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
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.
Radiomic features calculated from routine medical images show great potential for personalised medicine in cancer. Patients with systemic sclerosis (SSc), a rare, multiorgan autoimmune disorder, have ...a similarly poor prognosis due to interstitial lung disease (ILD). Here, our objectives were to explore computed tomography (CT)-based high-dimensional image analysis ("radiomics") for disease characterisation, risk stratification and relaying information on lung pathophysiology in SSc-ILD.
We investigated two independent, prospectively followed SSc-ILD cohorts (Zurich, derivation cohort, n=90; Oslo, validation cohort, n=66). For every subject, we defined 1355 robust radiomic features from standard-of-care CT images. We performed unsupervised clustering to identify and characterise imaging-based patient clusters. A clinically applicable prognostic quantitative radiomic risk score (qRISSc) for progression-free survival (PFS) was derived from radiomic profiles using supervised analysis. The biological basis of qRISSc was assessed in a cross-species approach by correlation with lung proteomic, histological and gene expression data derived from mice with bleomycin-induced lung fibrosis.
Radiomic profiling identified two clinically and prognostically distinct SSc-ILD patient clusters. To evaluate the clinical applicability, we derived and externally validated a binary, quantitative radiomic risk score (qRISSc) composed of 26 features that accurately predicted PFS and significantly improved upon clinical risk stratification parameters in multivariable Cox regression analyses in the pooled cohorts. A high qRISSc score, which identifies patients at risk for progression, was reverse translatable from human to experimental ILD and correlated with fibrotic pathway activation.
Radiomics-based risk stratification using routine CT images provides complementary phenotypic, clinical and prognostic information significantly impacting clinical decision making in SSc-ILD.
Abstract
Objective
SSc is a severe, heterogeneous multi-organ disease where population-based estimates on phenotypic spectrum, overall disease burden and societal impact are largely missing. Here the ...objective was to provide the first-ever complete national-level data on phenotype and major organ afflictions in SSc.
Methods
A stepwise strategy was applied to find and characterize every SSc patient resident in Norway from 2000 to 2012. First we identified every case in the country registered with an International Classification of Diseases, Tenth Revision code for SSc (M34). Next we manually reviewed all cases coded as M34 to determine whether they met the 1980 ACR and/or 2013 ACR/EULAR classification criteria for SSc and could be included in the Norwegian SSc cohort (Nor-SSc). Finally, all disease features from SSc onset to study end were reviewed.
Results
The Nor-SSc cohort included 815 SSc patients. The mean age at diagnosis was 53 years, with 84% females and 77% limited cutaneous SSc. The estimated incidence increased from 4 per million in 2000 to 13 per million in 2012. We identified high cumulative frequencies of internal organ involvement, coexistence of multiple organ afflictions across disease subsets and autoantibody status and stable frequencies of pulmonary arterial hypertension across haemodynamic definitions, but indications of referral-related differences in pulmonary hypertension detection rates across the study area.
Conclusion
This nationwide cohort study provides new, unbiased evidence for a high disease burden in SSc patients of Caucasian descent and indicates the existence of hurdles preventing equality of assessment across the SSc population.
Abstract
Objectives
To evaluate the severity and evolution of patient-reported gastrointestinal tract (GIT) symptoms in systemic sclerosis (SSc) patients, assess predictive factors for progression ...and determine the impact of standard of care treatment.
Methods
SSc patients from the Leiden and Oslo cohorts were included. We assessed clinical data and patient-reported GIT symptoms measured by the validated University of California, Los-Angeles Gastrointestinal-tract (UCLA-GIT) score at baseline and annually. GIT severity and progression was determined. Logistic regression was applied to identify risk factors associated with baseline GIT symptom severity. Linear mixed-effect models were applied to assess progression in GIT symptom burden and to identify predictive factors. We repeated all analysis in patients with early disease (inception cohort) to exclude the effect of longstanding disease and increase insights in development of GIT symptom burden early in the disease course.
Results
We included 834 SSc patients with baseline UCLA GIT scores, 454 from Leiden and 380 from Oslo. In the total cohort, 28% reported moderate-severe GIT symptoms at baseline, with increased risk for severity conferred by ACA, smoking and corticosteroid use, while use of calcium channel blockers appeared protective. In the inception cohort, 23% reported moderate-severe GIT symptoms at baseline, with increased risk for females and with smoking. Over time, symptom burden increased mainly for reflux/bloating. Female sex and ACA predicted GIT symptom progression.
Conclusion
High GIT symptom burden is present early in SSc disease course. Both for prevalence and for progression of GIT symptom burden, female sex and smoking were identified as risk factors.
Introduction
Systemic sclerosis (SSc) is a heterogenous disorder that appears to result from interplay between vascular pathologies, tissue fibrosis and immune processes, with evidence for ...deregulation of chemokines, which normally control immune trafficking. We recently identified altered levels of chemokine CCL21 in SSc associated pulmonary arterial hypertension (PAH). Here, we aimed to define target organ expression and biomarker characteristics of CCL21.
Materials and methods
To investigate target organ expression of CCL21, we performed immunohistochemistry (IHC) on explanted lung tissues from SSc-PAH patients. We assessed serum levels of CCL21 by ELISA and Luminex in two well-characterized SSc cohorts from Oslo (OUH, n=552) and Zurich (n=93) University hospitals and in 168 healthy controls. For detection of anti-CCl21 antibodies, we performed protein array analysis applying serum samples from SSc patients (n=300) and healthy controls. To characterize circulating CCL21 in SSc, we applied immunoprecipitation (IP) with antibodies detecting both full length and tailless and a custom-made antibody detecting only the C-terminal of CCL21. IP products were analyzed by SDS-PAGE/western blot and Mass spectrometry (MS).
Results
By IHC, we found that CCL21 was mainly expressed in the airway epithelial cells of SSc patients with PAH. In the analysis of serum levels of CCL21 we found weak correlation between Luminex and ELISA (r=0.515, p<0.001). Serum levels of anti-CCL21 antibodies were higher in SSc patients than in healthy controls (p<0.001), but only 5% of the SSc population were positive for anti-CCL21 antibodies in SSc, and we found no correlation between anti-CCl21 and serum levels of CCL21. By MS, we only identified peptides located within amino acid (aa) 23-102 of CCL21, indicating that CCL21 in SSc circulate as a truncated protein without the C-terminal tail.
Conclusion
This study demonstrates expression of CCL21 in epithelial lung tissue from SSc patients with PAH, and indicate that CCL21 in SSc circulates as a truncated protein. We extend previous observations indicating biomarker potential of CCL21, but find that Luminex is not suitable as platform for biomarker analyses. Finally,
in vivo
generated anti-CCL21 antibodies exist in SSc, but do not appear to modify serum CCL21 levels in patients with SSc-PAH.
Primary cardiac affection is common and is a major cause of death in systemic sclerosis (SSc), but there are knowledge gaps regarding the effect of cardiac dysfunction on mortality.
The purpose of ...this study was to evaluate diastolic function in a large, unselected SSc cohort and assess the effect of diastolic dysfunction (DD) on mortality.
SSc patients followed prospectively at the Oslo University Hospital from 2003 to 2016 with available echocardiographies and matched control subjects were included. DD was assessed by echocardiography according to the 2016 American Society of Echocardiography/European Association of Cardiovascular Imaging guidelines. Pulmonary hypertension (PH) was diagnosed by right heart catheterization. Vital status was available for all patients. Cox regression analyses with hazards ratios (HRs) were conducted.
Diastolic function was assessed in 275 SSc patients at baseline and in 186 patients at follow-up. At baseline, 46 of the 275 SSc patients (17%) were diagnosed with DD and 195 (71%) had normal diastolic function. After a median follow-up of 3.4 years (interquartile range: 1.6 to 6.2 years), the proportion of DD increased from 17% to 29%. During follow-up, 57% of patients with DD at baseline died, compared with 13% of patients with normal diastolic function. At baseline, 86 patients had performed right heart catheterization, and 43 were diagnosed with PH; of these 60% deceased. In multivariable Cox regression analyses, DD was a stronger predictor of death (HR: 3.7; 95% CI: 1.69 to 8.14; c-index 0.89) than PH (HR: 2.0; 95% CI: 1.1 to 3.9; c-index 0.84).
DD is frequent in SSc, and the presence of DD is associated with high mortality. DD exceeds PH with respect to predicting mortality.
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IntroductionIn the multisystem inflammatory disorder systemic sclerosis (SSc), gastrointestinal tract (GIT) affliction is highly prevalent. There are no known disease modifying therapies and the ...negative impact is substantial. Aiming for a new therapeutic principle, and inspired by recent work showing associations between gut microbiota changes and GIT symptoms in SSc, we performed a pilot study on faecal microbiota transplantation (FMT) with the single-donor bacterial culture ‘Anaerobic Cultivated Human Intestinal Microbiome (ACHIM)’. Motivated by positive pilot study signals, we designed the ReSScue trial as a phase II multicentre, placebo-controlled, randomised 20-week trial to evaluate safety and efficacy on lower GIT symptoms of FMT by ACHIM in SSc.Methods and analysesWe aim to include 70 SSc participants with moderate to severe lower GIT symptoms, defined by the validated patient-reported University of California Los Angeles Scleroderma Clinical Trial Consortium GIT 2.0 2.0 questionnaire. The trial includes three parts. In part A1 (induction phase) lasting from week 0 to week 12, participants will be randomised 1:1 to repeat infusions of 30 mL ACHIM or placebo at week 0 and 2 by gastroduodenoscopy. In part A2, which is an 8-week subsequent maintenance phase, all study participants will receive 30 mL ACHIM at week 12 and followed until week 20 on continued blind. In part B, which will last until the last participant completes part A2, the participants will be followed through a maximum 16-week extended monitoring period, for longer-term data on safety and intervention effects. Primary endpoint is change from baseline to week 12 in UCLA GIT subscale scores of diarrhoea or bloating, depending on the worst symptom at baseline evaluated separately for each patient. Secondary endpoints are safety measures and changes in UCLA GIT scores (total, diarrhoea and bloating).Ethics and disseminationThis protocol was approved by the Northern Norwegian Committee for Medical Ethics. Study findings will be published.Trial registration numberNCT04300426; Pre-results.Protocol versionV.3.1.
Abstract
Objectives
In SSc, gastrointestinal tract (GIT) involvement is a major concern, with no disease-modifying and limited symptomatic therapies available. Faecal microbiota transplantation (FMT) ...represents a new therapeutic option for GIT-affliction in SSc, showing clinical promise in a recent controlled pilot trial. Here, we aim to investigate effects of FMT on duodenal biopsies collected from SSc patients by immunohistochemistry and transcriptome profiling.
Methods
We analysed duodenal biopsies obtained pre-intervention (week 0) and post-intervention (weeks 2 and 16) from nine SSc patients receiving an intestinal infusion of FMT (n = 5) or placebo (n = 4). The analysis included immunohistochemistry (IHC) with a selected immune function and fibrosis markers, and whole biopsy transcriptome profiling.
Results
In patients receiving FMT, the number of podoplanin- and CD64-expressing cells in the mucosa were lower at week 2 compared with baseline. This decline in podoplanin- (r = 0.94) and CD64-positive (r = 0.89) cells correlated with improved patient-reported lower GIT symptoms. Whole biopsy transcriptome profiling from week 2 showed significant enrichment of pathways critical for cellular and endoplasmic reticulum stress responses, microvillus and secretory vesicles, vascular and sodium-dependent transport, and circadian rhythm. At week 16, we found enrichment of pathways mandatory for binding activity of immunoglobulin receptors, T cell receptor complexes, and chemokine receptors, as well as response to zinc-ions. We found that 25 genes, including Matrix metalloproteinase-1 were upregulated at both week 2 and week 16.
Conclusion
Combining selective IHC and unbiased gene expression analyses, this exploratory study highlights the potential for disease-relevant organ effects of FMT in SSc patients with GIT involvement.
Trial registration
ClinicalTrials.gov, http://clinicaltrials.gov, NCT03444220.
Abstract
Objective
The DETECT algorithm was developed for screening patients with SSc at high risk of pulmonary arterial hypertension (PAH). We evaluated the impact of this algorithm in a SSc ...population.
Methods
Patients from the unselected, prospective Oslo University Hospital SSc study were divided into the Early and DETECT cohorts, respectively, depending on whether an incident right heart catheterization (RHC) was performed before (2009-13) or after (2014-17) the DETECT algorithm was instituted. A PAH diagnosis and patient risk stratification (low, intermediate and high risk) were performed according to 2015 European Society of Cardiology guidelines.
Results
At the time of the incident RHC, PAH frequency was similar between the DETECT (15/84 with PAH; 18%) and Early (16/77; 21%) cohorts, but more patients had borderline pulmonary hypertension (PH) in the DETECT (31%) than in the Early (17%) cohort. PAH risk levels were distributed differently. In the DETECT cohort, 27% and 27% were at low and high risk, respectively, at the time of PAH diagnosis. In the Early cohort, 19 and 44% were at low and high risk, respectively. A follow-up RHC, performed after mean (SD) 2.4 (1.8) years, showed that 39% of patients with borderline PH in the Early cohort had developed PAH.
Conclusion
The DETECT algorithm did not alter PAH incidence in this unselected SSc population. However, it appeared to affect the risk distribution at the time of PAH diagnosis and increased the frequency of borderline PH cases. These findings may translate into novel opportunities for earlier PAH treatment and, possibly, prevention.
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