Brief Report: Pulmonary Function Tests: High Rate of False-Negative Results in the Early Detection and Screening of Scleroderma-Related Interstitial Lung Disease.

Validated methods for the screening and early diagnosis of systemic sclerosis (SSc; scleroderma)-related interstitial lung disease (ILD) are needed. The aim of this study was to evaluate the performance of pulmonary function tests (PFTs) compared with that of high-resolution computed tomography (HRCT) of the chest for the detection of SSc-related ILD in clinical practice, and to identify predictors of lung involvement that is functionally occult but significant on HRCT. Prospectively enrolled patients with SSc were assessed according to the European League Against Rheumatism (EULAR)/EULAR Scleroderma Trial and Research standards. The assessment included PFTs and HRCT. The HRCT images were evaluated in a blinded manner by 2 experienced radiologists. The performance parameters of PFTs for the diagnosis of SSc-related ILD were calculated. Predictors of significant ILD as determined by HRCT in patients with normal forced vital capacity (FVC) values were identified through logistic regression. Among the 102 patients, 64 (63.0%) showed significant ILD on HRCT, while only 27 (26.0%) had an FVC <80% of predicted, and 54 (53.0%) had a decrease in the results of at least 1 PFT. Forty (62.5%) of 64 patients with significant ILD on HRCT had a normal FVC value, translating into a high false-negative rate. Notably, 5 of 40 patients with a normal FVC value had severe, functionally occult lung fibrosis; in 2 of these patients, the results of all of the PFTs were within normal limits. Patients with normal FVC values despite evidence of fibrosis on HRCT more frequently had anti-Scl-70 antibodies and diffuse SSc and less frequently had anticentromere antibodies (ACAs) compared with patients with both normal FVC values and normal HRCT results. The derived evidence-based data reveal a high risk of missing significant SSc-related ILD when relying solely on PFTs. More comprehensive screening algorithms for early detection are warranted. In particular, additional imaging investigations for the early detection of SSc-related ILD should be considered in ACA-negative patients with normal FVC values.

Suliman YA ，Dobrota R ，Huscher D ，Nguyen-Kim TD ，Maurer B ，Jordan S ，Speich R ，Frauenfelder T ，Distler O ... -  《-》

Predictive value of serial high-resolution computed tomography analyses and concurrent lung function tests in systemic sclerosis.

Systemic sclerosis (SSc) carries a high risk of progressive interstitial lung disease (ILD), but tools for stratifying individual risk are scarce. The purpose of this study was to assess detailed data from serial lung fibrosis measurements and paired pulmonary function tests (PFTs) as outcome prediction tools in a prospective cohort of SSc patients. Paired PFTs and high-resolution computed tomography (HRCT) scans were obtained at baseline and at followup in 305 SSc patients who met the American College of Rheumatology/European League Against Rheumatism 2013 classification criteria. The extent of fibrosis was scored on 10 sections from every HRCT scan and expressed as the percentage of the total lung volume. Baseline HRCT analyses revealed 3 SSc subgroups: those with >20% lung fibrosis (n = 40), those with 1-20% fibrosis (n = 157), and those with no fibrosis (n = 108). At followup HRCT (mean of 3.1 years later), all 108 group 3 patients were still free of fibrosis. In group 2 patients, 146 continued to have 1-20% fibrosis (group 2a), whereas 11 (marked by short disease duration of 1.3 years) had experienced progression to >20% fibrosis (group 2b). The annual fibrosis progression rate differed across the 4 groups: 0.9% in group 1, 0.7% in group 2a, 5.9% in group 2b, and 0% in group 3. The annual fibrosis progression rate correlated with the total decline in the forced vital capacity (FVC) (7.1%, 5.7%, 8.7%, and 2.9% in groups 1, 2a, 2b, and 3, respectively), but not the diffusing capacity for carbon monoxide (DLco) (8.4%, 7.7%, 7.7%, and 8.6%, respectively). Multivariate analyses identified anticentromere antibodies (odds ratio [OR] 4.7) and baseline DLco (OR 1.04) as predictors of no fibrosis at followup and baseline fibrosis (OR 1.3) and FVC (OR 0.96) as predictors of >20% fibrosis at followup. These prospective cohort data suggest that HRCT performed at baseline predicts the development of fibrosis, the rate of progression of fibrosis, and the decline in pulmonary function in SSc.

Hoffmann-Vold AM ，Aaløkken TM ，Lund MB ，Garen T ，Midtvedt Ø ，Brunborg C ，Gran JT ，Molberg Ø ... -  《-》

Performance of Forced Vital Capacity and Lung Diffusion Cutpoints for Associated Radiographic Interstitial Lung Disease in Systemic Sclerosis.

Showalter K ，Hoffmann A ，Rouleau G ，Aaby D ，Lee J ，Richardson C ，Dematte J ，Agrawal R ，Chang RW ，Hinchcliff M ... -  《-》

KL6 and IL-18 levels are negatively correlated with respiratory function tests and ILD extent assessed on HRCT in patients with systemic sclerosis-related interstitial lung disease (SSc-ILD).

Interstitial lung disease (ILD) is one of the leading causes of mortality in patients with systemic sclerosis (SSc). Serum biomarkers have been suggested as indicators for pulmonary damage with clinical value in the diagnosis and prognosis of SSc-ILD. To investigate the role of serum biomarkers (Krebs von den Lungen-6 KL-6, IL-18 and IL-18BP) as a potential biomarker reflecting the severity of SSc-ILD as assessed through high-resolution computed tomography (HRCT) and pulmonary function tests (PFT), including forced vital capacity (%FVC) and diffusing capacity of the lung for carbon monoxide (%DLCO). A cross-sectional study including patients with SSc fulfilling the 2013 ACR/EULAR criteria was performed. Patients were classified according to disease duration and pulmonary involvement (presence of ILD). All SSc patients underwent chest HRCT scans and pulmonary function test at baseline. Serum concentration of KL-6, IL8 and IL18BP were determined using the quantitative ELISA technique, sandwich type (solid phase sandwich Enzyme Linked-Immuno-Sorbent Assay), with kits from MyBiosource for KL-6 and from Invitrogen for IL18 and IL18BP. A semiquantitative grade of ILD extent was evaluated through HRCT scan (grade 1, 0-20%; grade 2, >20%). Extensive disease was defined as >20% lung involvement on HRCT, and FVC <70% predicted and limited lung involvement as ≤20% ILD involvement on HRCT, and an FVC ≥70% predicted. 74 patients were included, 27% were male. The mean age at diagnosis was 57.5±15 years and the mean time since diagnosis was 7.67±8 years. 28 patients had ILD (38%). 64% of patients had <20% ILD extent classified through HRCT scan. SSc-ILD patients had elevated serum KL-6 and IL-18 levels compared to patients without ILD (p=0.003 and p=0.04), and those findings were preserved after adjusting for age and sex. Negative correlation between KL-6 levels and%FVC (β=-0.25, p 0.037) and% DLCO (β=-0.28, p 0.02) and between IL-18 levels and%FVC (β=-0.38, p 0.001) and%DLCO (β=-0.27, p 0.03) were found. Serum KL-6 and IL-18 levels successfully differentiated grades 1 and 2 of the semiquantitative grades of ILD extent (p = 0.028 and p = 0.022). Semiquantitative grades of ILD on the HRCT scan were significantly proportional to the KL-6 (p = 0.01) and IL-18 (p = 0.03). A positive correlation between extensive lung disease and KL-6 (β=0.42, p = 0.007) but not with IL-18 was found. Serum KL-6 levels and IL-18 were increased in patients with SSc-ILD and showed a positive correlation with ILD severity as measured using a semiquantitative CT grading scale and negative correlation with PFT parameters. Serum KL-6 and IL-18 could be a clinically useful biomarker in screening and evaluating SSc-ILD.

Sieiro Santos C ，Antolín SC ，Lorenzo JC ，Garay CL ，Morales CM ，de Miguel EB ，Guerrero MR ，Herránz LS ，Álvarez ED ... -  《-》

Clinical algorithms for the diagnosis and prognosis of interstitial lung disease in systemic sclerosis.

Interstitial lung disease (ILD) is currently the primary cause of death in systemic sclerosis (SSc). Thoracic high-resolution computed tomography (HRCT) is considered the gold standard for diagnosis. Recent studies have proposed several clinical algorithms to predict the diagnosis and prognosis of SSc-ILD. To test the clinical algorithms to predict the presence and prognosis of SSc-ILD and to evaluate the association of extent of ILD with mortality in a cohort of SSc patients. Retrospective cohort study, including 177 SSc patients assessed by clinical evaluation, laboratory tests, pulmonary function tests, and HRCT. Three clinical algorithms, combining lung auscultation, chest radiography, and percentage predicted forced vital capacity (FVC), were applied for the diagnosis of different extents of ILD on HRCT. Univariate and multivariate Cox proportional models were used to analyze the association of algorithms and the extent of ILD on HRCT with the risk of death using hazard ratios (HR). The prevalence of ILD on HRCT was 57.1% and 79 patients died (44.6%) in a median follow-up of 11.1 years. For identification of ILD with extent ≥10% and ≥20% on HRCT, all algorithms presented a high sensitivity (>89%) and a very low negative likelihood ratio (<0.16). For prognosis, survival was decreased for all algorithms, especially the algorithm C (HR = 3.47, 95% CI: 1.62-7.42), which identified the presence of ILD based on crackles on lung auscultation, findings on chest X-ray, or FVC <80%. Extensive disease as proposed by Goh et al. (extent of ILD > 20% on HRCT or, in indeterminate cases, FVC < 70%) had a significantly higher risk of death (HR = 3.42, 95% CI: 2.12-5.52). Survival was not different between patients with extent of 10% or 20% of ILD on HRCT, and analysis of 10-year mortality suggested that a threshold of 10% may also have a good predictive value for mortality. However, there is no clear cutoff above which mortality is sharply increased. Clinical algorithms had a good diagnostic performance for extents of SSc-ILD on HRCT with clinical and prognostic relevance (≥10% and ≥20%), and were also strongly related to mortality. Non-HRCT-based algorithms could be useful when HRCT is not available. This is the first study to replicate the prognostic algorithm proposed by Goh et al. in a developing country.

Hax V ，Bredemeier M ，Didonet Moro AL ，Pavan TR ，Vieira MV ，Pitrez EH ，da Silva Chakr RM ，Xavier RM ... -  《-》