonide in a dose of

date a lack of any clear prognostic signs in this 16001ig per day have shown that it produces copyright. disease. This leaves in dispute the question of who clinical benefit with minimal side effects in patients and when to treat. Usually therapy is started late, with active pulmonary sarcoidosis. Yet these inves- and consists of systemic corticosteroids in varying tigations have not documented whether such doses and regimes with variable clinical efficacy. therapy would be effective in modulating local Systemic corticosteroids have been shown to con- immune reactivity, or indeed whether the inhaled trol the local inflammatory response in sarcoidosis mode of administration is effective in depositing by decreasing the CD4/CD8 T cell ratio, with the drug at the site of the alveolitis.

consequent increase in CD8 + T-lymphocyte Essentially, all previous work on sarcoidosis has http://pmj.bmj.com/ accumulation at the site of the granuloma.' In invariably focused on lymphocyte activity and its addition, there is also suppression oflocal immunog- manipulation with therapy. It is now becoming lobulin production, and a reduction in the lym- increasingly recognized that both the T-cell activa- phocytic production of interleukin-2.2 Invariably, tion and the granuloma formation occurring in however, undesirable side effects occur. For this sarcoidosis are mechanisms controlled by macro- reason systemic steroid therapy is often started too phage-like cells.7 In support we have conclusively late (or curtailed too soon), with many of the shown that the immune aberrations within the patients already developing pulmonary fibrosis. sarcoid lung extend to the non-lymphoid popula- on September 24, 2021 by guest. Protected When this happens the lung damage is irreversible, tion, involving subpopulations of macrophages with steroid therapy often being found to be with distinctive phenotype and function.8'9 In parti- ineffective both clinically and at the cellular level.3'4 cular, we have observed the emergence ofa specific Against such a background, there is clearly a population ofcells with the morphological appear- need for a therapeutic regimen that is safe enough ance of alveolar macrophages (AM), but co- to commence early in disease, that can be targeted expressing antigenic characteristics of both mature to the lung, and that can be shown (as with systemic phagocytes and dendritic antigen-presenting cells. steroids) to modulate the underlying cellular dys- Experiments on the functional capacity of these function occurring in the lungs of sarcoid patients. macrophages with the double phenotype have Inhaled corticosteroids became available 15 shown them to suppress autologous and allogeneic years ago for the treatment of patients with bron- 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 Correspondence: M.A. Spiteri, Ph.D., M.R.C.P. monoclonal antibody (MoAb) probes that speci- Received: 19 September 1990 fically identify subpopulations of macrophages Postgrad Med J: first published as 10.1136/pgmj.67.786.327 on 1 April 1991. Downloaded from 328 M.A. SPITERI within the bronchoalveolar lavage (BAL) of active a general reflection of local anti-inflammatory sarcoid patients.'3 It appears that the persistent action. granulomata and fibrosis seen in pulmonary sar- To address this question, glucocorticosteroid coidosis are features determined as much by AM as receptor antibody probes, in combination with by T-lymphocytes. It follows, therefore, that in well-proven immunocytological methods'6 were order for steroids to be properly evaluated as a used to relate the above changes in AM phenotype means of treating pulmonary sarcoidosis their and function to steroid receptor expression. Initial immune-regulatory effect on the macrophage results using appropriately treated cytospins (i.e. population in the lung must be ascertained. fixed in 2% paraformaldehyde and permeabilized with 0.05% Triton X-100) showed a significant increase in the intensity of nuclear GR staining in Studies AM obtained from patients treated with inhaled steroids. This was not seen in the placebo group. Initial placebo-controlled studies were designed to In separate experiments the effect ofcontact with analyse the effects of inhaled steroids on the steroid on cell phenotype and function was deter- phenotype and functional capacity of AM obtain- mined by setting up cultures of cell suspensions of ed by BAL from a homogeneous group of previ- whole lavage from healthy subjects, into which ously untreated active sarcoid patients. The varying concentrations of inhaled steroid in sus- observed local cellular results were correlated with pension were introduced under pre-set conditions clinical, radiological and physiological parameters. (established in earlier studies). Parallel control The placebo group consisted ofan equal number of cultures (with no steroid) were also set up. In vitro active sarcoid patients who seemed to be in the incubation with steroid resulted in significant same stage of their disease as the treated group (in change in AM phenotype, in particular the down- so far as clinical status, pulmonary function and regulation of the phenotype of dendritic cells, with radiological grading). The results showed that simultaneous reduction in the proportion of in situ regimens of inhaled steroids such as budesonide antigen-presenting macrophages. A general reduc- administered via a 750 cm2 spacer device in a tion in Fc receptor expression on AM was also copyright. relatively small dose of 800 jig twice daily achieve noted. However, in contrast to the above results approximately 10% alveolar deposition and effect- using cytospins of unfractionated BAL cells from ive symptomatic relief with no adverse effects.'4 inhaled steroid-treated patients, the in vitro effect of Furthermore, within 4 months the inhaled therapy exposure to steroid on the expression ofcell steroid was shown capable of modulating the tested receptor was phasic.'" More recently these results features of the aberrant immunological reactions were substantiated by similar in vitro experiments existent in the lung in this disease. Inhaled steroids carried out on the AM population from patients not only produced a decrease significant in lavage with sarcoidosis. Again, a direct effect of the http://pmj.bmj.com/ lymphocytosis, but concurrently induced a return instilled steroid on sarcoid AM subsets was clearly to normal in the phenotypic proportion of AM shown.'8 subpopulations.'4 As the rising proportions of particular macrophage subsets in sarcoid BAL had been previously found to reflect severity of Conclusion disease," the above results gave the first indicator that inhaled steroids might be able to efficaciously The above data promote the hypothesis that the modify the disease process in sarcoidosis. In sup- altered AM function observed in vivo after treat- on September 24, 2021 by guest. Protected port, after treatment with inhaled steroid, the ment ofpatients with active pulmonary sarcoidosis induced changes in the proportion of phenotypi- occurs as a result of a direct contact of the steroid cally distinct macrophage subsets were accompan- with AM subpopulations. It would appear that not ied by a reversal of the suppressive AM function only do targeted steroid regimes allow the appro- previously observed in active sarcoid BAL.'4 priate drug to be delivered to the site of inflam- Although these observations were not associated mation, but they also effectively modulate the with any striking improvement in chest X-ray aberrant macrophage-lymphocyte interactions appearance or lung function, in an extended study existent in the sarcoid lung without any systemic over 18 months, inhaled therapy succeeded in upset.'5 In fact, the dose of inhaled steroid (bude- keeping patients in remission, while maintaining a sonide) used in the in vivo studies (1600 pg per day) modulatory effect on the cellular aberrations in has been shown to be equivalent to 5.0 mg per day their lungs.'5 No similar changes were seen in the of oral prednisolone in terms of ability to suppress placebo control group. cortisol levels.'9 The results prompted the intriguing questions of On the basis of the above results, it would seem whether the above observations occurred as a logical that inhaled steroids deserve a place in the direct effect ofinhaled steroid at the cellular level or early management of patients with pulmonary Postgrad Med J: first published as 10.1136/pgmj.67.786.327 on 1 April 1991. Downloaded from INHALED CORTICOSTEROIDS IN PULMONARY SARCOIDOSIS 329

sarcoidosis, either as sole therapy or in combina- drug at particular cell subpopulations (perhaps tion with lower doses of conventional systemic with the help of liposomes) in order to arrest the immuno-suppressive drugs. The rationale of such evolution of the exaggerated immune response in an approach would be aimed at aborting the sarcoidosis, and prevent clinical deterioration. In potential persistence of granulomata within their this context a detailed evaluation of AM sub- lung parenchyma, and the subsequent development populations in the sarcoid lung could also provide of fibrosis. Further in vitro evaluation needs to be criteria for staging disease activity, as well as undertaken to delineate the appropriate dose and guiding therapy in these patients. frequency of administration of inhaled steroids to increase their clinical and physiological efficacy in sarcoid inflammation. Use of molecular biological techniques may provide the answer to the nature of Acknowledgements the macrophage glucocorticoid steroid receptor, its Most of the above studies were carried out while the and relationship to the different AM subsets in author was at the Royal Free Hospital, London. They health and during inflammation. Such information were in part supported by a grant from the Fellowship of would enable us to increase the efficacy of the Postgraduate Medicine. We are grateful to Miss M. inhaled steroid at the cellular level by directing the O'Malley for her secretarial assistance.

References

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