Objective
Interstitial lung disease (ILD) in systemic sclerosis (SSc) runs a highly variable course, and prediction tools are highly desired. The aim of this study was to assess the diagnostic and ...prognostic performance of 4 candidate serum biomarkers for SSc‐associated ILD.
Methods
Serum samples from a combined cohort of SSc patients (from Paris, France and Oslo, Norway; n = 427) were analyzed by enzyme‐linked immunosorbent assay for concentrations of lung epithelial–derived surfactant protein D (SP‐D), Krebs von den Lungen 6 glycoprotein (KL‐6), CCL18, and OX40 ligand (OX40L). Lung fibrosis was measured by high‐resolution computed tomography and pulmonary function tests. Associations of these candidate biomarkers with baseline disease involvement and prediction of disease progression over time (mean ± SD follow‐up 3.2 ± 4.4 years) were investigated.
Results
In SSc patients at baseline, serum levels of KL‐6 correlated with the forced vital capacity (FVC) (r = −0.317, P < 0.001), diffusing capacity for carbon monoxide (r = −0.335, P < 0.001), and extent of lung fibrosis (r = 0.551, P < 0.001). In multivariate analyses, serum levels of KL‐6 and SP‐D, but not CCL18 and OX40L, were associated with lung fibrosis (odds ratio OR 2.41, 95% confidence interval 95% CI 1.43–4.07 P = 0.001 and OR 3.15, 95% CI 1.81–5.48 P < 0.001, respectively). In SSc patients with ILD at baseline, longitudinal, multivariate analyses showed that CCL18 serum levels were an independent predictor of a >10% decrease in the FVC (hazard ratio HR 2.90, 95% CI 1.25–6.73; P = 0.014) and de novo development of extensive disease (HR 3.71, 95% CI 1.02–13.52; P = 0.048). Matrix‐based logistic regression models for the diagnosis and prognosis of SSc‐associated ILD were constructed, and these models discriminated 3 groups of risk (mild, moderate, or high) for the diagnosis or worsening of lung fibrosis according to the serum levels of SP‐D (for diagnosis) and serum levels of CCL18 (for progression of disease).
Conclusion
These results show that SP‐D is a relevant diagnostic biomarker for SSc‐associated ILD, whereas KL‐6 could be used to assess the severity of lung fibrosis. CCL18 appears to be a potential predictive marker for progression of ILD in SSc.
Objective
To analyze the efficacy and safety of nintedanib in patients with fibrosing autoimmune disease–related interstitial lung diseases (ILDs) with a progressive phenotype.
Methods
The INBUILD ...trial enrolled patients with a fibrosing ILD other than idiopathic pulmonary fibrosis, with diffuse fibrosing lung disease of >10% extent on high‐resolution computed tomography, forced vital capacity percent predicted (FVC%) ≥45%, and diffusing capacity of the lungs for carbon monoxide percent predicted ≥30% to <80%. Patients fulfilled protocol‐defined criteria for progression of ILD within the 24 months before screening, despite management deemed appropriate in clinical practice. Subjects were randomized to receive nintedanib or placebo. We assessed the rate of decline in FVC (ml/year) and adverse events (AEs) over 52 weeks in the subgroup with autoimmune disease–related ILDs.
Results
Among 170 patients with autoimmune disease–related ILDs, the rate of decline in FVC over 52 weeks was −75.9 ml/year with nintedanib versus −178.6 ml/year with placebo (difference 102.7 ml/year 95% confidence interval 23.2, 182.2; nominal P = 0.012). No heterogeneity was detected in the effect of nintedanib versus placebo across subgroups based on ILD diagnosis (P = 0.91). The most frequent AE was diarrhea, reported in 63.4% and 27.3% of subjects in the nintedanib and placebo groups, respectively. AEs led to permanent discontinuation of trial drug in 17.1% and 10.2% of subjects in the nintedanib and placebo groups, respectively.
Conclusion
In the INBUILD trial, nintedanib slowed the rate of decline in FVC in patients with progressive fibrosing autoimmune disease–related ILDs, with AEs that were manageable for most patients.
Video
Interstitial lung diseases (ILDs), which can arise from a broad spectrum of distinct aetiologies, can manifest as a pulmonary complication of an underlying autoimmune and connective tissue disease ...(CTD-ILD), such as rheumatoid arthritis-ILD and systemic sclerosis (SSc-ILD). Patients with clinically distinct ILDs, whether CTD-related or not, can exhibit a pattern of common clinical disease behaviour (declining lung function, worsening respiratory symptoms and higher mortality), attributable to progressive fibrosis in the lungs. In recent years, the tyrosine kinase inhibitor nintedanib has demonstrated efficacy and safety in idiopathic pulmonary fibrosis (IPF), SSc-ILD and a broad range of other fibrosing ILDs with a progressive phenotype, including those associated with CTDs. Data from phase II studies also suggest that pirfenidone, which has a different-yet largely unknown-mechanism of action, may also have activity in other fibrosing ILDs with a progressive phenotype, in addition to its known efficacy in IPF. Collectively, these studies add weight to the hypothesis that, irrespective of the original clinical diagnosis of ILD, a progressive fibrosing phenotype may arise from common, underlying pathophysiological mechanisms of fibrosis involving pathways associated with the targets of nintedanib and, potentially, pirfenidone. However, despite the early proof of concept provided by these clinical studies, very little is known about the mechanistic commonalities and differences between ILDs with a progressive phenotype. In this review, we explore the biological and genetic mechanisms that drive fibrosis, and identify the missing evidence needed to provide the rationale for further studies that use the progressive phenotype as a target population.
Objective
To compare mycophenolate mofetil (MMF) with placebo for the treatment of systemic sclerosis (SSc)–related interstitial lung disease (ILD).
Methods
We included participants enrolled in the ...placebo arm of Scleroderma Lung Study (SLS) I and the MMF arm of SLS II. SLS I randomized participants to receive either oral cyclophosphamide (CYC) or placebo for 1 year, while SLS II randomized participants to receive either MMF for 2 years or oral CYC for 1 year followed by 1 year of placebo. Eligibility criteria for SLS I and SLS II were nearly identical. The primary outcome was % predicted forced vital capacity (FVC), and key secondary outcomes included % predicted diffusing capacity for carbon monoxide (DLco), the modified Rodnan skin thickness score (MRSS), and dyspnea. Joint models were created to evaluate the treatment effect on the course of these outcomes over 2 years.
Results
At baseline, the MMF‐treated group in SLS II (n = 69) and the placebo‐treated group in SLS I (n = 79) had similar percentages of men and women and similar disease duration, SSc subtype, extent of skin disease, and % predicted FVC. MMF‐treated patients in SLS II were slightly older (mean ± SD age 52.6 ± 9.7 years versus 48.1 ± 12.4 years; P = 0.0152) and had higher % predicted DLco (mean ± SD 54.0 ± 11.1 versus 46.2 ± 13.3; P = 0.0002) than placebo‐treated patients in SLS I. After adjustment for baseline disease severity, treatment with MMF in comparison with placebo was associated with improved % predicted FVC (P < 0.0001), % predicted DLco (P < 0.0001), MRSS (P < 0.0001), and dyspnea (P = 0.0112) over 2 years.
Conclusion
Although there are inherent limitations in comparing participants from different trials, treatment with MMF was associated with improvements in physiologic outcomes and dyspnea compared with placebo, even after accounting for baseline disease severity. These results further substantiate the use of MMF for the treatment of SSc‐related ILD.
Interstitial lung disease (ILD) represents a major challenge in systemic sclerosis (SSc), but there are no precise, population-based data on its overall impact, limiting opportunities for screening ...and management strategies.
Evaluate impact of ILD in a unique, nationwide, population-based SSc cohort.
ILD was assessed prospectively in the Norwegian SSc (Nor-SSc) cohort, including all 815 patients with SSc resident in the country from 2000 to 2012. Lung high-resolution computed tomography (HRCT) scans were available for fibrosis quantification at baseline (
= 650, 80%) and follow-up. Pulmonary function tests were assessed at baseline (
= 703, 86%) and follow-up. Vital status and standardized mortality ratios (SMRs) were estimated at study end (2018) in the 630 incident Nor-SSc cases and 15 individually matched control subjects. Cumulative survival rates were computed.
At baseline, 50% of the subjects with SSc (
= 324) had ILD by HRCT and 46% displayed pulmonary function declines consistent with ILD progression. Mortality correlated with extent of lung fibrosis as SMR increased from 2.2 with no fibrosis to 8.0 with greater than 25% fibrosis. SMR was inversely related to baseline FVC% and increased at all FVC levels below 100%. In patients with normal-range baseline FVC (80-100%), the 5- and 10-year survival rates correlated with presence or absence of lung fibrosis, being 83% and 80%, respectively, with no fibrosis and 69% and 56%, respectively, with lung fibrosis (
= 0.03).
The mere presence of ILD at baseline appears to affect outcome in SSc, suggesting that all patients with SSc should undergo a baseline pulmonary function test and lung HRCT screening to diagnose ILD early and tailor further management.
Objective
Systemic sclerosis (SSc) is a major cause of pulmonary arterial hypertension (PAH). Murine models indicate key roles for chemokines CCL19 and CCL21 and their receptor CCR7 in lung ...inflammation leading to PAH. The objective of this study was to assess the chemokine CCL19–CCL21 axis in patients with SSc‐related PAH.
Methods
Serum samples obtained from 2 independent prospective SSc cohorts (n = 326), patients with idiopathic PAH (n = 12), and healthy control subjects (n = 100) were analyzed for CCL19/CCL21 levels, by enzyme‐linked immunosorbent assay. The levels were defined as either high or low, using the mean + 2 SD value in controls as the cutoff value. Risk stratification at the time of PAH diagnosis and PAH‐related events were performed. Descriptive and Cox regression analyses were conducted.
Results
CCL21 levels were higher in patients with SSc compared with controls and were elevated prior to the diagnosis of PAH. PAH was more frequent in patients with high CCL21 levels (≥0.4 ng/ml) than in those with low CCL21 levels (33.3% versus 5.3% P < 0.001). In multivariate analyses, CCL21 was associated with PAH (hazard ratio HR 5.1, 95% CI 2.39–10.76 P < 0.001) and occurrence of PAH‐related events (HR 4.7, 95% CI 2.12–10.46, P < 0.001). Risk stratification at the time of PAH diagnosis alone did not predict PAH‐related events. However, when risk at diagnosis was combined with high or low CCL21 level, there was a significant predictive effect (HR 1.3, 95% CI 1.03–1.60 P = 0.027). A high CCL21 level was associated with decreased survival (P < 0.001).
Conclusion
CCL21 appears to be a promising marker for predicting the risk of SSc‐related PAH and PAH progression. CCL21 may be part of a dysregulated immune pathway linked to the development of lung vascular damage in SSc.
Objective
Little is known on the disease course of very early systemic sclerosis (SSc). Among the information yet to be elucidated is whether anticentromere antibody (ACA) isotype levels can serve as ...biomarkers for future SSc development and for organ involvement. This study was undertaken to evaluate whether IgG, IgM, and IgA ACA levels in IgG ACA–positive patients are associated with disease severity and/or progression from very early SSc to definite SSc.
Methods
IgG ACA–positive patients from 5 different cohorts who had very early SSc or SSc fulfilling the American College of Rheumatology (ACR)/European Alliance of Associations for Rheumatology (EULAR) 2013 criteria were included. A diagnosis of very early SSc was based on the presence of IgG ACAs and Raynaud’s phenomenon, and/or puffy fingers and/or abnormal nailfold capillaroscopy, but not fulfilling the ACR/EULAR 2013 criteria for SSc. Multivariable regression analyses were performed to determine the association between baseline ACA isotype levels and progression to definite SSc with organ involvement.
Results
Six hundred twenty‐five IgG ACA–positive patients were included, of whom 138 (22%) fulfilled the criteria for very early SSc and 487 (78%) had definite SSc. Levels of IgG ACAs (odds ratio 2.5 95% confidence interval 1.8–3.7) and IgM ACAs (odds ratio 1.8 95% confidence interval 1.3–2.3) were significantly higher in patients with definite SSc. Of 115 patients with very early SSc with follow‐up, progression to definite SSc occurred within 5 years in 48 (42%). Progression to definite SSc was associated with higher IgG ACA levels at baseline (odds ratio 4.3 95% confidence interval 1.7–10.7).
Conclusion
ACA isotype levels may serve as biomarkers to identify patients with very early SSc who are at risk for disease progression to definite SSc.
Objective
Pulmonary arterial hypertension (PAH) is a major complication in systemic sclerosis (SSc), a disease marked by vascular and lymphatic vessel abnormalities. This study was undertaken to ...assess the role of the lymphangiogenic factors vascular endothelial growth factor C (VEGF‐C) and angiopoietin 2 (Ang‐2) and the soluble forms of their respective cognate receptors, soluble VEGF receptor 3 (sVEGFR‐3) and soluble TIE‐2, in patients with SSc, and to evaluate their predictive ability as markers for PAH development in SSc.
Methods
In this cohort study, we used multiplex bead assays to assess serum levels of lymphangiogenic factors in 2 well‐characterized SSc cohorts: an unselected identification cohort of SSc patients from Oslo University Hospital (n = 371), and a PAH‐enriched validation cohort of SSc patients from Zurich University Hospital and Oslo University Hospital (n = 149). As controls for the identification and validation cohorts, we obtained serum samples from 100 healthy individuals and 68 healthy individuals, respectively. Patients in whom SSc‐related PAH was identified by right‐sided heart catheterization (RHC) in both cohorts were studied in prediction analyses. PAH was defined according to the European Society of Cardiology/European Respiratory Society 2015 guidelines for the diagnosis and treatment of PAH. Associations of serum levels of lymphangiogenic factors with the risk of PAH development were assessed in logistic regression and Cox regression analyses. Associations in Cox regression analyses were expressed as the hazard ratio (HR) with 95% confidence interval (95% CI).
Results
In the identification cohort, SSc patients had lower mean serum levels of VEGF‐C and higher mean serum levels of Ang‐2 compared to healthy controls (for VEGF‐C, mean ± SD 2.1 ± 0.5 ng/ml in patients versus 2.5 ± 0.4 ng/ml in controls; for Ang‐2, mean ± SD 6.1 ± 7.6 ng/ml in patients versus 2.8 ± 1.8 ng/ml in controls; each P < 0.001); these same trends were observed in SSc patients with PAH compared to those without PAH. The association of serum VEGF‐C levels with SSc‐PAH was confirmed in the PAH‐enriched RHC validation cohort. For prediction analyses, we assembled all 251 cases of SSc‐PAH identified by RHC from the identification and validation cohorts. In multivariable Cox regression analyses adjusted for age and sex, the mean serum levels of VEGF‐C and sVEGFR‐3 were predictive of PAH development in patients with SSc (for VEGF‐C, HR 0.53 95% CI 0.29–0.97, P = 0.04; for sVEGFR‐3, HR 1.21 95% CI 1.01–1.45, P = 0.042).
Conclusion
These findings support the notion that lymphangiogenesis is deregulated during PAH development in SSc, and indicate that VEGF‐C could be a promising marker for early PAH detection in patients with SSc.
To identify overall disease course, progression patterns and risk factors predictive for progressive interstitial lung disease (ILD) in patients with systemic sclerosis-associated ILD (SSc-ILD), ...using data from the European Scleroderma Trials And Research (EUSTAR) database over long-term follow-up.
Eligible patients with SSc-ILD were registered in the EUSTAR database and had measurements of forced vital capacity (FVC) at baseline and after 12±3 months. Long-term progressive ILD and progression patterns were assessed in patients with multiple FVC measurements. Potential predictors of ILD progression were analysed using multivariable mixed-effect models.
826 patients with SSc-ILD were included. Over 12±3 months, 219 (27%) showed progressive ILD: either moderate (FVC decline 5% to 10%) or significant (FVC decline >10%). A total of 535 (65%) patients had multiple FVC measurements available over mean 5-year follow-up. In each 12-month period, 23% to 27% of SSc-ILD patients showed progressive ILD, but only a minority of patients showed progression in consecutive periods. Most patients with progressive ILD (58%) had a pattern of slow lung function decline, with more periods of stability/improvement than decline, whereas only 8% showed rapid, continuously declining FVC; 178 (33%) experienced no episode of FVC decline. The strongest predictive factors for FVC decline over 5 years were male sex, higher modified Rodnan skin score and reflux/dysphagia symptoms.
SSc-ILD shows a heterogeneous and variable disease course, and thus monitoring all patients closely is important. Novel treatment concepts, with treatment initiation before FVC decline occurs, should aim for prevention of progression to avoid irreversible organ damage.
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