Idiopathic pulmonary fibrosis (IPF)/usual interstitial pneumonia is a deadly disease with no effective treatment. The purpose of this randomised prospective multicentric study was to characterise the clinical effects of interferon gamma (IFN-γ) 1b administered subcutaneously thrice weekly versus colchicine for 2 yrs. This study had no pre-specified end-points.
Fifty consecutive IPF patients were randomised. Patients with mild-to-moderate IPF were eligible for the study if they had histologically proven IPF, or, in the absence of surgical biopsy, fulfilled the European Respiratory Society/American Thoracic Society criteria.
In the intent-to-treat population, five out of 32 (15.6%) IFN-γ-1b patients and seven out of 18 (38.8%) colchicine patients died after a median follow-up period of 25 months Patients treated with IFN-γ 1b showed a better outcome after 2 yrs of therapy, and fewer symptoms, as assessed using the St George’s Respiratory Questionnaire, after 12 months of therapy. Also, the IFN-γ-1b group exhibited a higher forced vital capacity (percentage of the predicted value) after 24 months of treatment. No significant differences were detected in resting arterial oxygen tension, total lung capacity (% pred), transfer factor of the lung for carbon monoxide (% pred) and high-resolution computed tomographic scoring between the two treatment groups.
These data suggest that long-term treatment with interferon gamma 1b may improve survival and outcome in patients with mild-to-moderate idiopathic pulmonary fibrosis. Further studies are needed to verify these results.
Idiopathic pulmonary fibrosis (IPF) or cryptogenic fibrosing alveolitis is the most common among the idiopathic interstitial pneumonias and has a dismal prognosis 1–3. The median survival of patients with IPF is 3–5 yrs after the onset of symptoms 4, 5. In this context, it is important to emphasise that this disorder is largely unresponsive to the currently recommended combined treatment with corticosteroids and immunosuppressives 1. Therefore, there is a need for novel therapies to reverse or at least limit the lung fibroblast proliferation/activation and aberrant connective tissue remodelling that characterise this devastating disease 6, 7.
Interferon gamma (IFN-γ) is a potential therapeutic candidate because it regulates both macrophage and fibroblast functions 6, 8, 9. The theoretical benefits would include diminished expression of insulin-like growth factor-I, a profibrogenic growth factor produced by macrophages, and suppression of fibroblast proliferation and collagen synthesis 9. A recent study by Strieter et al. 10, regarding the effects of IFN-γ 1b, provides direct evidence that this multifunctional cytokine alters the expression of certain molecules postulated, with trends towards downregulation of fibrotic and angiogenic markers. In addition, IPF seems to be characterised by the predominant expression of T-helper cell type 2 cytokines, and IFN-γ may shift the Th2 balance towards a Th1 profile 11.
The first observation showing the therapeutic effectiveness of IFN-γ 1b in IPF was reported in the small study of Ziesche et al. 12. Recently, a large clinical trial in the USA failed to show a beneficial effect on progression-free survival, pulmonary function or quality of life after 1 yr of treatment 13. However, a subanalysis suggested that patients with less severe pulmonary function impairment showed better survival. Therefore, there is a need for data verification in a cohort of patients with less advanced disease and for a longer period of treatment.
Colchicine is a well-tolerated antifibrotic drug that is taken orally. Previous studies have suggested that its effects are similar to those of prednisone, with fewer side-effects, whereas median survival remains unchanged 14, 15. The rationale for using colchicine is its multiple effects, including arrest of cell division, inhibition of granulocyte migration and release of several proteins from cells, and blocking of the in vitro release of fibronectin from alveolar macrophages 15.
Therefore, a prospective randomised comparative trial was undertaken using IFN-γ 1b, taken subcutaneously at a dose of 200 μg three times weekly for 2 yrs, compared with colchicine, at a dose of 1 mg·day-1 orally, in combination with low-dose prednisolone.
MATERIALS AND METHODS
The protocol was approved by the ethics committee of the University General Hospital of Iráklion (Crete, Greece). Between March 2000 and June 2003, 68 patients were recruited from eight centres and 50 underwent randomisation after informed consent. Patients with mild-to-moderate IPF were eligible for the study if they had histologically proven IPF (usual interstitial pneumonia (UIP)) on surgical lung biopsy, or, in the absence of surgical biopsy, fulfilled the recent American Thoracic Society (ATS)/European Respiratory Society (ERS) criteria 1.
Eligible patients were aged 40–80 yrs, had shown clinical symptoms of IPF for ≥3 months, and had a forced vital capacity (FVC) of ≥55% and ≤90% of the predicted value, a transfer factor of the lung for carbon monoxide (TL,CO) of ≥35% pred and an arterial oxygen tension (Pa,O2) of >7.3 kPa while breathing room air at rest.
Newly diagnosed untreated symptomatic IPF patients or long-diagnosed IPF patients with a decrease in lung function of ≥10% despite continuous or repeated treatment with glucocorticoids, other immunosuppressive agents or both for ≥6 of the previous 12 months, or evidence of worsening disease on a chest radiograph, or of worsening dyspnoea at rest or on exertion within 1 yr before enrolment were included in the present study. Patients previously treated with IFN or colchicine were excluded from the study.
Criteria for exclusion were a significant history of exposure to organic or inorganic dust or drugs known to cause pulmonary fibrosis and connective tissue disease or other chronic lung diseases causing pulmonary fibrosis, a ratio of the forced expiratory volume in one second to FVC of <0.6 after bronchodilator use, a residual volume of >120% pred, active infection within 1 week before enrolment, unstable cardiovascular or neurological disease, uncontrolled diabetes, pregnancy, lactation, any active malignancy likely to result in death or any condition other than IPF likely to result in death within 3 yrs.
Patients were categorised as nonsmokers, current smokers or ex-smokers (a minimum of 1 cigarette·day-1 for a minimum of 1 yr, stopping ≥6 months before presentation).
The present randomised, multicentric, open-label, parallel-group, efficacy study started with a run-in period of 2 months (visits 1–2). Randomisation was performed using a random number table.
The study was originally designed to investigate the molecular perspective after both treatment regimens. Owing to technical difficulties, this aim was only investigated in a subgroup of 10 patients (data not shown). The study did not have pre-specified end-points.
The study objectives were to compare the clinical effects of the two treatment regimens after 6, 12 and 24 months of therapy using: pulmonary function tests (FVC, total lung capacity (TLC), TL,CO and Pa,O2 at rest), the extent of lung fibrosis on high-resolution computed tomography (HRCT), quality of life (St George’s Respiratory Questionnaire (SGRQ)), treatment outcome (using the ATS/ERS criteria), and overall survival.
During the run-in period, all eligible patients received 50 mg·day-1 oral prednisolone for 4 weeks, with subsequent tapering of the dose to 10 mg·day-1 over a 1-month period, regardless of any previous treatment. The duration of the treatment was 24 months over eight visits. If the glucocorticoid treatment was ineffective, the patients were randomly assigned (2:1) to receive either 200 μg IFN-γ 1b subcutaneously three times per week plus 10 mg oral prednisolone daily for 24 months or 1 mg·day-1 oral colchicine plus 10 mg oral prednisolone daily for the same treatment period. No other treatments were allowed during the study. A response to corticosteroids was considered to have occurred with an increase of >10% in FVC (% pred) and/or TL,CO (% pred). All new symptoms were recorded as adverse events. All patients were followed for the duration of the study regardless of whether or not they continued IFN-γ 1b or colchicine.
Pulmonary function tests
All patients were evaluated spirometrically and by measurement of lung volumes, diffusion capacity and arterial blood gas levels (at rest).
Spirometry and measurement of lung volumes using the helium-dilution technique and TL,CO (corrected for the haemoglobin) using the single-breath method 16 were performed using a computerised system (Jaeger 2.12; MasterLab, Würzburg, Germany). Predicted values were obtained from the standardised lung function testing of the European Coal and Steel Community, Luxembourg (1993) 17. Arterial blood gas determination was performed at rest using an arterial blood gas analyser (AVL330; MasterLab system).
Scoring of disease extent and progression
Two readers, blinded to the clinical functional data and type of treatment, examined the HRCT images. HRCT slices from five predetermined levels (the great vessels, the aortic arch, the carina, the right inferior pulmonary vein and 2 cm above the right hemidiaphragm) were evaluated.
HRCT extent of disease score
At each level, the overall extent of disease was visually estimated to the nearest 5%, including a reticular pattern or ground-glass opacification with or without traction bronchiectasis. In order to obtain the mean fibrosis score, percentages from all slices examined were summed and divided by the number of slices (five). This mean (range 0–100%) was considered the extent of fibrosis, irrespective of the predominant pattern. This visual method of disease extent quantification has been extensively used for HRCT scoring in interstitial lung disease with good functional correlations by Wells and co-workers 18, 19.
HRCT disease progression score
Repeat HRCT studies at 12 months after initiation of treatment were compared with those performed at baseline. HRCT changes were measured on a scale of 1–5, representing likelihood of improvement or deterioration (HRCT progress score). A score of 1 indicated definite improvement, a score of 2 indicated that subtle improvement was most likely, a score of 4 was given when subtle or little deterioration was most likely, and a score of 5 when definite deterioration was seen. Stable disease was recorded as 3. This scoring system forms a five-point scale for disease changes in each HRCT slice (range 5–25 for each patient). In order to obtain the mean HRCT disease progression score, the rating values from all slices examined were summed and divided by the number of slices (five).
Definite improvement was agreed to be recognised when unquestionable resolution of ground glass or interstitial abnormalities was seen. Definite deterioration was recognised when unquestionable new areas of ground-glass opacities or reticulation emerged or when a microcystic reticular pattern changed into macrocystic disease (coarsening of reticulation to honeycomb) or unquestionable traction bronchiectasis had developed in an area of previous ground-glass opacification. In addition, consensus agreement upon level of certainty (either towards improvement or deterioration, notably scores of 1 or 5, respectively) was agreed also to be based upon the relative predominance of the above signs of improvement or deterioration within each individual slice.
In addition, the extent of emphysema was visually estimated at each level to the nearest 5%, first independently and then by consensus. The mean (range 1–100%) was considered to be the extent of emphysema.
Finally, a qualitative comment on the type of change was noted, including: 1) ground-glass development or resolution, 2) reticulation development or resolution, and 3) coarsening of the reticulation (microcystic reticular pattern replaced by macrocystic disease). The above qualitative parameters were roughly quantitatively characterised overall 20, 21.
Outcome was evaluated according to the established ATS/ERS criteria 1. A favourable (or improved) and a stable (and presumed favourable) response to treatment were classified as improvement or stabilisation of outcome in each separate patient. Symptoms (dyspnoea and cough), HRCT and physiological evaluation (changes of 10% for FVC and TLC, and >15% for TL,CO and 0.53 kPa (for Pa,O2) were measured in each patient at the different time-points of the study. Symptomatology and pulmonary function test (PFT) results were measured at baseline and at 3-month intervals and classified as improved, stable and deteriorated, according to the above criteria 1. Disease progression was evaluated by HRCT after 6, 12 and/or 24 months of treatment.
In detail, a favourable (or improved), stable or failed response to therapy is defined by two or more of the following, documented on two consecutive visits over a 3–6-month period, respectively: 1) decreased, stable or increased symptoms (dyspnoea and/or cough); 2) reduced, stable or increased parenchymal abnormalities on HRCT scan; and 3) physiological improvement, stability or deterioration, defined by two or more of the following: 1) >10% increase in TLC or FVC; 2) >15% increase in TL,CO;and 3) an improvement in Pa,O2, with a >0.53 kPa increase from the previous measurement.
Quality of life
Assessment of dyspnoea was effected by the modified UK Medical Research Council (MRC) dyspnoea scale, a four-point scale for evaluating this symptom 24. The status of cough was evaluated (as dry, productive or absent) at baseline and at 3-month intervals and classified as improved, stable and deteriorated.
Comparisons between and within groups were made using an unpaired t-test, paired t-test, Wilcoxon rank-sum test, Mann–Whitney U-test or Chi-squared test as appropriate. Comparisons for the different outcomes (PFTs and quality-of-life parameters) at each time-point were made using the ANCOVA test for repeated measurements. Survival estimation was performed using Kaplan–Meier analysis. Comparisons of survival between two groups were made using the log rank test, whereas Cox regression analysis was used to adjust for possible covariates. A p-value of ≤0.05 was considered to indicate significance 25, 26.
Of 68 patients screened, 50 were included in the study and underwent randomisation; 32 patients received IFN-γ 1b and 18 colchicine. Twelve patients were excluded because they did not meet all of the entry criteria and the other six because they responded to corticosteroids. All patients remained in the study until January 2004, unless withdrawn for other reasons (death, clinical worsening or social/personal reasons). Baseline patient characteristics are shown in table 1⇓. In the first group (IFN-γ 1b), the incident/prevalent ratio was 19:13 (incident cases 59%) and in the second group 12:6 (incident cases 66%; p = 0.4). No imbalances in HRCT evaluation were apparent at baseline (table 1⇓). The diagnosis was confirmed by the identification of UIP on surgical lung biopsy in 84% (27) of patients in the IFN-γ-1b group and in 83% (15) in the colchicine group. The median duration of treatment was 20 months (range 2–44 months) in the IFN-γ-1b group and 15 months (range 5–44 months) in the colchicine group. Clubbing was present in 13 (40.6%) IFN-γ-1b patients and nine (50%) colchicine patients (p = 0.52).
The vital status of all randomised patients was ascertained at the time of study completion. In the intent-to-treat population, five out of 32 (15.6%) IFN-γ-1b patients and seven out of 18 (38.8%) colchicine patients had died (p = 0.028). Mean survival was 39 months (95% confidence interval (CI) 35–43 months) for the IFN-γ-1b group and 30 months (22–38 months) for the colchicine group (fig. 1⇓). The hazard ratio for death in the IFN-γ-1b group, compared with the colchicine group, was 0.30 (95% CI 0.07–0.86). Cox regression analysis showed that the difference between the two groups remains significant after adjustment for age and comorbid conditions (p = 0.04). Subanalysis suggested that the effect of treatment on the risk of death depended on the FVC at baseline. Among patients with a baseline FVC above the median (≥71% pred), none of the IFN-γ-1b patients died, compared with 44% of the nine patients in the colchicine group (p = 0.008; fig. 2⇓). Conversely, among 25 patients with a baseline FVC that was <71% pred, no survival benefit was apparent (p = 0.68). Among patients with a baseline TL,CO that exceeded the median (≥51% pred), no IFN-γ-1b-treated patient died, compared with 30% in the colchicine group (p = 0.028; fig. 3⇓).
Respiratory insufficiency or disease progression accounted for three out of the five IFN-γ-1b patients who died and for five out of the seven patients in the colchicine group. The other causes of death were lower respiratory tract infections. Pseudomonas aeruginosa was cultured in two cases.
After 6 months of treatment, 24 (75%) patients in the IFN-γ-1b group showed improvement or stabilisation of their disease compared with seven (41%) in the colchicine group (p = 0.022). After 24 months of treatment, 61.9% of IFN-γ-1b patients had improved or stabilised compared with 16.7% of colchicine patients (p = 0.014; table 2⇓). Individual assessment of the three criteria used in this study is shown in figure 4⇓.
Pulmonary function tests
No significant differences in lung mechanics, lung volumes, TL,CO and Pa,O2were found between the two groups after 6 and 12 months of treatment (table 3⇓). A significant difference in FVC (% pred) was detected after 24 months of treatment, in favour of the IFN-γ-1b group (table 3⇓). Mean FVC (% pred) and Pa,O2at three time-points in the study are shown in figure 5⇓.
Overall, for the entire cohort of patients (n = 50), the mean±sd baseline extent of fibrosis using HRCT scoring was 35.3±10.45% (range 14–59%). For the IFN-γ-1b-treatment group, the baseline extent of fibrosis on HRCT scoring was 32.9±8.7% (range 14–48%), and, for the colchicine group, 40±12.2% (range 23–59%). There was no significant difference in mean HRCT extent of disease score between the groups at baseline (p = 0.184, Mann–Whitney U-test). The mean HRCT progression score from both readers was 3.72±0.73% (range 1.9–4.9%). There were no differences in progression score between the two groups after 12 months of treatment in 27 patients treated with IFN-γ 1b and in 14 patients in the colchicine arm (p = 0.14). Furthermore, no marked differences were found in disease severity score between the two groups after 6 (13 IFN-γ 1b and nine colchicine patients, p = 0.08) and 24 months of treatment (16 IFN-γ 1b and five colchicine patients, p = 0.4).
Symptomatology and quality of life
Neither dyspnoea, as assessed by the modified MRC scale, nor cough differed between the two treatment groups at each time-point. Nonetheless, quality of life, according to the SGRQ as regards symptomatology, was significantly better after 12 months only in the IFN-γ group (table 4⇓).
Constitutional symptoms, such as fever, myalgia, rigors, headache and flu-like syndrome, were significantly more common among patients who received IFN-γ (p<0.01), whereas mild diarrhoea was observed in only two patients in the colchicine group. None of the above symptoms were life-threatening. In the majority of patients, the IFN-γ-related symptoms subsided within the first 9–12 weeks. Indeed, in some of the present patients, the drug was well tolerated after the first few administrations. Respiratory tract infections were observed in eight patients in the IFN-γ group and two in the colchicine group. There were 12 recorded hospitalisations, eight (25%) in the IFN-γ-1b group and four in the colchicine group (p = 0.8).
In total, 17 (11 in the IFN-γ-1b group and six in the colchicine group) of the 50 patients discontinued treatment before 24 months. Of the 11 patients in the IFN-γ-1b group, eight stopped because of an adverse event and/or disease progression and three for social reasons. Of the colchicine group, six patients withdrew; two stopped because of disease progression and four for social reasons.
The present study is the only study in the literature comparing IFN-γ 1b and colchicine. It is also the second-largest study exploring the therapeutic role of IFN-γ 1b in patients with IPF. In this well-defined patient population, an apparent beneficial effect of IFN-γ 1b on survival, outcome and FVC (% pred), after a 24-month treatment, was observed compared with colchicine.
On the one hand, the major finding of the present study was the apparent survival benefit in the IFN-γ-1b group compared with the colchicine group. A recent retrospective analysis, performed in order to optimise selection of the end-point criteria for the study of Raghu et al. 13, showed that mortality was the most inclusive end-point for future trials involving IFN-γ 1b 27.
On the other hand, several limitations exist in the design of the present study. First, there were no specific pre-specified end-points, and hence no power calculations were undertaken for the sample size. Secondly, but no less importantly, this study was not placebo-controlled. Additional major limitations include the very small group of patients who had received >2 yrs of treatment and the analysis of the lung function data in a limited number of patients remaining in the study for >2 yrs.
Conversely, no survival benefit was found with colchicine. The present study is the second randomised study that provides data affirming the inefficacy of colchicine in the treatment of IPF. In the first randomised study, Douglas et al. 28 found that neither prednisone nor colchicine resulted in objective improvement, and the disease continued to progress. Colchicine appears to be a safer alternative than a trial of high-dose prednisone, but may be no different to no therapy 14. The use of colchicine instead of placebo could be a valid alternative in certain cases. With the present data, there is no evidence to suggest a beneficial role for colchicine in the treatment of IPF.
In addition, a rigorous attempt to make an accurate diagnosis was undertaken. A strength of the study is the high percentage (85%) of patients receiving surgical lung biopsy confirmation of IPF and pathological evaluation following the new classification of idiopathic interstitial pneumonias by an expert pulmonary pathologist. Additionally, the duration of follow-up, with a mean of 2 yrs, is another strength of this trial, as well as the ascertainment of the status of all patients in a randomised and multicentric enrolment.
An additional finding of the present study is the significant difference in FVC in favour of IFN-γ 1b treatment after 24 months of treatment. Importantly, King et al. 27 found that a fall in FVC of >10% pred was both reliable and predictive of mortality. Moreover, both Collard et al. 29 and Flaherty et al. 30 identified a decrease of ≥10% pred in FVC at 6 months as predictive of mortality in recent reports.
Quality of life was significantly improved in the IFN-γ group as regards the symptoms component of the SGRQ. Although this questionnaire is not specific for interstitial lung diseases 23, it has recently been demonstrated that the SGRQ is a sensitive tool for assessing health-related quality of life in IPF patients 31. Interestingly, lung volumes (FVC and TLC) and duration of disease correlated with SGRQ score 31. However, others failed to find any difference 12.
Moreover, although HRCT has been used as one of the multiple parameters 32 for evaluating response to IFN-γ treatment, there were no published studies focusing on longitudinal changes in HRCT features of UIP in patients receiving this treatment. A recently published study showed that extent of reticulation on HRCT is an important independent predictor of mortality in patients with IPF, confirming once again the crucial role of this tool 33. Importantly, the same study provides evidence that treatment assignment to IFN-γ 1b significantly reduced the risk of death in this group of patients 33.
The mechanism by which survival may be prolonged by this pleiotropic cytokine is unclear. Recent findings suggest that mortality in patients with IPF could potentially be altered by IFN-γ 1b through antimicrobial, antiangiogenic, antifibrotic and/or immunomodulatory effects 10. In addition, the better survival in the IFN-γ group may be explained by the mild-to-moderate disease (median FVC 71% pred, median TL,CO 51% pred) of the present patients, and possibly also the longer period of treatment. The recent report of Raghu et al. 13, which included patients with more advanced disease, failed to show a survival difference between the IFN-γ and placebo groups. However, a secondary analysis suggested that the effect of treatment on risk of death depended on FVC at baseline, and that treatment appeared to have had a greater effect on survival among patients with less severe impairment in lung function than among those with more severe disease. These observations indicate that IFN-γ 1b may be beneficial only in patients with mild-to-moderate disease 13.
Two small retrospective noncomparative 34, 35 and one prospective noncomparative study 36 of IFN-γ therapy for IPF have shown controversial results regarding the usefulness of IFN-γ therapy. Kalra et al. 34 observed symptomatic and functional improvement in only one out of the 21 patients treated. Similarly, Prasse et al. 36 found improvement in physiological function in only one of five patients. In contrast, Nathan et al. 35 reported that, paradoxically, patients with advanced disease appear to derive the most benefit from IFN-γ therapy.
Three patients in the IFN-γ-1b arm died with respiratory failure. As is already known, data on the natural history of IPF are sparse and the cause of clinical deterioration is often unclear. Disease progression is difficult to distinguish from complications of the disease and adverse effects of treatment. Honore et al. 37 reported respiratory failure and alveolar opacities in four IPF patients after initiation of IFN-γ-1b therapy. This possibility is considered more plausible in patients with severe disease 38. Moreover, novel data suggest that rapid respiratory decompensation in patients with mild-to-moderate IPF is substantially more common than is currently perceived 39.
In conclusion, the present data suggest that interferon gamma-1b may improve survival and outcome in a well-defined subpopulation of idiopathic pulmonary fibrosis patients. The apparent beneficial role of interferon gamma-1b may be restricted to patients with mild-to-moderate disease, based on measurements of pulmonary function. The present authors’ view is that long-term administration of interferon gamma-1b is required in order to achieve clinical effects on disease course. However, the current results should not be overestimated, and, because of the limitations of this study, conclusions regarding the treatment effects of interferon gamma-1b cannot be drawn from the present results. The results of the ongoing long-term INSPIRE (International Study of Survival Outcomes in Idiopathic Pulmonary Fibrosis with Interferon gamma-1b Early Intervention) clinical trial will, hopefully, clarify whether or not interferon gamma-1b is efficacious in patients with idiopathic pulmonary fibrosis.
The authors gratefully acknowledge N.M. Siafakas and A. Wells for their continuous help in the realisation of this study. The authors would also like to thank N. Bachlitzanakis, Ch. Lambrakis, J. Drositis, G. Birba, D. Mermigkis, Ch. Mermigkis, I. Lambiri, G. Maltezakis and G. Meletis for the recruitment and evaluation of patients. The authors particularly thank the histopathologist A. Koutsopoulos for input in this study.
- Received March 20, 2006.
- Accepted April 5, 2006.
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