Nicole Goh

RATIONALE: In interstitial lung disease complicating systemic sclerosis (SSc-ILD), the optimal prognostic use of baseline pulmonary function tests (PFTs) and high-resolution computed tomography (HRCT) is uncertain. OBJECTIVES: To construct a readily applicable prognostic algorithm in SSc-ILD, integrating PFTs and HRCT. METHODS: The prognostic value of baseline PFT and HRCT variables was quantified in patients with SSc-ILD (n = 215) against survival and serial PFT data. MEASUREMENTS AND MAIN RESULTS: Increasingly extensive disease on HRCT was a powerful predictor of mortality (P < 0.0005), with an optimal extent threshold of 20%. In patients with HRCT extent of 10-30% (termed indeterminate disease), an FVC threshold of 70% was an adequate prognostic substitute. On the basis of these observations, SSc-ILD was staged as limited disease (minimal disease on HRCT or, in indeterminate cases, FVC >or= 70%) or extensive disease (severe disease on HRCT or, in indeterminate cases, FVC < 70%). This system (hazards ratio [HR], 3.46; 95% confidence interval [CI], 2.19-5.46; P < 0.0005) was more discriminatory than an HRCT threshold of 20% (HR, 2.48; 95% CI, 1.57-3.92; P < 0.0005) or an FVC threshold of 70% (HR, 2.11; 95% CI, 1.34-3.32; P = 0.001). The system was evaluated by four trainees and four practitioners, with minimal and severe disease on HRCT defined as clearly < 20% or clearly > 20%, respectively, and the use of an FVC threshold of 70% in indeterminate cases. The staging system was predictive of mortality for all scorers, with prognostic separation higher for practitioners (HR, 3.39-3.82) than trainees (HR, 1.87-2.60). CONCLUSIONS: An easily applicable limited/extensive staging system for SSc-ILD, based on combined evaluation with HRCT and PFTs, provides discriminatory prognostic information.

OBJECTIVE: The lack of randomized controlled trials (RCTs) in pulmonary fibrosis in systemic sclerosis (SSc) has hampered an evidence-based approach to treatment. This RCT was undertaken to investigate the effects of intravenous (IV) cyclophosphamide (CYC) followed by azathioprine (AZA) treatment in pulmonary fibrosis in SSc. METHODS: Forty-five patients were randomized to receive low-dose prednisolone and 6 infusions (monthly) of CYC followed by oral AZA, or placebo. Primary outcome measures were change in percent predicted forced vital capacity (FVC) and change in single-breath diffusing capacity for carbon monoxide (DLCO). Secondary outcome measures included changes in appearance on high-resolution computed tomography and dyspnea scores. An intent-to-treat statistical analysis was performed. RESULTS: At baseline, there were no significant group differences in factors linked to outcome, including severity of pulmonary fibrosis and autoantibody status. Sixty-two percent of the patients completed the first year of treatment. Withdrawals included 9 patients (6 from the placebo group) with significant decline in lung function, 2 with treatment side effects (both from the active treatment group), and 6 with non-trial-related comorbidity. No hemorrhagic cystitis or bone marrow suppression was observed. Estimation of the relative treatment effect (active treatment versus placebo) adjusted for baseline FVC and treatment center revealed a favorable outcome for FVC of 4.19%; this between-group difference showed a trend toward statistical significance (P = 0.08). No improvements in DLCO or secondary outcome measures were identified. CONCLUSION: This trial did not demonstrate significant improvement in the primary or secondary end points in the active treatment group versus the group receiving placebo. However, for FVC there was a trend toward statistical significance between the 2 groups. This suggests that treatment of pulmonary fibrosis in SSc with low-dose prednisolone and IV CYC followed by AZA stabilizes lung function in a subset of patients with the disease. Therapy was well tolerated with no increase in serious adverse events.

In idiopathic pulmonary fibrosis, the quantitation of disease severity using pulmonary function tests is often confounded by emphysema. We have identified the composite physiologic index (CPI) most closely reflecting the morphologic extent of pulmonary fibrosis. Consecutive patients with a clinical/computed tomography (CT) diagnosis of idiopathic pulmonary fibrosis (n = 212) were divided into group I (n = 106) and group II (n = 106). The CPI was derived in group I (by fitting pulmonary function tests against disease extent on CT) and was tested in Group II. The formula for the CPI was as follows: extent of disease on CT = 91.0 - (0.65 x percent predicted diffusing capacity for carbon monoxide [DLCO]) - (0.53 x percent predicted FVC) + (0.34 x percent predicted FEV1). In group II, the CPI correlated more strongly with disease extent on CT (r2 = 0.51) than the individual pulmonary function test (DLCO the highest value, r2 = 0.38). A subanalysis demonstrated that the better fit of the CPI was ascribable to a correction of the confounding effects of emphysema. Mortality was predicted more accurately by the CPI than by a pulmonary function test in all clinical subgroups, including a separate cohort of 36 patients with histologically proven usual interstitial pneumonia (CPI, p < 0.0005; FVC, p = 0.002; PO2, p = 0.002). In conclusion, a new CPI, derived against CT and validated using split sample testing, is a more accurate prognostic determinant in usual interstitial pneumonia than an individual pulmonary function test.

PURPOSE: To evaluate computed tomographic (CT) patterns of lung disease in patients with systemic sclerosis (SSc) and compare them with CT appearance in patients with biopsy-proved idiopathic pulmonary fibrosis (IPF) and idiopathic nonspecific interstitial pneumonia (NSIP). MATERIALS AND METHODS: The CT features of consecutive patients with SSc (n = 225; male patients, 44; female patients, 181; median age, 47 years; age range, 16-78 years), IPF (n = 40; men, 26; women, 14; median age, 54.5 years; age range, 36-77 years) and NSIP (n = 27; men, 18; women, nine; median age, 53 years; age range, 32-68 years) were quantified separately by two observers. The extent of interstitial lung disease, ground-glass opacification, emphysema, and the coarseness of a reticular pattern were quantified. Group comparisons were made nonparametrically with the Wilcoxon rank sum test. Differences in CT features were identified with multiple logistic regression analysis. RESULTS: The coarseness of fibrosis was similar in patients with SSc and idiopathic NSIP but strikingly different between patients with SSc (median coarseness score, 5.5; range, 0.0-13.3) and IPF (median coarseness score, 8.8; range, 2.5-15.0) (P <.001). The proportion of ground-glass opacification at CT was similar in patients with SSc and idiopathic NSIP but differed significantly between patients with SSc (median proportion, 49.9%; range, 0.0%-100.0%) and IPF (median proportion, 23.5%; range, 0.0%-97.2%) (P <.001). At logistic regression analysis, there were no differences in the CT features between patients with SSc and those with NSIP after controlling for age, disease extent, and the percentage predicted forced vital capacity and carbon monoxide diffusing capacity. CONCLUSION: Interstitial lung disease in patients with SSc is less extensive, less coarse, and characterized by a greater proportion of ground-glass opacification than that in patients with IPF. The CT features of lung disease in patients with SSc closely resemble those in patients with idiopathic NSIP.

Despite silica dust exposure being one of the earliest recognized causes of lung disease, Australia, USA, Israel, Turkey and other countries around the world have recently experienced significant outbreaks of silicosis. These outbreaks have occurred in modern industries such as denim jean production, domestic benchtop fabrication and jewellery polishing, where silica has been introduced without recognition and control of the hazard. Much of our understanding of silica-related lung disease is derived from traditional occupations such as mining, whereby workers may develop slowly progressive chronic silicosis. However, workers in modern industries are developing acute and accelerated silicosis over a short period of time, due to high-intensity silica concentrations, oxidative stress from freshly fractured silica and a rapid pro-inflammatory and pro-fibrotic response. Appropriate methods of screening and diagnosis remain unclear in these workers, and a significant proportion may go on to develop respiratory failure and death. There are no current effective treatments for silicosis. For those with near fatal respiratory failure, lung transplantation remains the only option. Strategies to reduce high-intensity silica dust exposure, enforced screening programmes and the identification of new treatments are urgently required.