Systemic sclerosis (SSc; scleroderma) is a connective tissue disease of unknown etiology characterized by microvascular injury, excessive fibrosis of the skin, and distinctive involvement of the viscera, including the heart, lung, kidney, and gastrointestinal tract (1). Lung disease is now the leading cause of morbidity and mortality in patients with SSc. About 40% of all SSc patients develop moderate to severe restrictive lung disease, with the greatest decline in pulmonary function usually occurring within the first 4 years after the onset of non–Raynaud's phenomenon SSc symptoms (2).
Progressive decrements in lung function of patients with symptomatic lung disease are likely to be accompanied by a decline in their emotional well-being and in their ability to perform day-to-day activities, that is, their health-related quality of life (HRQOL). Treatments for active alveolitis commonly used in clinical practice include corticosteroids and other immunosuppressive agents. Cyclophosphamide is currently being tested against placebo in the Scleroderma Lung Study, a multicenter, parallel-group, double-blind, randomized, placebo-controlled trial in SSc patients with active alveolitis sponsored by the National Heart, Lung, and Blood Institute. Since cyclophosphamide and other immunosuppressive agents are associated with significant side effects and toxicity, it is important to consider HRQOL as a separate therapeutic end point in SSc.
No validated method of assessing HRQOL in this patient population is currently available. The aim of the present study was to evaluate the impact of SSc with active alveolitis on function and HRQOL and to evaluate the relationship between HRQOL and measures of breathlessness, the major symptom of SSc alveolitis. A secondary aim was to quantify baseline levels of functional impairment and HRQOL in patients with scleroderma lung disease compared with those in patients with another chronic lung ailment, chronic obstructive pulmonary disease (COPD) and the healthy US general population.
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- PATIENTS AND METHODS
Although it is well known that SSc can be disabling, little attention has been paid to a systematic evaluation of HRQOL in patients with SSc. This may in part be due to the low prevalence of SSc and the relative scarcity of large multicenter studies in which this outcome measure could be evaluated. The Scleroderma Lung Study, therefore, provides a unique opportunity to evaluate dyspnea and its effect on HRQOL, as measured by the SF-36, in SSc patients with alveolitis participating in a longitudinal clinical trial.
When breathlessness (measured by the BDI and the VAS for breathing) was compared with the PCS and MCS, both of these HRQOL scales were able to discriminate between SSc patients with alveolitis who reported more dyspnea (BDI ≤6.0 or VAS for breathing >23) and those who reported less dyspnea (BDI >6.0 or VAS for breathing ≤23) (P < 0.05 for both scales). Also, the PCS and MCS collectively were able to discriminate between patients with more abnormalities or less abnormalities of the measures of physiologic functioning (e.g., between those with an FVC >70% predicted and those with an FVC ≤70% predicted as well as between those with a DLCO ≥50% predicted and those with a DLCO <50% predicted).
Patients with worse dyspnea, as demonstrated by a BDI ≤6.0 and a VAS score for breathing >23, had a significantly worse score for the HAQ DI, showing the discriminative role of this arthritis-specific questionnaire (Table 2). The advantage of using the HAQ DI in the present study is its ability to quantify patient-reported disability and differentiate it from the extrapulmonary complications of their SSc. The HAQ DI showed a higher correlation with the MRSS, one of the surrogates for severity of SSc (r = 0.49, P < 0.0001) than with the PCS (r = −0.25, P < 0.05) (data not shown). The HAQ DI also was able to differentiate patients based on the extent of skin thickening, with a score of 0.51 in patients with limited cutaneous SSc and a score of 1.02 in those with diffuse cutaneous SSc (P < 0.001). In contrast, the SF-36 was not able to differentiate limited versus diffuse cutaneous SSc (PCS of 35.6 in limited cutaneous SSc versus 32.1 in diffuse cutaneous SSc; P = 0.06) (Table 1).
Thus, the HAQ DI complemented the SF-36 and other measures used to evaluate SSc. It was able to capture functional disability due to SSc more effectively than either of the SF-36 summary scales.
Evaluation of HRQOL in patients with SSc and active alveolitis at baseline revealed a marked decrease in their HRQOL, as indicated by significantly low scores in all the 8 SF-36 domains (Figure 1). This impairment is similar to that noted in patients with symptomatic COPD (18), idiopathic pulmonary fibrosis (19, 20), and previously reported series of patients with early SSc (21), and it is considerably different from the age- and sex-matched healthy US population.
There are some limitations of the present study. First, it is conceivable that patients without active alveolitis may have been included in the trial. The main objective of the Scleroderma Lung Study was to evaluate the benefits/risks of an antiinflammatory/immunosuppressive agent (oral cyclophosphamide) versus placebo in patients with relatively early SSc with symptomatic interstitial lung disease and findings suggestive of active alveolitis (neutrophilia/eosinophilia on BAL and/or ground-glass opacification on thoracic HRCT). Since there is no perfect system for a priori identification of patients with progressive alveolitis, it is possible that the ground-glass opacification seen in a few patients with negative findings on BAL represented a process other than active alveolitis. To increase the sensitivity for the diagnosis of active alveolitis, patients were also required to have symptomatic dyspnea and abnormalities on pulmonary function testing. At the completion of the trial, with all of these parameters captured, we will be able to relate our baseline findings to clinical responses and thereby better define populations that are likely to progress.
Second, we did not include a disease-specific questionnaire for pulmonary symptoms, which would have further strengthened our study. A formal respiratory-specific validated questionnaire is not available for SSc-associated interstitial lung disease. However, Chang et al (19) tested the SF-36 and 2 respiratory-specific instruments (Chronic Respiratory Questionnaire and St. George's Respiratory Questionnaire [SGRQ]) in 50 patients with idiopathic interstitial lung disease. The SGRQ had a better correlation than did the PCS of the SF-36 with the FVC (r = −0.45, P < 0.01 versus r = 0.31, P < 0.05) and the DLCO (r = −0.55, P < 0.01 versus r = 0.32, P < 0.05). The correlation coefficient for the 6-minute walk distance and the dyspnea score was similar (r < 0.5, P < 0.01) for both the SF-36 PCS and the SGRQ. The authors suggested that both the SF-36 and the SGRQ are sensitive tools for assessing HRQOL in these patients.
Third, we did not evaluate exercise tolerance in the SSc patients. Chang et al (19) found a statistically significant correlation between the SF-36 PCS and the 6-minute walk distance in patients with interstitial lung disease (19). However, due to the arthritis and contractures associated with SSc, some patients in the present study would have been expected to have difficulty performing the 6-minute walk, even in the presence of relatively mild pulmonary disease, as a result of concomitant arthritis. Also, the 6-minute walk distance has not yet been validated as a measure of pulmonary morbidity and mortality in patients with scleroderma interstitial lung disease, with or without arthritis.
Fourth, echocardiograms were not included as a part of the study. It is possible that patients with mild-to-moderate pulmonary hypertension not requiring specific therapy were included in the study. An isolated decrease in the DLCO could be due to pulmonary hypertension rather than pulmonary involvement.
Last, the present study analyzed only cross-sectional data. Subsequent completion of the 2-year trial of cyclophosphamide in SSc interstitial lung disease should allow analysis of the responsiveness of the SF-36 to a therapeutic intervention. This would be key to determining whether the SF-36 or its components would be a worthwhile outcome measure in clinical studies.
In conclusion, in patients with active alveolitis associated with SSc, values for Mahler's BDI and the VAS for breathing (both measures of breathlessness) were associated with performance on both the physical and mental component summary measures of the SF-36 and, to a lesser degree, with the DLCO. The SF-36 was able to discriminate between patients with more severe versus less severe breathlessness, the primary symptom of active alveolitis. We have also shown the usefulness of 2 VAS scales (the VAS for breathing and the PGA VAS) in assessing patients with active alveolitis and SSc. Although physiologic variables are helpful to the clinicians, most patients are concerned about their symptoms, their ability to perform day-to-day activities, and their general well-being. As lung disease progresses in SSc, the patients invariably become severely limited in their activities and may become dependent on supplemental oxygen. The potential toxicity of current therapy for SSc is of particular interest in this longitudinal clinical trial. Although cyclophosphamide therapy may result in disease stabilization or actual improvement of lung function, potentially undesirable side effects could counterbalance the efficacious effects on HRQOL.
The overall findings from this baseline analysis of lung function, breathing problems, and various quality of life measures in participants in the Scleroderma Lung Study should be helpful to physicians. Pulmonary disability is an important determinant of HRQOL in this population. When extended to include a followup assessment after completion of therapy in the Scleroderma Lung Study, the findings should provide us with additional important information on the balance between the possible efficacy of cyclophosphamide in stabilizing or improving lung function and respiratory symptoms and its potential toxicity, both of which would be expected to influence HRQOL.
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- PATIENTS AND METHODS
The following centers participated in the Scleroderma Lung Study: Boston University, Boston, MA, Georgetown University, Washington, DC, Johns Hopkins University/University of Maryland, Baltimore, MD, Medical University of South Carolina, Charleston, University of Alabama at Birmingham, University of Illinois at Chicago, University of Medicine and Dentistry of New Jersey, New Brunswick, NJ, Virginia Mason Research Center, Seattle, WA, Wayne State University, Detroit, MI, University of Connecticut, Farmington, University of California, San Francisco, and University of Texas, Houston.