The impact of coexisting connective tissue disease on survival in patients with fibrosing alveolitis

R. Hubbard and A. Venn

Division of Respiratory Medicine, Nottingham University, Nottingham, UK


    Abstract
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 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
Objectives. Previous reports have suggested that patients who have fibrosing alveolitis in association with a connective tissue disease (FA-CTD) have a better prognosis than patients with ‘lone’ cryptogenic fibrosing alveolitis (LCFA). The present study was designed to compare the survival of a general population-based sample of patients with FA-CTD and LCFA both with each other and with the general population.

Methods. A survival analysis was performed using data for 107 patients with FA-CTD, 872 with LCFA and 5958 controls matched for age, sex and general practice, drawn from the General Practice Research Database. The data were analysed using Cox regression, adjusting for a number of potential confounders, including age, gender, smoking habit and use of oral corticosteroids.

Results. The median follow-up period was 2.1 yr and during this time 54 (50%) patients with FA-CFA, 386 (44%) patients with LCFA and 601 (10%) controls died. The mortality rates for patients with FA-CTD, LCFA and the controls were 284, 270 and 41 per 1000 person-yr respectively. After adjusting for age, gender, smoking habit and exposure to oral corticosteroids, patients with FA-CTD had a marginally worse survival than patients with LCFA (hazard ratio 1.20, 95% confidence interval 0.90–1.61). Compared with the general population controls, patients with either LCFA or FA-CTD had a considerably worse prognosis (hazard ratio 5.56, 95% confidence interval 4.77–6.49).

Conclusions. The median survival in patients with fibrosing alveolitis is less then 3 yr. We found no evidence to support previous reports of a better prognosis amongst patients with FA-CTD.

KEY WORDS: Fibrosing alveolitis, Pulmonary fibrosis, Connective tissue disease, Survival analysis, General Practice Research Database.


    Introduction
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
Fibrosing alveolitis (also known as idiopathic pulmonary fibrosis) is a chronic, progressive, interstitial lung disease that leads to more than 1000 deaths each year in England and Wales [1]. The prognosis for patients with cryptogenic fibrosing alveolitis is poor and more than half will die within 3 yr of diagnosis [2]. Historically, research into the natural history of fibrosing alveolitis has centred on the analysis of case series collected at tertiary referral centres, and these data suggest that approximately 20% of patients presenting with fibrosing alveolitis have a coexisting connective tissue disease [35]. More recently, however, patients with fibrosing alveolitis in association with a connective tissue disease (FA-CTD) have been considered to have a separate disease entity from patients with so-called ‘lone’ cryptogenic fibrosing alveolitis (LCFA). This policy has been reinforced by the recent guidelines on the management of fibrosing alveolitis produced jointly by the American Thoracic and European Respiratory Societies [6]. The guidelines justify the separation on the basis that patients with FA-CTD have a disease of known aetiology [6], even though the radiological [7] and pathological [8] characteristics of the two patient groups appear similar. As a consequence, most of the recent therapy trials for patients with fibrosing alveolitis have excluded patients with connective tissue disease [911]. There are some data which suggest that patients with systemic sclerosis and fibrosing alveolitis may have a better survival than patients with LCFA [12] and that patients with FA-CTD may have more stable disease than patients with LCFA [13], but there have been no population-based comparisons of survival amongst patients with FA-CTD and LCFA. In order to provide more informative data on the survival of patients with FA-CTD and LCFA, both in comparison with each other and also the general population, we analysed a longitudinal data set containing 979 patients with fibrosing alveolitis and 5958 members of the general population drawn from the UK General Practice Research Database (GPRD).


    Methods
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 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
The data for this study were derived from the GPRD, which is the largest primary care population database in the United Kingdom [14]. The full details of the cohort have been described elsewhere [15]. Briefly, patients were defined as having fibrosing alveolitis if a diagnosis of fibrosing alveolitis was recorded anywhere in the GPRD record. Patients were defined as having FA-CTD if a coexisting diagnosis of connective tissue disease (rheumatoid arthritis, dermatomyositis/polymyositis, systemic sclerosis/scleroderma, systemic lupus erythematosus or mixed connective tissue disease) was recorded in their records, or LCFA if there was no coexisting diagnosis. In addition, we derived a general population control cohort by matching six patients to each case of fibrosing alveolitis on the basis of age, sex and general practice. We have previously established that the diagnosis of fibrosing alveolitis in the GPRD appears to be accurate in comparison with the clinical diagnosis made by a hospital specialist [15]. For each subject with LCFA or FA-CTD, the date of diagnosis was defined as the date of the first recorded diagnosis of fibrosing alveolitis and matched controls were assigned the same date of diagnosis. Information on gender, age at diagnosis, smoking status (non-smoker, current smoker, ex-smoker or missing data) and use of corticosteroids was then extracted for all subjects. The follow-up period was estimated as the time from the date of diagnosis to either death or the last recorded data collection. Because data on the specific cause of death are limited within the GPRD, our analyses were based solely on all-cause mortality.

Initially we compared survival between patients with LCFA, FA-CFA and the general population using Kaplan–Meier plots. We then compared survival between patients with LCFA and those with FA-CFA using a Cox regression model. In our regression model we examined the effect of adjusting for gender, age (modelled as a continuous variable), smoking status (with missing data fitted as a separate category) and exposure to corticosteroids, and also fitted multiplicative interaction terms to look for evidence of effect modification by these variables. We performed a similar analysis to compare survival between patients with fibrosing alveolitis and the general population. All analyses were performed using STATA (STATA Corporation, College Station, TX, USA; version 7) and the proportional hazards assumption for our final multivariate models was confirmed using the software's diagnostics section.


    Results
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 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
Our initial cohorts included 998 patients with fibrosing alveolitis diagnosed between April 1989 and October 1997, of whom 108 (11%) had a coexisting diagnosis of a connective tissue disease, and 5988 controls. Follow-up data after the date of diagnosis were available for 872 (98%) patients with LCFA, 107 (99%) patients with FA-CTD and 5958 (99%) controls (total person-yr for analysis, 16 452); the latest follow-up data were for November 1997. Within the patients with FA-CTD, the most common diagnosis was rheumatoid arthritis (n=86, 80%) followed by systemic sclerosis/scleroderma (n=15, 14%) (Table 1Go). Compared with patients with LCFA, those with FA-CTD had the diagnosis of fibrosing alveolitis made at a younger age (median age at diagnosis 68.8 vs 71.2 yr; unpaired t-test of log transformed data, P=0.004) and were more likely to be female (50 vs 38%; {chi}2 test, P=0.012). The prevalence of connective tissue diseases was much lower amongst the general population controls at 2% (Table 1Go), giving a prevalence ratio for connective tissue disease in patients with fibrosing alveolitis compared with controls of 6.26 (95% confidence interval 4.82–8.13). Amongst patients with fibrosing alveolitis, smoking rates were very similar whether or not there was a coexisting diagnosis of connective tissue disease, and overall 421 (43%) were non-smokers, 199 (20%) were current smokers, 69 (7%) were ex-smokers and for 290 (30%) data were missing. Amongst the general population controls, 2436 (41%) were non-smokers, 1036 (17%) were current smokers, 327 (5%) were ex-smokers and for 2159 (36%) data were missing. A total of 698 (71%) of patients with fibrosing alveolitis were prescribed at least one course of oral corticosteroids compared with 705 (12%) of controls; patients with FA-CTD were more likely to receive oral corticosteroids than patients with LCFA (84 vs 70%, {chi}2 test, P=0.002).


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TABLE 1.  Distribution of coexisting diagnosis of connective tissue disease amongst subjects with fibrosing alveolitis and general population controls

 
During follow-up, 386 (44%) patients with LCFA, 54 (50%) patients with FA-CFA (45 patients with rheumatoid arthritis, three with dermatomyositis/polymyositis, five with systemic sclerosis/scleroderma and one with mixed connective tissue disease) and 601 controls (10%) died. The mortality rate for patients with LCFA was 270 per 1000 person-yr (95% confidence interval 244–298) and for patients with FA-CTD it was 284 per 1000 person-yr (95% confidence interval 218–371). In contrast, the mortality rate in the general population controls was 41 per 1000 person-yr (95% confidence interval 37–44). The median actuarial survival for patients with LCFA was 2.6 yr and that for patients with FA-CTD was 2.4 yr (Fig. 1Go). In our univariate Cox regression model, survival was similar for patients with FA-CTD compared with patients with LCFA (hazard ratio 1.07, 95% confidence interval 0.80–1.42). Amongst the confounder variables, male gender (hazard ratio 1.29, 95% confidence interval 1.06–1.57) and increasing age (hazard ratio per 5 yr increase in age at diagnosis 1.27, 95% confidence interval 1.21–1.34) were associated with a worse prognosis, but no statistically significant associations were seen with the use of oral corticosteroids (hazard ratio 1.20, 95% confidence interval 0.96–1.50) or being a current smoker (hazard ratio 0.76, 95% confidence interval 0.58–1.01) or ex-smoker (hazard ratio 1.19, 95% confidence interval 0.82–1.73). When the model was adjusted for age, gender, smoking status and corticosteroid exposure, patients with FA-CTD appeared to have a marginally worse survival than patients with LCFA, although this difference was not statistically significant at the 5% level (hazard ratio 1.20, 95% confidence interval 0.90–1.61). The results were similar when the FA-CTD group was restricted to patients with a diagnosis of rheumatoid arthritis (hazard ratio 1.16, 95% confidence interval 0.85–1.59).



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FIG. 1.  Kaplan–Meier plot of survival amongst patients with LCFA and FA-CTD, and general population controls.

 
As the mortality rates were so similar for patients with LCFA and FA-CTD, the two groups were combined and compared with the general population control group. After adjusting the model for the effects of age, gender, smoking status, corticosteroid exposure and the presence of a connective tissue disease, patients with fibrosing alveolitis had a dramatically worse survival than the general population controls (hazard ratio 5.56, 95% confidence interval 4.77–6.49).


    Discussion
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
The results of our study reinforce the poor prognosis associated with a clinical diagnosis of fibrosing alveolitis. Our data provide no evidence to suggest that the prognosis for patients with FA-CTD is any better than that for patients with LCFA; if anything it appears marginally worse.

The data within the GPRD are collected as part of routine primary care in the UK and this provides both advantages and disadvantages. The definition of fibrosing alveolitis we used is based on the diagnosis recorded by the general practitioner, although we know from our previous diagnosis validation study [15] that most patients are referred to a specialist for a secondary opinion, and a recent study has demonstrated that the specificity of a clinical diagnosis of fibrosing alveolitis is high [16]. In reality it is unlikely that primary-care doctors in the UK record the diagnosis of fibrosing alveolitis unless a specialist has confirmed this. We did not validate the diagnoses of connective tissue disease, but again it seems unlikely that general practitioners would record such a diagnosis without supportive evidence from either blood tests or a secondary opinion. The prevalence of connective tissue amongst patients with fibrosing alveolitis in this study was lower than that in previous reports [35]. However, these previous studies were based on case series collected at tertiary referral centres and it is possible that secondary referral patterns may have led to the inclusion of a disproportionately high number of patients with FA-CTD.

We have demonstrated previously that there is misclassification of ex-smokers as non-smokers in the GPRD [15], and this may explain why we did not find an adverse effect of smoking history on survival. Others have also found evidence that, within patients with fibrosing alveolitis, current smokers actually have marginally better survival rates that non-smokers [17], and this may reflect selection bias in that patients with the most rapidly progressive disease will presumably be those most likely to stop smoking. Overall, the recorded smoking data for patients with FA-CTD and those with LCFA were similar, and so it is unlikely that this misclassification will have affected our results appreciably.

The prescribing data within the GPRD have consistently been shown to be accurate [14] and so our data on recent exposure to oral corticosteroids are likely to be correct. The reason why exposure to oral corticosteroids is associated with worse survival is probably because exposure to oral corticosteroids is acting as a proxy marker of disease severity in this data set. We have found a similar adverse effect of exposure to oral corticosteroids before within a cohort of patients with LCFA [2].

The clinical presentation of fibrosing alveolitis appears to be similar in patients with LCFA and FA-CTD, at least in terms of clinical examination, lung histology and radiology [7, 8, 18], but there are few data available on the comparative survival of the two patient groups. In one of the largest and most detailed studies to date, the survival rates of 205 patients with LCFA and 68 with fibrosing alveolitis in association with systemic sclerosis were compared [12]. The researchers matched the two groups carefully on the basis of the computed tomography scans to try to remove problems of lead-time bias, i.e. earlier diagnosis of interstitial lung disease amongst patients with systemic sclerosis due to clinical screening. The patients with systemic sclerosis had a much better prognosis than those with LCFA. Clearly, the main difference between this study and our study lies in the specific connective tissue disease diagnoses. In contrast to the previous study [12], our findings relate mainly to patients with rheumatoid arthritis because within the general population this is the connective tissue disease that, in absolute terms, is associated with most cases of interstitial lung disease. Despite the large size of our study, we do not have enough data to provide specific results on the basis of individual connective tissue diseases and so we cannot be sure that patients with systemic sclerosis do not have a better prognosis than patients with LCFA—but note that five of our 15 patients with systemic sclerosis/scleroderma did die during follow-up.

In summary, patients with a clinical diagnosis of fibrosing alveolitis have a median survival of less than 3 yr and have a mortality rate which is five times greater than the general population rate. This poor prognosis is present whether or not there is a coexisting diagnosis of a connective tissue disease. The similarity in the natural history of fibrosing alveolitis whether or not there is a coexisting connective tissue disease is in keeping with the similarities in the histological and radiological findings and does not support the current policy of excluding patients with coexisting connective tissue diseases from research studies or therapeutic trials.


    Acknowledgments
 
We would like thank Hassy Devalia and Alison Bourke of the Epidemiology and Pharmacology Information Core (EPIC) for their advice on using the General Practice Research Database. We thank the Trent National Health Service Research and Development Project Grant for funding this work.


    Notes
 
Correspondence to: R. Hubbard, Division of Respiratory Medicine, Clinical Sciences Building, City Hospital, Hucknall Road, Nottingham NG5 1PB, UK. Back


    References
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 

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Submitted 30 July 2001; Accepted 7 January 2002