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) 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.
Methods
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.
Results
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.
Conclusion
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.
Objective
To explore the associations between microvascular abnormalities as assessed by nailfold capillaroscopy (NFC) and pulmonary and cardiac involvement in patients with juvenile dermatomyositis ...(DM) who are assessed after medium‐ to long‐term follow‐up.
Methods
Fifty‐eight patients with juvenile DM were examined a mean ± SD of 17.0 ± 10.6 years after symptom onset. Nailfold capillary density (NCD) and a neovascular pattern (defined as an active or late scleroderma pattern) were analyzed, with blinding to clinical data. Pulmonary involvement was assessed by pulmonary function tests including spirometry, diffusing capacity for carbon monoxide (DLco), and body plethysmography. High‐resolution computed tomography (HRCT) was also performed. Cardiac involvement was assessed by electrocardiography, Holter monitoring (heart rate variability), and echocardiography.
Results
Patients with low NCD (<6 capillaries/mm) (n = 21), compared to patients with normal NCD (≥6 capillaries/mm) (n = 37) had lower forced vital capacity (89.7% versus 98.5% predicted), total lung capacity (87.8% versus 94.5% predicted), and more often had low DLco values (15 71% of 21 patients versus 14 38% of 37 controls) (all P < 0.05). Use of HRCT to assess airway disease was more frequent in the group with low NCD (6 30% of 20 patients versus 3 8% of 36 patients in the normal NCD group; P = 0.034). No associations between NCD and cardiac parameters or between neovascular pattern and pulmonary or cardiac parameters were observed.
Conclusion
In patients with juvenile DM, low NCD was associated with lung involvement, which was mostly subclinical. No significant associations with cardiac involvement were observed. These results shed light on possible mechanisms underlying organ involvement, but further and preferably larger studies are needed to identify NCD as a potential biomarker for lung and cardiac involvement in juvenile DM.
Abstract
Background
Abnormal remodelling of the extracellular matrix (ECM) has generally been linked to pulmonary inflammation and fibrosis and may also play a role in the pathogenesis of severe ...COVID‐19. To further elucidate the role of ECM remodelling and excessive fibrogenesis in severe COVID‐19, we examined circulating levels of mediators involved in various aspects of these processes in COVID‐19 patients.
Methods
Serial blood samples were obtained from two cohorts of hospitalised COVID‐19 patients (
n
= 414). Circulating levels of ECM remodelling mediators were quantified by enzyme immunoassays in samples collected during hospitalisation and at 3‐month follow‐up. Samples were related to disease severity (respiratory failure and/or treatment at the intensive care unit), 60‐day total mortality and pulmonary pathology after 3‐months. We also evaluated the direct effect of inactivated SARS‐CoV‐2 on the release of the different ECM mediators in relevant cell lines.
Results
Several of the measured markers were associated with adverse outcomes, notably osteopontin (OPN), S100 calcium‐binding protein A12 and YKL‐40 were associated with disease severity and mortality. High levels of ECM mediators during hospitalisation were associated with computed tomography thorax pathology after 3‐months. Some markers (i.e. growth differential factor 15, galectin 3 and matrix metalloproteinase 9) were released from various relevant cell lines (i.e. macrophages and lung cell lines)
in vitro
after exposure to inactivated SARS‐CoV‐2 suggesting a direct link between these mediators and the causal agent of COVID‐19.
Conclusion
Our findings highlight changes to ECM remodelling and particularly a possible role of OPN, S100A12 and YKL‐40 in the pathogenesis of severe COVID‐19.
Background
We investigated the impact of varying contrast medium (CM) densities and x-ray tube potentials on contrast enhancement (CE), image quality and radiation dose in thoracic computed ...tomography (CT) using two different scanning techniques.
Methods
Seven plastic tubes containing seven different CM densities ranging from of 0 to 600 HU were positioned inside a commercial chest phantom with padding, representing three different patient sizes. Helical scans of the phantom in single-source mode were obtained with varying tube potentials from 70 to 140 kVp. A constant volume CT dose index (CTDIvol) depending on phantom size and automatic dose modulation was tested. CE (HU) and image quality (contrast-to-noise ratio, CNR) were measured for all combinations of CM density and tube potential. A reference threshold of CE and kVp was defined as ≥ 200 HU and 120 kVp.
Results
For the medium-sized phantom, with a specific CE of 100–600 HU, the diagnostic CE (200 HU) at 70 kVp was ~ 90% higher than at 120 kVp, for both scan techniques (
p
< 0.001). Changes in CM density/specific HU together with lower kVp resulted in significantly higher CE and CNR (
p
< 0.001). When changing only the kVp, no statistically significant differences were observed in CE or CNR (
p
≥ 0.094), using both dose modulation and constant CTDIvol.
Conclusions
For thoracic CT, diagnostic CE (≥ 200 HU) and maintained CNR were achieved by using lower CM density in combination with lower tube potential (< 120 kVp), independently of phantom size.
Background
T‐cell activation is associated with an adverse outcome in COVID‐19, but whether T‐cell activation and exhaustion relate to persistent respiratory dysfunction and death is unknown.
...Objectives
To investigate whether T‐cell activation and exhaustion persist and are associated with prolonged respiratory dysfunction and death after hospitalization for COVID‐19.
Methods
Plasma and serum from two Norwegian cohorts of hospitalized patients with COVID‐19 (n = 414) were analyzed for soluble (s) markers of T‐cell activation (sCD25) and exhaustion (sTim‐3) during hospitalization and follow‐up.
Results
Both markers were strongly associated with acute respiratory failure, but only sTim‐3 was independently associated with 60‐day mortality. Levels of sTim‐3 remained elevated 3 and 12 months after hospitalization and were associated with pulmonary radiological pathology after 3 months.
Conclusion
Our findings suggest prolonged T‐cell exhaustion is an important immunological sequela, potentially related to long‐term outcomes after severe COVID‐19.
Extensive skin disease and renal crisis are hallmarks of anti-RNA polymerase III (RNAP)-positive systemic sclerosis (SSc), while lung and heart involvement data are conflicting. Here, the aims were ...to perform time-course analyses of interstitial lung disease (ILD) and pulmonary hypertension (PH) in the RNAP subset of a prospective unselected SSc cohort and to use the other autoantibody subsets as comparators.
The study cohort included 279 patients with SSc from the observational Oslo University Hospital cohort with complete data on (1) SSc-related autoantibodies, (2) paired, serial analyses of lung function and fibrosis by computed tomography, and (3) PH verified by right heart catheterization.
RNAP was positive in 33 patients (12%), 79% of which had diffuse cutaneous SSc. Pulmonary findings were heterogeneous; 49% had no signs of fibrosis while 18% had > 20% fibrosis at followup. Forced vital capacity at followup was < 80% in 39% of the RNAP subset, comparable to the antitopoisomerase subset (ATA; 47%), but higher than anticentromere (ACA; 13%). Accumulated frequency of PH in the RNAP subset (12%) was lower than in ACA (18%). At 93% and 78%, the 5- and 10-year survival rates in RNAP were comparable to the ATA and ACA subsets.
In this cohort, the RNAP subset was marked by cardiopulmonary heterogeneity, ranging from mild ILD to development of severe ILD in 18%, and PH development in 12%. These data indicate that cardiopulmonary risk stratification early in the disease course is particularly important in RNAP-positive SSc.
To retrospectively evaluate the efficacy and safety of rituximab (Rtx) treatment in patients with anti-synthetase syndrome (ASS) and severe interstitial lung disease (ILD).
Patients with severe ILD ...and >12 months follow-up post-Rtx were identified from the Oslo University Hospital ASS cohort (n = 112). Clinical data, including pulmonary function tests (PFTs), were retrospectively collected from medical reports. Extent of ILD pre-, and post-Rtx was scored on thin-section high-resolution CT (HRCT) images and expressed as a percentage of total lung volume. Muscle strength was evaluated by manual muscle testing of eight muscle groups (MMT8).
Altogether, 34/112 ASS patients had received Rtx; 24/34 had severe ILD and >12 months follow-up post-Rtx (median 52 months). In these 24 patients, the median percentage of predicted forced vital capacity, forced expiratory volume in 1 s (FEV1) and diffusing capacity of the lungs for carbon monoxide (DLCO) increased by 24%, 22% and 17%, respectively, post-Rtx. Seven patients (all with disease duration <12 months and/or acute onset/exacerbation of ILD) had >30% improvement in all three PFTs. HRCT analysis showed a median 34% reduction in ILD extent post-Rtx. MMT8 score increased post-Rtx. During follow-up, 7/34 (21%) Rtx-treated ASS patients died; 6/7 deaths were related to infections. The mortality rate in the Rtx-treated group was comparable to that of the remaining ASS cohort (25/78 deceased; 32%).
This study, which included 24 Rtx-treated ASS patients with severe ILD, reports improved PFTs after a median 52 months follow-up post-Rtx. The best outcome was observed in patients with a disease duration <12 months and/or acute onset/exacerbation of ILD. The study indicates that Rtx could be a treatment option for selected ASS patients, but infections should be given attention.
MCTD is a chronic, immune-mediated disorder defined by the combined presence of serum anti-RNP antibodies and distinct clinical features, including progressive lung fibrosis. The aim of the study was ...to evaluate the potential impact of anti-SSA (i.e. Ro52 and Ro60) and anti-SSB autoantibodies as markers for disease outcomes in MCTD.
Stored serum samples from 113 patients included in the cross-sectional, nationwide Norwegian MCTD cohort were screened for the presence of anti-Ro52, anti-Ro60 and anti-SSB by a commercial line immunoassay. Correlation analyses were carried out with clinical parameters, including quantitative lung fibrosis scores by high-resolution CT. Lung fibrosis was defined by reticular pattern changes according to the Fleischner Society CT criteria for interstitial lung disease.
Anti-Ro52 antibodies were present in 29%, anti-Ro60 in 19% and anti-SSB in 6% of the MCTD sera. High-resolution CT scoring identified lung fibrosis in 38 of 113 (34%) MCTD patients. Anti-Ro52 antibodies were detected in 50% (19 of 38) of the MCTD patients with lung fibrosis and in 19% (14 of 75) without lung fibrosis (P < 0.001). The odds ratio for the presence of anti-Ro52 antibodies in lung fibrosis was 4.4 (95% CI 1.8, 10.3). Anti-Ro52 antibodies were equally frequent in patients with mild to moderate (eight of 17; 44%) and severe fibrosis (11 of 21; 52%). Anti-Ro52 was not associated with any of the other clinical parameters assessed, nor was anti-Ro60 or anti-SSB.
Our cross-sectional data suggest that anti-Ro52 antibodies may serve as a potential marker for lung fibrosis in MCTD.
The phenotypic stability of mixed connective tissue disease (MCTD) is not clear, and knowledge about disease activity and remission is scarce. We aimed to establish the occurrence of evolution from ...MCTD to another defined rheumatic condition, and the prevalence and durability of remission after long-term observation.
In this large population-based prospective observational MCTD cohort study (N = 118), disease conversion was defined by the development of new auto-antibodies and clinical features compliant with another well-defined rheumatic condition. Remission was defined by a combination of systemic lupus erythematosus disease activity index 2000 (SLEDAI-2 K) of 0 and European League Against Rheumatism scleroderma trials and research (EUSTAR) activity index <2.5. Predictors of phenotypic stability and disease remission were assessed by logistic regression.
Among 118 patients, 14 (12%) developed another well-defined rheumatic condition other than MCTD after mean disease duration of 17 (SD 9) years. Puffy hands predicted a stable MCTD phenotype in univariable regression analysis (OR 7, CI 2-27, P = .010). Disease activity defined by SLEDAI-2 K, decreased gradually across the observation period and > 90% of patients had EUSTAR activity index <2.5. There were 13% patients in remission throughout the whole mean observation period of 7 (SD 2) years. The strongest predictor of remission was percentage of predicted higher forced vital capacity.
Our results strengthen the view of MCTD as a relatively stable disease entity. Long-term remission in MCTD is not frequent; however, the low SLEDAI-2 K and EUSTAR scores during the observation period suggests that the disease runs a milder course than systemic lupus erythematosus and systemic sclerosis.
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