INTRODUCTION

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Sarcoidosis is a granulomatous disease of unknown etiology. It has its effects chiefly in the pulmonary system, but often also involves other target organs such as the eyes, skin, and nervous system. Pathologically, sarcoidosis is characterized by noncaseating epithelioid granulomas and derangement of normal tissue architecture (1). The disease is often acute and self-limiting, but may also have a chronic pattern, waxing and waning over a long period.

Although corticosteroids are considered to be beneficial in treating pulmonary sarcoidosis (2, 3), uncertainty surrounds the use and value of immunosuppressive agents such as methotrexate (4), chlorambucil (5), azathioprine (6), and cyclosporin A (CsA) (7). Anecodotal studies suggest that CsA may benefit some patients with sarcoidosis (8); but no controlled trials of its use have been performed to date. A study by Martinet and coworkers examined in vitro and in vivo effects of CsA on the alveolitis of active sarcoidosis (11). Although CsA suppressed in vitro release of interleukin-2 (IL-2), a comparable therapeutic effect was not seen in eight patients treated over a 6-mo period, and lung function was not improved.

CsA inhibits the amplification of T-cell-related immune mechanisms and may be effective in decreasing the granulomatous inflammation associated with sarcoidosis (11, 12). In theory, the drug may also be used in conjunction with corticosteroids, allowing the dose of corticosteroids to be reduced, and we have observed some benefit of CsA in patients with interstitial lung disease of unknown etiology (13).

We hypothesized that CsA may have beneficial effects in sarcoidosis that are additional to benefits conferred by corticosteroid treatment. This possibility was examined in an open, randomized, controlled trial comparing combination therapy with CsA and prednisone with treatment with prednisone alone.

	METHODS

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Patients

Patients with biopsy-proven sarcoidosis and no evidence of mycobacterial or fungal infection or a history of exposure to agents known to cause granulomatous disease were eligible. These included newly diagnosed patients as well as previously diagnosed patients who had been in remission and off treatment for at least 3 mo. Inclusion criteria were objective evidence of recent (within 3 mo) deterioration of lung function and/or dyspnea.

Informed consent was obtained from all subjects, and the study was approved by the Ethics Committee of The University of Stellenbosch and Tygerberg Hospital.

Treatment Protocol

Patients were randomized to receive one of two treatment regimens: (1) prednisone 20 mg/d for 3 mo, followed by 15 mg/d for 3 mo and 10 mg/d for up to 18 mo (P); or (2) prednisone as in (1) combined with CsA 5 to 7 mg/kg/d (P-CsA). Blood trough levels of CsA were determined every 2 to 4 wk and the CsA dose adjusted to maintain levels of 100 to 200 ng/ml. If treatment failed, patients were crossed over to the alternative treatment regimen.

Evaluations

Patients were assessed at baseline and at 3, 9, and 18 mo for a response to therapy. The follow-up evaluation included a clinical assessment of dyspnea, pulmonary function (PF) tests, chest radiographs, bronchoalveolar lavage (BAL), and monitoring of adverse effects.

Evaluation of dyspnea. The patients' level of dyspnea was classified on a scale of I to IV, as outlined by the New York Heart Association (NYHA) (14). This classification is in general use in the Stellenbosch University Hospital, and all previous assessments of the level of dyspnea had been made with this method (13).

PF testing. PF tests were performed on all study subjects and consisted of standard spirometry done with a Med-Science wedge spirometer (Med-Science Electronics, St. Louis, MO). Lung volumes were obtained using an N₂-washout method (13). The measurement of lung function was made with standard protocols and conformed to American Thoracic Society guidelines (15). The predicted normal values used were those proposed by Schoenberg and colleagues for spirometry (16), and by Goldman and Becklake for lung volume (17).

Chest radiographs. Chest radiographs were made in the posterior-anterior and lateral projections, and were classified by a single experienced reader, blinded to the patients' clinical history, in a standard manner according to the radiographic stage (0 to IV) (18).

BAL. Fiberoptic bronchoscopy and BAL were performed according to standard methods (19).

Adverse effects. New symptoms and signs that manifested during the treatment period were documented as possible adverse effects. During each visit, patients were asked specific questions related to side effects of the treatment. Hepatic, renal, and hematologic function was also monitored.

Definitions

A significant change in FVC and FEV₁ was defined as a 15% change from baseline. For TLC, a significant change was defined as a 10% change from baseline. Clinical improvement was defined as a significant increase in at least two PF parameters or one PF parameter with a compatible change in the patient's level of dyspnea. Clinical deterioration was defined as a significant decrease in two PF parameters or one PF parameter with a compatible worsening in the patient's level of dyspnea. A good therapeutic response was defined as normalized PF and minimal symptoms after at least 9 mo of treatment. Relapse was defined as a clinical deterioration after treatment had been stopped for at least 3 mo. Failure of treatment was defined as clinical deterioration after a patient had been treated for at least 9 mo.

Statistical Analysis

The significance of the effect of treatment within groups was assessed with Wilcoxon's signed rank test (numeric data) and the Stuart-Maxwell test (ordinal data) by comparing data at baseline with data at 3, 9, and 18 mo. Between-group comparisons at baseline and at 3, 9, and 18 mo were done with the Mann-Whitney U-test (numeric data), the chi-square test, and Fisher's exact test (ordinal data). The significance of the difference between the two clinical improvement (see definition) rates at 9 and 18 mo was assessed with the z statistic as described by Fleiss (20). To control for a Type I error, the p values obtained were multiplied by the number of pairwise comparisons performed (numeric data). Data at 18 mo were analyzed both as current treatments and on an intention-to-treat basis. Significance was defined as p < 0.05.

	RESULTS

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Baseline Observations

Thirty-seven patients with active deteriorating sarcoidosis were entered into the study between January 1988 and June 1993, employing the inclusion criteria outlined earlier. Eighteen of the patients were randomized to the P group and 19 to the P-CsA group. Of the 37 patients enrolled in the study, seven were enrolled twice, three because of failure of treatment and four because of relapse of the disease. All patients received treatment for at least 9 mo. Only seven and 11 patients (P and P-CsA, respectively) received treatment for at least 18 mo. However, five patients in the P and one patient in the P-CsA group, who did not complete 18 mo of treatment after a good therapeutic response, were included in an intention-to-treat analysis at 18 mo, yielding a total of 12 patients in each treatment group. An outline of the patients' demographic and clinical characteristics is given in Table 1. Overall, no significant differences were noted between the treatment groups.

The mean age of the patients was 38 yr in the P group and 36 yr in the P-CsA group. In the two treatment groups, 61% and 68% of the patients, respectively, were female and 56% and 58%, respectively, were of mixed race. The majority of patients in each group were lifetime nonsmokers. Pulmonary disease with extrapulmonary manifestations occurred in six patients: three in each group (two with uveitis, two with skin involvement, and two with cardiac involvement).

Clinical and PF data were complete for all subjects. Twenty nine of the 37 patients in the study had complete roentgenographic follow-up. Seven patients did not have a chest radiograph at 3 mo and one did not have a chest radiograph at 9 mo. The following BAL results were incomplete: two at baseline, 10 at 3 mo, eight at 9 mo, and four at 18 mo.

The majority of patients had more than NYHA Grade 1 dyspnea, and more than half the patients had severe radiologic involvement. Both groups had mild to moderate impairment of PF, with a mean FEV₁ of 70.8% (P) and 63.6% (P-CsA) predicted, and a mean FVC of 70.4% (P) and 67.4% (P-CsA) predicted, respectively. The mean pretreatment lymphocytes (percentage of total cell count) were 31.5% and 27.3%, respectively, for the P and P-CsA groups.

Treatment

The average (mean ± SEM) daily dose of CsA was 6.8 ± 0.3 mg/kg, 4.8 ± 0.4 mg/kg, 3.0 ± 0.3 mg/kg, and 2.5 ± 0.3 mg/kg after 1 wk, 3 mo, 9 mo, and 18 mo, respectively. The median blood CsA concentration was: 959.4 ng/ml (range 95 to 1,870 ng/ml) at baseline; 706.6 ng/ml (range: 40 to 2,200 ng/ml) at 3 mo; 247.6 ng/ml (range: 19 to 424 ng/ml) at 9 mo; and 351.1 ng/ml (range: 40 to 1,176 ng/ml) at 18 mo. The mean starting dose of prednisone was 20 mg/d for both groups, and thereafter it was 17.5 mg/d and 16.5 mg/d (at 3 mo), 11.25 mg/d and 12.2 mg/d (at 9 mo), and 10.7 mg/d and 12.5 mg/d (at 18 mo) for the P and P-CsA groups, respectively.

Outcome Parameters

Dyspnea. As compared with the baseline evaluation, a significant (p < 0.05) improvement in the degree of dyspnea was found for up to 9 mo in the P group and 18 mo in the P-CsA group. There were no statistically significant differences between the treatment groups in the improvement in the dyspnea levels.

PF testing. A significant (p < 0.05) improvement in PF test results (FVC; Figure 1) was found until 9 and 3 mo in the P and P-CsA groups, respectively. A combined assessment of dyspnea and lung function responses to treatment (Table 2) showed clinical improvement (see definition) in 67% of the P group and 53% of the P-CsA group patients at 9 mo and in 67% of the P group and 58% of the P-CsA group patients at 18 mo. The groups did not differ statistically significantly with respect to these improvement rates. Only three patients experienced clinical deterioration despite treatment over the 18-mo study period.

View larger version (14K): [in this window] [in a new window]   Figure 1.   Changes in percent predicted FVC with treatment (*p < 0.05 versus baseline). No statistically significant difference was found between treatment groups.

Chest radiographs. No statistically significant change was observed in the radiologic staging of sarcoidosis in either treatment group at any time during the treatment period (data not shown).

BAL. Cellular changes in BAL, although not statistically significant (p < 0.07) demonstrated decreases in total cell counts and in the percentage of lymphocytes. A statistically significant (p < 0.05), reduction in the mean percentage of lymphocytes (Figure 2) occurred at 9 mo in the P group only.

View larger version (26K): [in this window] [in a new window]   Figure 2.   Changes in BAL total cell counts and percent lymphocytes with treatment. (*p < 0.05 versus baseline). No statistically significant difference was found between groups.

Adverse effects. The following infections occurred in six patients in the P group and 11 patients in the P-CsA group: acute bronchitis in 15 patients, pneumonia in one patient and acute sinusitis in one patient. The average (mean ± SEM) plasma creatinine concentration increased significantly (p < 0.05) in the P-CsA group, from 74.8 ± 4.4 mmol/l at baseline to 90.3 ± 6.4, 90.0 ± 3.8, and 89.7 ± 4.2 mmol/l at 3, 9, and 18 mo, respectively. At 3 and 9 mo the mean creatinine concentrations of the two treatment groups differed significantly (p < 0.05). Paresthesias (in one and 11 patients in the P and P-CsA groups, respectively) and hypertrichosis (in 0 and 9 patients in the P and P-CsA groups, respectively) were significantly more frequent (p < 0.05) in the P-CsA group.

Newly developed hypertension, defined as either a systolic pressure of more than 140 mm Hg or diastolic blood pressure of more than 90 mm Hg on two or more consecutive occasions, was diagnosed in two patients in the P group and 4 patients in the P-CsA group. A worsening in preexisting hypertension was noted in one patient in the P group and two patients in the P-CsA group. At 3 and 9 mo, the average diastolic blood pressure was significantly higher (p < 0.05) in the P-CsA group. Body weight and serum cholesterol levels also increased significantly (p < 0.05) from baseline in both treatment groups, but differences between the two groups were not statistically significant.

Other, less frequent side effects, reported equally in both groups, included cushingoid facies, nausea, tremor, peripheral edema, gingival hyperplasia, hyperglycemia, depression, muscle weakness, and headache. No evidence was found for hepatotoxicity. In general, reactions were mild and well tolerated, and fully reversible after termination of treatment. The withdrawal of patients because of adverse events was necessary in the P-CsA group owing to renal impairment (n = 1) and hypertrichosis (n = 1), and in the P group because of hypertension (n = 1).

Discontinuation of treatment between 9 and 18 mo.

1. Good therapeutic response. The treatment of five patients in the P and three patients in the P-CsA group was stopped because of a good therapeutic response.
2. Failure of treatment. The respective treatment protocols failed in two patients in the P and one in the P-CsA group, and these patients were crossed over to the alternative treatment regimen. No subsequent treatment failure or relapse was observed during the study period in this group of patients.
3. Withdrawal. Withdrawals in the P group were the result of adverse events (n = 1), pregnancy (n = 1) and loss to follow-up (n = 2). In the P-CsA group, withdrawals were due to adverse events (n = 2); noncompliance with treatment (n = 1), and loss to follow-up (n = 1).

Discontinuation of treatment at 18 mo.

1. Good therapeutic response. A further four patients in each of the P and P-CsA groups, respectively, had a good therapeutic response and were taken off all treatment.

	DISCUSSION

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We conducted an open, randomized, controlled trial to examine the potential benefits of treatment with CsA in sarcoidosis. Combination therapy with P and CsA was compared with treatment with P as a single agent. No evidence was found that the combination was more effective than P alone. In addition, serious side effects were associated more frequently with combination therapy.

Although corticosteroids have for more than 30 yr been the mainstay of treatment for sarcoidosis, their role in the management of the disease remains uncertain. This is the result of a significant side-effect profile and an apparent lack of evidence for the ultimate improvement of outcome in treated patients. Various alternative treatments have been employed, including methotrexate (4), chloroquine (21), chlorambucil (5), and azathioprine (6, 22), with varying success. However, side effects remain a significant problem. The efficacy of CsA in sarcoidosis has been suggested by anecdotal reports, and this has raised the possibility that the drug may have significant steroid-sparing activity or additional beneficial actions on the underlying pathophysiology of the disease. Treatment with CsA is attractive on a theoretical basis because its immunomodulating effects may complement steroid action (23) and possibly reverse the basic underlying immunopathology in sarcoidosis (11). However, CsA is expensive and toxic, and it should be used only in situations in which its efficacy has been proven.

We compared equivalent intermediate dosages of corticosteroids, adding CsA in one of our two treatment groups. Evidence suggests that the doses used (20 mg/d) were high enough to produce clinical improvement in sarcoidosis (24), while still permitting detection of additional benefits given by CsA therapy. The use of a placebo arm was not considered ethical in patients with evidence of progressive disease.

No randomized controlled trails have evaluated CsA for the treatment of sarcoidosis. In an open study of eight subjects over a period of 6 mo, Martinet and coworkers (11), administered CsA in a dose of 10 mg/kg/d. Efficacy was judged by spontaneous in vitro release of IL-2 from lung T-cells before and during treatment. However, a lack of in vivo effect of CsA was observed, paralleled by the absence of improvement in PF measurements. Our study was similar in design to that of Martinet and coworkers, and demonstrated a similar lack of benefit for PF measurements with CsA treatment for up to 18 mo, suggesting that the lack of efficacy of CsA was not related to the short duration of treatment in the study by Martinet and colleagues (11). It remains a possibility that the P in our treatment groups caused a maximal effect, and that CsA could not increase that response. Because this was not a formal steroid-sparing trial, no firm conclusions can be made in this regard.

It is noteworthy that despite the Stage III or IV disease in the majority of our patients, both of our treatment groups demonstrated an improvement in dyspnea and PF measurements at the 3-mo assessment, suggesting that the degree of illness was at least partially reversible. In the combined assessment of dyspnea and PF, 67% of patients in the P group and 58% in the P-CsA group showed improvement at 18 mo, which compares favorably with the results in published studies (3, 24). It is also of note that nine patients in the P group and seven patients in the P-CsA group had normalization of PF within 18 mo of treatment, and that therapy for these patients could subsequently be withdrawn. In support of these findings, the BAL results demonstrated similar trends, although neither treatment could normalize the percentage of BAL lymphocytes. Decreases in both total cell counts and the percentage of lymphocytes were noted, suggesting some reversal of the patient's underlying immunopathology. Although the differences were not statistically significant, the BAL responses appeared to be more marked in the steroid-only group. Subtyping of T cells to further examine this possibility, was not done. It remains possible that a higher corticosteroid dose would have yielded even greater clinical and functional responses. If that had been true, one would have expected the additional therapeutic effect of CsA to become apparent.

The lack of benefit of CsA as an adjunct to corticosteroids in sarcoidosis is in contrast to its beneficial effect in the management of kidney and heart allografts as combined with prednisone (11, 12, 27). Although conventional doses of CsA were used, there is some evidence that therapeutic levels may not be attained in the lung tissue itself (11). Despite the fact that blood levels of CsA were maintained at around 200 ng/ml, its lack of pulmonary bioavailability may have been responsible for the absence of a therapeutic effect, a concept supported by lower CsA levels in lung tissues than in other organs (11, 28).

Other reasons for the observed lack of benefit of CsA in our study have to be considered, as follows: (1) Because it is very difficult to study patients who have similar degrees of illness (29), beneficial responses in a subgroup of patients may not have been demonstrable. Too few patients with failed P therapy were studied to evaluate the benefits of CsA in this important subgroup of patients. (2) In assessing the therapeutic response, we used both symptoms and PF parameters. Although this method is reported to be most useful for staging the activity of disease (30), it remains possible that marginal therapeutic benefits of CsA were not detectable. (3) In studies of rare conditions, the relatively small number of patients in each treatment group, compounded by the number of dropouts, is of concern (31). The power of our statistical analysis to detect a 40% difference in improvement rates between our two treatment groups with 95% confidence is 70%. Furthermore, the consistent clinical and functional responses suggest that it is unlikely that the combination therapy was superior.

Patients treated with P did well, and CsA could only be considered as a steroid-sparing drug for this group. However, patients treated with CsA experienced more side effects. Side-effects of CsA and corticosteroids are well recognized, and were carefully monitored in our study. Problems were identified in both treatment groups, the most important in both groups being hypertension and infections. Although not statistically significant, there was almost a doubling of the number of infections in the P-CsA group. A significant increase in serum creatinine was observed in the P-CsA group, although treatment had to be terminated in only one patient. Other problems that were observed included paraesthesias and hypertrichosis. Withdrawal because of adverse events was necessary for three patients because of renal failure, uncontrolled hypertension, or severe hypertrichosis. A recent study by Lacono and associates (32) demonstrated that aerosolized CsA can be administered without systemic toxicity in lung transplant recipients, and the efficiency of this form of drug delivery to the lung in sarcoidosis needs to be assessed.

Despite compelling theoretical and in vitro evidence suggesting the efficacy of CsA in sarcoidosis, our study failed to support this notion. It remains a possibility that CsA is effective in certain subgroups with this disease. Appropriate indications and the duration and dosage of the drug for optimal treatment have yet to be determined, and further trials may be useful. However, at present, CsA does not appear to be useful for the routine treatment of sarcoidosis.