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* From the Meltola Hospital (Drs. Pietinalho and Selroos), Karjaa, Finland; the Departments of Pulmonary Medicine (Dr. Tukiainen), and Allergic Diseases (Dr. Haahtela), University Central Hospital, Helsinki, Finland; and Astra Draco AB (Dr. Persson), Lund, Sweden.
Correspondence to: Olof Selroos, MD, FCCP, Solvegatan 3A, S-233 62 Lund, Sweden; e-mail: olof.selroos{at}draco.se.astra.com
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Abstract |
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 TOP Abstract IntroductionMaterials and MethodsResultsDiscussionAppendix 1References |
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Design: Double-blind, placebo-controlled, parallel-group, multicenter study.
Setting: Twenty pulmonary medicine departments in Finland.
Patients: One hundred eighty-nine adult patients were randomized to treatment. Patients with erythema nodosum or stage IV sarcoidosis (pulmonary fibrosis), and patients requiring immediate treatment with oral corticosteroids for extrapulmonary lesions or chronic illnesses were excluded.
Treatment: The patients received either oral prednisolone for 3 months (20 mg/d for 8 weeks, 15 mg/d for 2 weeks, and 10 mg/d for 2 weeks) followed by inhaled budesonide (Pulmicort Turbuhaler; Astra Draco; Lund, Sweden) for 15 months at 800 µg bid, or placebo tablets followed by placebo inhaler therapy.
Measurements: Chest radiographs, lung volumes (FVC), diffusing capacity of the lung for carbon monoxide (DLCO), serum angiotensin-converting enzyme (SACE), and ß2-microglobulin at 3-month intervals.
Results: After 3 months of treatment, radiographic improvements were seen in the active-treatment group when compared to the placebo-treatment group. At 6 months, the difference was still statistically significant. Later, no differences were found. In patients with initial stage I lesions, neither the FVC nor the DLCO (the percent predicted mean values) changed during the study, as they were normal from the beginning. In patients with initial stage II disease, the difference in the FVC mean values between the groups also remained unchanged throughout the study. In stage II patients treated for 18 months, but not earlier, the difference in DLCO became statistically significant; the largest differences were seen in patients with initial FVC values < 80% of predicted and DLCO values < 75% of predicted. The decrease in SACE in the active-treated stage II patients was significantly larger than in the placebo-treated patients. No difference was observed in adverse events between the active-treated patients and the placebo-treated patients.
Conclusion: Treatment is not required for patients with stage I disease. An initial treatment with prednisolone followed by long-term inhalation of budesonide is more effective than placebo in patients with stage II disease. Sequential oral and inhaled corticosteroid therapy may be an alternative treatment regimen for stage II sarcoidosis patients, rather than long-term oral corticosteroid therapy alone.
Key Words: angiotensin-converting enzyme • budesonide • chest radiograph • glucocorticosteroids • inhalation • lung volumes • prednisolone • sarcoidosis
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Introduction |
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TOPAbstractIntroductionMaterials and MethodsResultsDiscussionAppendix 1References |
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A widely accepted clinical routine for the management of patients with pulmonary lesions is to follow up symptom-free patients for 6 to 12 months in the hope of achieving a spontaneous recovery. If symptoms or lung function indicate deterioration, or if radiographic lesions progress during an observation period, treatment with glucocorticosteroids is started.7 8 9
Oral corticosteroids are the most common agents used to treat sarcoidosis, and therapy usually results in an initial improvement in symptoms, radiographic findings, lung function, BAL findings, and 67Ga uptake.10 Increased enzyme activity, such as serum angiotensin-converting enzyme (SACE), and increased concentrations of serum lysozyme normalize during treatment with corticosteroids.11 Relapses may be prevented with continuous low-dose corticosteriod treatment,12 and even fibrotic changes may be prevented with aggressive corticosteriod treatment.13 However, the side effects of oral corticosteroids, including weight gain, fluid retention, hyperglycemia, hypertension, osteoporosis, cataract, and glaucoma, greatly limit their use. Most clinical studies have shown that the long-term prognosis has not been influenced by corticosteriod treatment.10 The poor long-term effect of corticosteroids in controlled clinical studies may be a result of the adopted follow-up strategy. The patients included in these studies may have had their pulmonary lesions far too long to respond to corticosteroids. It is unknown whether the long-term outcome would be different if treatment had been started earlier, eg, immediately after diagnosis.
The duration of treatment may vary: it may last months, or it may be lifelong. The side effects of oral corticosteroids often cause problems. Inhaled corticosteroids have a different and more favorable safety profile.14 However, only a few studies (some without a proper control group) have evaluated the effects of inhaled corticosteroids in pulmonary sarcoidosis; some clinical efficacy has been shown,15 16 17 18 and cellular findings in BAL fluid have changed,19 20 indicating beneficial effects of the treatment.
Inhaled budesonide is taken up in the lung parenchyma in sufficient concentrations to ensure good receptor binding,21 22 and the risk of side effects is low when compared to the risks associated with oral corticosteroids.14 Consequently, if it is shown to be effective, treatment with budesonide could be started early, instead of waiting and hoping for a spontaneous recovery (the standard follow-up). The ethical dilemma is that some patients would probably be treated unnecessarily.
We performed an 18-month, double-blind, placebo-controlled study with prednisolone, followed by budesonide, in patients with newly diagnosed radiographic stage I and stage II pulmonary sarcoidosis. The patients could be symptom-free and have normal lung function; therefore, no established clinical indications for starting treatment were required. A future aim is to follow these patients for a total of 5 years to evaluate whether early treatment with prednisolone followed by budesonide influences the 5-year prognosis of pulmonary sarcoidosis.
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Materials and Methods |
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TOPAbstractIntroductionMaterials and MethodsResultsDiscussionAppendix 1References |
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Patients
Sarcoidosis patients of either gender and 
18 years old were
included. They all had newly detected (diagnosed within 3 months from
the first symptoms or signs) radiographic stage I or stage II pulmonary
sarcoidosis, with a typical clinical picture of sarcoidosis. Other lung
diseases were carefully excluded. A positive tissue biopsy or
cytological finding, increased SACE activity, or a positive Kveim test
was desirable, but not obligatory.
The exclusion criteria were erythema nodosum, because of its generally good prognosis, and obvious pulmonary fibrosis. Patients with extrapulmonary sarcoidosis who required immediate treatment with oral corticosteroids or patients receiving treatment with corticosteroids for some other reason were also excluded, as were pregnant and lactating women, and patients with other specified, poorly controlled diseases.
Protocol
Active treatment consisted of oral prednisolone (20 mg/d for 8
weeks, 15 mg/d for 2 weeks, and 10 mg/d for 2 weeks) or corresponding
placebo tablets. The active-treatment group then received budesonide
via an inspiratory flow-driven, multidose, dry-powder 400-µg inhaler
at two inhalations bid (a daily dose of 1,600 µg) for 15 months. The
patients who were treated with placebo tablets continued with a placebo
inhaler.
The patients visited the clinics every third month during the 18-month treatment period. The clinical picture, chest radiographs, lung function tests (spirometry, diffusing capacity of the lung for carbon monoxide [DLCO]), SACE (Lieberman's modification of Cushman's method; reference value, 22 to 70 U/mL), serum and urinary calcium, as well as serum ß2-microglobulin (Phadebas ß2-Microtest; Pharmacia AB; Uppsala, Sweden) were monitored during the study. Serum cortisol levels were checked (Amerlex Radioimmunoassay; Amersham International; Amersham, UK) at the beginning of the study and at the 12-month visit. All tests and measurements were performed at the participating centers with the methods locally used.
A patient was defined as a treatment failure and was withdrawn from the
study if symptoms developed that were severe enough to interfere with
daily life activities, if there was an objective deterioration in
radiographic findings, or if there was a decrease 15% in
FVC or 20% in DLCO compared to baseline values.
Also, the patient was withdrawn if defined extrathoracic manifestations
of sarcoidosis developed that required systemic treatment with
corticosteroids.
The chest radiographs taken at each clinic visit were interpreted by the local chest physician/radiologist and were classified as stage 0, I, II, or III. They were then compared to the patient's first chest radiograph and were classified as normalized (score 0), improved (score 1), unchanged (score 2), or deteriorated (score 3). Decisions to be made on radiographic grounds during the study were based on these interpretations. After the study, all of the changes in chest radiographs were evaluated blindly by an independent radiologist and were categorized into six defined groups: normal, markedly improved, slightly improved, unchanged, slightly deteriorated, and markedly deteriorated (scores 0 to 5). The final stage was also reported (stage 0, I, II, or III).
At all clinic visits, the patients were asked whether any health problems or drug-related side effects had occurred since the previous visit. If any drug-related side effects had occurred, the responsible physician decided whether or not to withdraw the patient from the study. Also, the patient could leave the study at his or her own request, or could be withdrawn if poor compliance was observed.
Ethical Requirements and Good Clinical Practice Guidelines
The ethics committee at each study center approved the study
protocol before any study-related procedures were undertaken. The study
was monitored according to the Good Clinical Practice guidelines for
the Nordic countries.
All of the patients received thorough information about the study, and written informed consent was obtained in all cases.
The study was monitored by clinical research assistants from Meltola Hospital.
Statistical Analysis
The primary analyses in the study are based on an
all-patients-treated approach. The last value-extended principle was
applied from visit 3 to visit 7, but not from visit 2, as this was the
point in time when the treatment was changed from oral to inhaled
medication (for visits see Table 1
). The analyses were performed using t tests and analysis of
variance. Separate analyses were done to investigate the influence of
the initial stages (I and II) on the outcome. In all analyses, a
statistically significant level refers to p values < 0.05.
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Results |
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TOPAbstractIntroductionMaterials and MethodsResultsDiscussionAppendix 1References |
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Randomization resulted in 92 patients in the active-treatment group and 97 patients in the placebo-treatment group. There were no statistically significant differences between the groups at baseline for gender and age distribution, smoking habits, symptoms, or chest radiographic stage. The patient characteristics are presented in Table 2 .
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= 0.513;
p < 0.001). The results based on the former evaluations are
presented. In the interpretation of the radiographic stage at entry, no statistically significant difference was found between the local investigators and the independent observer, although more patients were classified by the independent observer as being at stage III at entry (n = 24) than were classified by the local investigator (n = 10).
In both treatment groups, the proportion of patients at radiographic stage I at entry was around 50% (budesonide group, 52%; placebo group, 47%).
In patients with initial stage I disease (n = 94), a significant difference between the groups was seen after treatment for 3 months (p = 0.003) and 6 months (p = 0.013), but not thereafter. In patients with initial stage II disease, no differences between the groups were seen during the entire study period. The improvements of the chest radiographs in the entire series of patients is shown in Figure 1 .
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Lung Function Tests
FVC, FEV1, and DLCO were
registered as absolute values and as percent of predicted values. The
differences between the active-treatment group and the
placebo-treatment group were consistent when comparing the results,
both in absolute numbers and in percent of predicted values.
FVC: The FVC values at baseline, after 3 months of prednisolone treatment, and at 18 months are shown in Table 4 . No significant difference was found between active-treated patients and placebo-treated patients with initial stage I disease. In patients with initial stage II disease, the FVC improved from baseline to 18 months on average by 0.15 L (4.56 to 4.71 L) in the active-treatment group, but remained the same (4.13 to 4.12 L) in the placebo-treatment group. The difference was not statistically significant (p = 0.39). However, when considering patients with an initial FVC < 80% of predicted values, the active-treated patients (n = 10) improved by 11.4 ± 6.9%, whereas the placebo-treated patients (n = 13) improved by 3.8 ± 10.1%. This difference was almost statistically significant (p = 0.057).
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Laboratory Test Values
SACE:
Treatment with corticosteroids resulted in a rapid decrease in
mean SACE activity. A spontaneous gradual decrease in SACE occurred in
the placebo-treatment group. After treatment for 18 months, no
significant difference was found between the active-treated patients
and the placebo-treated patients (for all patients and for patients
with initial stage I disease; see Table 4
). However, in patients with
initial stage II disease, there was an almost significant difference
between the groups at 3 months of treatment with prednisolone
(p = 0.058), but a significant difference at 6 months (p = 0.014).
This difference remained statistically significant throughout the study
period (Fig 2
).
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Serum Cortisol: The serum cortisol values were measured at the beginning of the study and after 12 months of treatment. There was a statistically significant decrease in mean (± SD) cortisol values in the active-treatment group (447 ± 177 to 331 ± 203 nmol/L) as compared with the placebo-treatment group (419 ± 197 to 428 ± 248 nmol/L). The difference between the changes was statistically significant (p = 0.002). All individual cortisol values except those for 2 patients in the placebo-treatment group and 11 patients in the active-treatment group remained within the normal reference range. The difference in serum cortisol mean values was also reflected in a difference in 24-h urinary cortisol values (active-treatment group, 367 ± 764 to 112 ± 536 nmol/24 h; placebo-treatment group, 205 ± 133 to 236 ± 154 nmol/24 h; difference, p = 0.007).
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Discussion |
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TOPAbstractIntroductionMaterials and MethodsResultsDiscussionAppendix 1References |
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Ninety-four stage I patients, 84 stage II patients, and 11 stage III patients were included in the study. At inclusion, both patient groups already had normal mean values for FVC and DLCO. It is well known that spontaneous recoveries are common in sarcoidosis,1 2 3 4 especially in patients having the acute type of sarcoidosis with erythema nodosum, arthralgia, and fever.1 2 The radiographic and functional improvements in the placebo-treated patients in this study were great, surpassing the improvements seen in a previous study in Finland.23 The spontaneous recoveries were especially frequent in patients with initial stage I chest radiographs. The reason for including the patients with stage I disease in the study, however, was to evaluate the 5-year prognosis, not just the immediate treatment effect. This 5-year follow-up study is underway.
When evaluating the effects of treatment in patients with initial stage II chest radiographic findings, the results are different. Although no significant difference between the groups could be found for radiographic developments, a difference in favor of steroid treatment was observed for DLCO values and SACE activity. The most striking difference between the treatment groups was found in patients with initial FVC values < 80% of predicted and initial DLCO values < 75% of predicted. This indicates that an initial 3-month course of oral prednisolone followed by a 15-month course of inhaled budesonide is a clinically effective treatment regimen for patients having a clinical indication for starting treatment with corticosteroids. The indication could be a restrictive abnormality in lung function tests in combination with increased SACE activity.
It is obvious that a third treatment group (a group receiving prednisolone for 3 months and placebo thereafter) would have been of interest. Now it remains unclear as to what extent the documented effects of corticosteroid treatment are due to the 3-month intervention with oral prednisolone. However, a 3-month course of oral steroids has not been considered to give stable and persisting treatment results.13 It was also noted that in stage II patients SACE values had not returned to normal during treatment with prednisolone, but did so during the later treatment with budesonide. The same trend was true of lung function tests, although not always statistically significantly different from placebo treatment.
Treatment with prednisolone, followed by budesonide, resulted in a statistically significant effect on serum and urinary cortisol mean values; however, very few of the individual values decreased to levels below the lower limit of the reference range, and the finding is probably not very important clinically. The side effects normally associated with systemic corticosteroid activity were not seen during the duration of the study.
When this study was initiated, it was known that single 1.6-mg doses of budesonide given to patients immediately before general anesthesia for thoracic surgery resulted in peripheral lung tissue concentrations of budesonide high enough to bind to glucocorticosteroid receptors and give an anti-inflammatory effect.22 Placebo-controlled studies in patients with active sarcoidosis using budesonide, 1.6 mg/d, showed changes in BAL cell findings consistent with beneficial effects.19 20 It was pertinent to expect that these changes could favorably influence the pathogenic mechanisms in pulmonary sarcoidosis.
In a prior study of 20 stage II to stage III sarcoidosis patients who did not improve spontaneously, openly given budesonide, 1.2 to 1.6 mg/d, seemed to diminish radiographic infiltrations, decrease SACE activity, and improve FVC values.15 A number of patients who were treated with oral corticosteroids and relapsed after stopping the treatment showed significant improvements with inhaled budesonide alone.24 In such cases, spontaneous remissions rarely occur. An oral corticosteroid-sparing effect of budesonide was reported in patients with chronic pulmonary sarcoidosis.25
When starting this study, we were aware of two double-blind studies that had been initiated but not completed. Both studies have now been reported. In the study by Zych et al,17 40 patients with stage II to stage III disease received an initial 6-week course of oral steroids. Thereafter, they were randomized to treatment with budesonide, 1.6 mg/d, or oral prednisolone, 10 mg/d. The study lasted for 12 months. No differences were found between the two maintenance treatments. Alberts et al18 included 47 patients with stage I to stage III disease in a double-blind, placebo-controlled study. At entry, the patients had abnormal lung function values (vital capacity [VC], < 79% of predicted; DLCO, < 77% of predicted) or > 20% lymphocytes in the BAL fluid (in stage II to stage III patients). Treatment consisted of budesonide, 1.2 mg once daily, or placebo for 6 months. A 6-month observation period without treatment followed. When compared to treatment with the placebo, budesonide treatment resulted in a significant increase in VC and in better subjective symptom control. However, both these studies were performed in patients who had had sarcoidosis for a considerable period of time. Therefore, we decided to include only patients who had had a diagnosis of sarcoidosis for < 3 months.
The results in stage II patients in our study are in agreement with the results of Zych et al17 and Alberts et al,18 showing beneficial effects during maintenance treatment with budesonide. However, this was not reported to be the case in a smaller study with several subgroups by Milman et al.26 Although they found an obvious increase in VC, the difference in change between the steroid-treated patients and placebo-treated patients was not statistically significant.
Clinical experience with budesonide as an initial treatment has indicated that functional and radiographic improvements develop gradually, but more slowly than improvements seen with high doses of oral steroids.15 The induction treatment should therefore probably consist of oral corticosteroids, and budesonide should be regarded as an oral corticosteroid-sparing agent during long-term maintenance treatment. The more favorable side-effect profile of budesonide (compared to that of oral corticosteroids) should be considered when deciding on a maintenance treatment. It should be noticed, however, that the reported study (as well as other studies17 18 showing efficacy with budesonide) was performed in white patients, who have a better overall prognosis than African-American patients.2
In this study, a significant difference was observed between the active-treated patients and the placebo-treated patients for serum and urinary cortisol mean values. When the study started, a budesonide dry-powder inhaler (Pulmicort Turbuhaler; Astra Draco) was considered equieffective with a budesonide pressurized metered-dose inhaler (pMDI). However, later studies27 documented a pulmonary deposition via a Turbuhaler that was twice as high as the pulmonary deposition via a pMDI. Therefore, the dosage of budesonide given in this study, 1,600 µg/d, may have been approaching a daily dosage of 3,200 µg as administered via a pMDI. This dosage is not recommended for clinical use and is associated with systemic corticosteroid activity.28 It is, of course, unknown whether a lower dose of budesonide administered via a Turbuhaler would have produced the same degree of clinical improvement.
Further double-blind, controlled studies are warranted. These studies should concentrate on patients with newly detected stage II to stage III disease, but with an impaired lung function. As a group, patients with stage I disease can be followed up without treatment in the hope of spontaneous recovery.
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Appendix 1 |
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TOPAbstractIntroductionMaterials and MethodsResultsDiscussionAppendix 1References |
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Acknowledgements |
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Footnotes |
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Dr. Persson is a full-time statistician employed by Astra Draco AB. 
Dr. Selroos, the author who initiated the study, has been appointed
a medical advisor to Astro Draco AB.
§ A complete list of the members of the Finnish Sarcoidosis Study Group
is given in the Appendix.
Financial support and all blinded study medication were provided by Astra Draco AB, Lund, Sweden.
Abbreviations: DLCO = diffusing capacity of the lung for carbon monoxide; pMDI = pressurized metered-dose inhaler; SACE = serum angiotensin-converting enzyme; VC = vital capacity
Received for publication September 29, 1998. Accepted for publication February 24, 1999.
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References |
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TOPAbstractIntroductionMaterials and MethodsResultsDiscussionAppendix 1References |
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