Rheumatology

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Rheumatology 2001; 40: 1022-1025
© 2001 British Society for Rheumatology

Original Papers

Interstitial lung disease in patients with rheumatoid arthritis: a comparison with cryptogenic fibrosing alveolitis

B. A. Rajasekaran¹, D. Shovlin¹, P. Lord³ and C. A. Kelly^1,2,

¹ Departments of Respiratory Medicine,
² Rheumatology and
³ Radiology, Queen Elizabeth Hospital, Sheriff Hill, Gateshead NE9 6SX, UK

	Abstract

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Objectives.There is a lack of information on the natural history of patients with rheumatoid arthritis (RA) and associated interstitial lung disease (ILD). However, cryptogenic fibrosing alveolitis (CFA) is known to have a poor long-term prognosis. As part of a longitudinal prospective study, we compared baseline characteristics in 18 patients with RA-ILD and 18 patients with CFA matched for age, sex and symptoms. We wished to establish whether there were significant baseline differences in clinical, physiological or radiological parameters.

Methods. A diagnosis of ILD was confirmed by high-resolution computed tomography (HRCT) and supported by clinical and physiological findings in all patients. A number of clinical, immunological, physiological and radiological parameters were compared between the two groups. The median age in each group was 77 yr and 10 patients in each group were male.

Results. Twelve of the RA patients had smoked in excess of 10 pack yr as compared with nine patients with CFA (not significant). Clubbing was found in five patients with RA-ILD and in 14 with CFA (P=0.008). Pulmonary function tests showed no significant differences between the groups in forced expiratory volume in 1s, vital capacity or gas transfer factor. HRCT showed more ground glass shadowing and peripheral disease in RA patients, but more established basal disease in those with CFA. Additionally, HRCT evidence of honeycombing was associated with an absence of rheumatoid factor and a low gas transfer factor.

Conclusions. Clubbing is more common in patients with CFA, while RA-ILD patients have a higher prevalence of rheumatoid factor. Together with the differences in baseline HRCT, these variables in two groups of patients with similar physiological impairment at baseline may be important predictors of outcome in the longer term.

KEY WORDS: Interstitial lung disease, Rheumatoid arthritis, Cryptogenic fibrosing alveolitis, High-resolution tomography.

	Introduction

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The natural history of cryptogenic fibrosing alveolitis (CFA) is known to be poor, with the median survival from diagnosis being 3–5 yr [1, 2]. Prognostic markers are not well established and there is limited evidence to guide attempts at therapeutic intervention [3]. Interstitial lung disease (ILD) is clinically detected in less than 5% of patients with rheumatoid arthritis (RA) [4], although studies have shown a much higher prevalence of interstitial changes using high-resolution computed tomography (HRCT) [5]. This technique has been proposed [6] and accepted [7] as the standard non-invasive method of diagnosing and following ILD in patients with RA. The results of HRCT have been shown to correlate closely with those of open lung biopsy in other connective tissue disorders [8], although less well with pulmonary function tests [6].

The natural history of ILD in RA has not been well studied. There is limited evidence suggesting that relatively small numbers of such patients die from respiratory failure [9, 10]. One study suggested that the prognosis may be better than that of CFA [11], although this is debated [12, 13], but there are no published data on prognostic factors and no information on comparative radiological investigations. We designed a prospective longitudinal study to compare the natural history of CFA with RA-associated ILD. The two groups were matched for age, sex and disease duration. Baseline characteristics, therapeutic intervention and 5-yr outcome measures are being collected. This paper describes and compares the baseline characteristics of each group.

	Methods

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We assessed all patients with a diagnosis of definite RA over a 2-yr period for clinical evidence of ILD. Patients with pneumoconiosis or allergic alveolitis were excluded. Patients without signs or symptoms did not undergo further respiratory investigation. Patients with dry cough or exertional dyspnoea had a chest radiograph. Those with symptoms associated with either bibasal crackles on chest examination or radiographic evidence of ILD were then investigated with HRCT using a Schimadzu SCT 3000TX scanner recording images 2 mm thick at 20 mm horizontal intervals. Technical factors were 120 kV and 300 mA. All patients with confirmed alveolitis or pulmonary fibrosis were then included within the study for which full ethical approval was obtained. Data on age, sex, disease duration and smoking history were recorded and the presence or absence of finger clubbing, bibasal lung crackles and autoantibodies was assessed. Patients were asked to consent to full pulmonary function tests on a Jaeger Master Lab machine, including gas transfer assessed by the single breath carbon monoxide technique. A technetium lung clearance scan [14] was also performed.

All index cases were then individually matched for age (within 5 yr), sex and duration of respiratory symptoms with patients diagnosed as having CFA over the same 2-yr period. If there was more than one possible matching control, the patient with the shorter symptom duration was used. These patients also fulfilled all the criteria described above in the diagnosis of ILD in RA. All HRCT scans were reported by the same radiologist (PL) without knowledge of the patients’ clinical status. Equivalent clinical data were recorded for these patients, who also underwent full up-to-date pulmonary function tests and technetium scanning. Lung biopsies were not routinely performed in either group but were occasionally used to exclude other diagnoses where this was judged necessary.

The ² test was used to calculate any significant differences between the clinical features of those patients with CFA and those with RA and ILD, while differences in pulmonary function and radiological measurements between the two groups of patients were assessed using Duncan's Multiple Comparison Test.

	Results

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Clinical
Eighteen RA patients with evidence of ILD were detected, with a median age of 77 yr (range 47–90 yr). The 18 CFA patients had the same median age of 77 yr with a similar range (44–88 yr). In both groups the slight majority of patients were male (10 vs eight female). The recorded duration of dyspnoea at entry into the study was similar in the two groups, i.e. 30 months (range 8–120 months) in RA-ILD and 32 months (range 13–96 months) in the CFA group. The median duration of articular symptoms in the RA patients was 40 months (range 12–120 months). There were more active smokers among the RA patients (12) than the CFA group, but this difference was insignificant and the total pack years consumed by the two groups were similar. Bibasal crackles were heard in all patients in each group, but the presence of finger clubbing assessed without knowledge of the clinical status of each patient was significantly lower in the RA group (five) than in CFA patients (14) (P=0.008).

Serological tests showed that 10 RA patients had IgM rheumatoid factor present in a titre of >1/40 as opposed to only two in the CFA group (P=0.005). No differences were detected with other autoantibodies, with four RA patients and three patients with CFA exhibiting either antithyroid or antinuclear antibodies.

Physiological
Table 1 shows the pulmonary function values in both groups of patients. The median forced expiratory volume in 1s (FEV1) was similar in the RA patients and the CFA group (1.78 and 1.65 l, respectively) and the median percentage predicted values were almost identical in each group. The median values for vital capacity were also very close, being 2.1 l in the RA patients and 2.2 l in the CFA group. Gas transfer factors were also similar at a median of 47% predicted in RA patients and 53% predicted in the CFA patients.

View this table: [in this window] [in a new window]   TABLE 1. The values of pulmonary function tests in matched patients with CFA and RA-ILD

 

Radiological
Table 2 shows the results of the radiological investigations in both groups. The HRCT scans demonstrated alveolitis in the form of ground glass opacification in four RA patients and one patient with CFA. All other patients had established pulmonary fibrosis, with three RA and four CFA patients exhibiting basal honeycombing. However, the RA patients were more likely to have disease that was peripheral in distribution, while CFA patients generally had extensive basal changes. The half-lives of the technetium lung clearance scans were not significantly different between the RA patients and those with CFA (median values of 16 and 24 min, respectively) and were identical once smokers were excluded from the analysis. Only six patients in each group had normal clearance half-lives of over 30 min.

View this table: [in this window] [in a new window]   TABLE 2. The distribution of specific radiological features on HRCT of the chest in matched patients with CFA and RA-ILD

 

Correlations
There were few significant correlations between the various investigative findings. However, HRCT evidence of honeycombing was associated with a lower carbon monoxide transfer factor (TLco) than was ground glass shadowing, independent of the aetiology of the pulmonary fibrosis. In addition, honeycombing of the lung was associated with a negative rheumatoid factor in both patient groups.

	Discussion

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The present study has identified 18 patients with RA-associated ILD, characterized their clinical and investigative features and compared them with 18 demographically matched individuals with CFA. There were no significant differences between the groups in clinical features except for the greater prevalence of finger clubbing among the CFA patients. While clubbing is a common finding in patients with certain chronic respiratory diseases including CFA [15], its aetiology remains obscure and its clinical significance uncertain. It has been linked with hypoxia and stimulation of the vagus, and has been shown to be associated with proliferation of the bronchial vasculature [16]. It has also been noted to recede in patients after successful resection of lung cancer and following single lung transplant surgery. It has been previously recognized that patients with RA-related ILD have a low prevalence of finger clubbing [6] and this paper confirms that this prevalence is significantly lower than that seen in CFA patients. Whether this is of prognostic relevance may only become evident over a period of follow-up.

Rheumatoid factor was found in both groups of patients, but was significantly more common in the RA patients. This is not unexpected, as most studies of RA demonstrate a prevalence of IgM rheumatoid factor of 60–75%, while lower rates are described in CFA patients [17]. Nonetheless, the presence of rheumatoid factor in CFA patients is considerably higher than the background population prevalence of around 3% and remains unexplained. Although the presence of rheumatoid factor appears to worsen the articular prognosis in RA, the effect of its presence on lung disease has been debated [18, 19]. Indeed, rheumatoid factor may prove to be protective against progressive fibrosis, as suggested by the finding that honeycombing was not seen in any patient with a positive rheumatoid factor.

Although the percentage of patients still smoking was higher in the RA group, there were no significant differences in tobacco consumption between the groups overall. Patients with RA are commonly reported to have a high prevalence of active smoking, and the effect of this on articular function is debated. Smoking will increase the rate of decline in pulmonary function and is likely to carry an adverse prognosis in patients with pulmonary fibrosis, independent of its aetiology [20]. Other factors which have been proposed as increasing the risk of developing progressive pulmonary fibrosis in RA patients include male sex and the use of disease-modifying drugs [21]. More recent evidence suggests that the risk of pneumonitis occurring in RA patients treated with methotrexate is 1 in 80 patient yr, and that this risk is related to the degree of baseline pulmonary dysfunction [22]. However, none of our patients had taken methotrexate prior to the diagnosis of ILD.

Tests of pulmonary function indicated a restrictive pattern with a marked reduction in gas transfer. This is entirely consistent with pulmonary fibrosis. The overall correlation of pulmonary function with radiographic appearances was poor, as previously described [6]. The exception to this rule was the association between the presence of honeycombing and a marked reduction in gas transfer which is in keeping with previous observations [23]. Pulmonary function was, however, closely matched between our two patient groups, with the slightly worse overall gas transfer values in the RA patients likely to relate to the increased prevalence of smoking in this group. This degree of matching was coincidental rather than intentional, but suggests that lung fibrosis was similar in each group. Given that age, sex and disease duration were controlled between the two patient groups, follow-up should help to ascertain whether there is a genuine difference between the rate of progression of each group.

Radiological investigations demonstrated a wide range in the extent of pulmonary fibrosis in both groups. Only five patients had evidence of ground glass shadowing, which is associated with active alveolitis. This is usually considered a feature of early and potentially reversible disease [24]. Four of these patients had RA while only one had CFA, although this difference was not statistically significant. At the other end of the scale, basal honeycombing, which indicates advanced and irreversible pulmonary fibrosis, was found in three patients with RA and a further four with CFA. The remainder of the patients had established fibrosis of variable extent, but RA patients had a more peripherally based distribution of disease which may favourably influence the rate of progression [25, 26]. Our results suggest that the pattern of abnormality on HRCT indicates that the RA-ILD patients may have a better prognosis than those with CFA.

Technetium clearance is an index of lung epithelial permeability and an increased clearance is a sensitive marker of inflammation [14]. Clearance was similar between the two groups and was abnormally fast in the majority of patients. A clearance half-life of under 30 min is taken as an indication of active fibrosis [27], although smoking also enhances clearance times [28]. There were no significant differences between our two patient groups, with the slightly faster clearance times in the RA patients probably explained by the greater number of active smokers in this group. The rate of technetium clearance from the lung has been shown to be a useful prognostic predictor in other causes of pulmonary fibrosis [27, 29] but has not been previously studied in RA.

Among the connective tissue disorders associated with ILD, systemic sclerosis has been best studied [30]. Although no physiological [31] or histological [32] differences could be shown when compared with CFA, the rate of progression of ILD in systemic sclerosis is significantly slower [33]. The present study affords some grounds for optimism that ILD associated with RA may also carry a better prognosis than CFA, but proof of this and the factors predicting prognosis must await a follow-up study.

	Acknowledgments

 
We would like to acknowledge the contributions made by our colleagues: Mrs Laura Jones who performed the pulmonary function tests and Mr Peter Bartholemew who undertook the technetium clearance scans. We declare no conflict of interests in this study.

	Notes

 
Correspondence to: C. A. Kelly

	References

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Submitted 25 April 2000; Accepted 27 March 2001

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