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Dr. Miller is Director, Pulmonary Medicine, Saint Vincent Catholic Medical Centers, Brooklyn Queens Region.
Correspondence to: Albert Miller, MD, FCCP, Director, Pulmonary Medicine, Saint Vincent Catholic Medical Centers, Brooklyn Queens Region, Suite 3-J, 88–25 153rd St, Jamiaca, NY 11432-3748; e-mail: amiller{at}cmcny.com
Sarcoidosis, an immunopathogenic inflammatory disease of unproven etiology and universal organ involvement, has generated a vast literature. We have a good understanding of its clinical and laboratory manifestations, and a consensus exists that symptomatic and/or significantly organ-impairing disease can be treated. Certain questions continue to be addressed, however, in much of the literature, with no clearer answers today than existed 25 years ago, as a recent revisit of the proceedings of an early international symposium on sarcoidosis held in New York in 1975 made eerily apparent: Are there acceptable substitutes for systemic corticosteroids? Are they useful early in therapy, or only when steroids have proven ineffectual or cannot be discontinued without relapse, or have caused morbidity? How can the course and outcome of a particular patient be predicted? What is the optimum dose and duration of therapy? Unquestionable advances in imaging and in understanding and measurement of immune and inflammatory processes have not answered these questions.
Certain observations made 3 decades ago still provide useful guidelines. Although rates of relapse have varied (the highest being 70%),1 there was a consensus that relapse did not occur until prednisone dosage was decreased to 10 to 15 mg/d. Most manifestations of this multiorgan disease are detectable within the first year of observation.2 The time of onset of chronic sarcoidosis cannot be specified, making any attempt at a prognostic timeline tenuous. The likelihood of ultimate remission is great (60 to 80% spontaneous remission) in stage I (mediastinal/hilar lymphadenopathy alone on standard radiographs) and stage II (adenopathy with infiltrate; 50 to 70% often with therapy), especially if the disease is acute in onset.3 4 5 Remission is much less likely (< 30%) in stage III (infiltrates alone) and virtually nil in stage IV (radiographic evidence of fibrosis, including bullae, microcysts, and retraction). Nevertheless, even patients with long-standing fibrotic disease may improve with therapy, and such patients deserve a trial.2 While symptoms, radiographic abnormalities, and vital capacity (VC) are likely to improve (in as many as 75% of patients treated),1 improvement in diffusing capacity of the lung for carbon monoxide (DLCO) is far less likely (< 33% in the same large study)1 ; when it does improve, it is often much later.6 Improvement in pulmonary function may prevent or delay cor pulmonale, one of the major mechanisms of mortality in sarcoidosis. An early investigation (1971)7 of pulmonary circulation in patients with sarcoidosis found that increased pulmonary vascular resistance, increased pulmonary artery pressure, and reduced cardiac index all correlated with impairment in DLCO. More recent techniques have demonstrated the correlation between right ventricular function and total lung capacity.8 Despite favorable remission rates for the most common presentations of pulmonary sarcoidosis, mortality of chronic disease is appreciable, life expectancy is shortened, with 75% of deaths occurring before the age of 60 years, and radiographic abnormalities often persist a lifetime.9
Are we accumulating sufficient experience to answer one of the most critical and long-standing questions: Does therapy, whatever its short-term benefits, affect the long-term status of sarcoidosis patients? Previous randomized prospective trials10 11 showed no differences in treatment arms, but enrolled patients with no or minimal symptoms and impairment whose prognosis without treatment would be favorable. More recently, the British Thoracic Society Sarcoidosis Study12 compared 27 stages II and III patients with stable radiographic findings assigned to treatment for 18 months, with 31 similar patients treated "selectively" if any had symptoms develop or had functional deterioration. At 5 years, VC was 9% of predicted larger in the patients treated long term and DLCO was 5% greater, compared with no or minimum increases in the selectively treated group; the increase in VC was statistically significant. The difference between the arms was lessened by two "treated" patients who did not receive steroids and six selectively treated patients who did.
The article by Pietinalho et al in this issue of CHEST (see page 24) provides useful information on this question based on a randomized trial of 60 patients with stage II/III disease: 3.5 years after a 1.5-year course of systemic followed by inhalational steroids, both VC and DLCO significantly improved in the treated group, by 220 mL or 5% from baseline and 0.56 mmol/min/kPa or 6% from baseline, respectively, compared with no appreciable change and a small decrease in the control group. These modest improvements are hauntingly similar to those reported by Colp et al2 in 1976 (as change in percent predicted) of 2 to 13% in VC and 4 to 10% in DLCO, with the patients with poorer function showing the greater improvements. Control patients in the present study required treatment much more frequently during the 5 years. These improvements in pulmonary function were minimized by the well-maintained functional status of most of the patients on initiation of treatment, the reporting of results as absolute values, which are expected to decline over 5 years, and the crossover of 16 control patients who required therapy.
Controlled clinical trials of therapy for sarcoidosis have been proposed for decades, and the difficulties in carrying them out have been recognized for just as long. The present authors cite "differences in patient populations, ethnic backgrounds, duration of disease ... and ... in study protocols, doses and duration [as well as mode] of treatment." Colp et al2 commented in 1976: "We have been talking about doing a controlled trial for 15 years and have not considered this practical ... we did not feel justified in putting patients with normal function, or close to normal, on long-term steroids. For the patients with severe functional impairment who were symptomatic, it did not seem justified to withhold therapy." These considerations remain valid and are illustrated by the present study. Baseline function was normal or close to normal, and date of onset was elusive, so that treatment was certainly not "immediate." Despite these not-unexpected difficulties, this 5-year study, "the first ... to ... demonstrate that ... treatment of patients with stage II sarcoidosis results in an improved functional outcome," provides a second scientific basis for treatment, that long-term as well as short-term benefits may be achieved. It also demonstrates the contribution of a nationwide cooperating system of sarcoidosis centers, and supports a therapeutic effect from inhaled steroids.
References
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