Systemic sclerosis (SSc) is a severe rheumatic disease characterized by a considerable heterogeneity in clinical presentations and pathophysiological mechanisms. This variability has a substantial ...impact on morbidity and mortality and limits the generalizability of clinical trial results. This review aims to highlight recent studies that have proposed new innovative approaches to decipher this heterogeneity, in particular, by attempting to optimize disease classification.
The historical dichotomy limited/diffuse subsets based on cutaneous involvement has been challenged by studies highlighting an underestimated heterogeneity between these two subtypes and showing that presence of organ damage and autoantibody profiles markedly influenced survival beyond skin extension. Advanced computational methods using unsupervised machine learning analyses of clinical variables and/or high-throughput omics technologies, clinical variables trajectories modelling overtime or radiomics have provided significant insights on key pathogenic processes that could help defining new subgroups beyond the diffuse/limited subsets.
We can anticipate that a future classification of SSc patients will integrate innovative approaches encompassing clinical phenotypes, variables trajectories, serological features and innovative omics molecular signatures. It nevertheless seems crucial to also pursue the implementation and standardization of readily available and easy to use tools that can be used in clinical practice.
Pathophysiology of systemic sclerosis (scleroderma) Rosendahl, Ann‐Helen; Schönborn, Katrin; Krieg, Thomas
The Kaohsiung journal of medical sciences,
March 2022, 2022-Mar, 2022-03-00, 20220301, 2022-03-01, Letnik:
38, Številka:
3
Journal Article
Recenzirano
Odprti dostop
Systemic sclerosis (scleroderma) is an autoimmune‐triggered chronic fibrosing disease that affects the skin and many other organs. Its pathophysiology is complex and involves an early endothelial ...damage, an inflammatory infiltrate and a resulting fibrotic reaction. Based on a predisposing genetic background, an altered balance of the acquired and the innate immune system leads to the release of many cytokines and chemokines as well as autoantibodies, which induce the activation of fibroblasts with the formation of myofibroblasts and the deposition of a stiff and rigid connective tissue. A curative treatment is still not available but remarkable progress has been made in the management of organ complications. In addition, several breakthroughs in the pathophysiology have led to new therapeutic concepts. Based on these, many new compounds have been developed during the last years, which target these different pathways and offer specific therapeutic approaches.
Objective
This study was performed to determine the prevalence of elevated C‐reactive protein (CRP) levels and the significance of CRP in clinical parameters in systemic sclerosis (SSc; scleroderma) ...patients.
Methods
Canadian Scleroderma Research Group data were used. Statistical comparisons were made for CRP levels ≤8 mg/liter versus >8 mg/liter, early (≤3 years from first non–Raynaud's phenomenon symptom) versus late SSc, and diffuse cutaneous SSc (dcSSc) versus limited cutaneous SSc (lcSSc). A survival analysis was analyzed between patients with normal versus elevated CRP levels.
Results
A total of 1,043 patients (mean ± SD age 55.4 ± 12.1 years, mean ± SD disease duration of 11.0 ± 9.5 years) were analyzed; elevation of CRP level and erythrocyte sedimentation rate (ESR; >20 mm/hour) occurred in 25.7% and 38.2%, respectively. Mean ± SD baseline CRP level in dcSSc (11.98 ± 25.41 mg/liter) was higher than in lcSSc (8.15 ± 16.09 mg/liter; P = 0.016). SSc patients with an early disease duration had a higher mean ± SD CRP level (12.89 ± 28.13 mg/liter) than those with a late disease duration (8.60 ± 17.06 mg/liter; P = 0.041). Although not consistent in all subsets, CRP was significantly associated (P < 0.01) with ESR, modified Rodnan skin score (MRSS), worse pulmonary function parameters, disease activity, damage, and Health Assessment Questionnaire. CRP level seemed to normalize in many SSc patients over time. Total lung capacity <80% predicted, MRSS, and serum creatinine were predictors of elevated CRP levels in SSc (odds ratio OR 2.76 95% confidence interval (95% CI) 1.73–4.40, P = 0.0001; OR 1.03 95% CI 1.01–1.05, P = 0.005; and OR 1.005 95% CI 1.001–1.010, P = 0.02, respectively). Survival for patients with elevated CRP levels was less than for patients with normal CRP levels (P = 0.001).
Conclusion
CRP level is elevated in one‐quarter of SSc patients, especially early disease. It is correlated with disease activity, severity, poor pulmonary function, and shorter survival.
Objective
To assess survival and incidence of organ‐based complications in a large single‐center cohort of unselected systemic sclerosis (SSc) patients, and to explore predictors of survival and ...clinically significant pulmonary fibrosis (PF) and pulmonary hypertension (PH).
Methods
The study cohort consisted of 398 consecutive SSc patients, followed up for up to 15 years. Cox proportional hazards analysis with demographic, clinical, and laboratory characteristics as predictor variables was used to develop prediction models for pulmonary complications and survival.
Results
The overall survival estimate at the end of followup was 57% among patients with limited cutaneous SSc (lcSSc) and 50% among patients with diffuse cutaneous SSc (dcSSc) (P = 0.017). We found that greater age at disease onset, dcSSc, lower diffusing capacity for carbon monoxide (DLco), lower hemoglobin levels, higher serum creatinine levels, and the presence of PH or cardiac involvement were independent predictors of worse survival. Over the entire followup period, 42% of dcSSc patients and 22% of lcSSc patients developed clinically significant PF (P < 0.001). The variables that predicted clinically significant PF development were dcSSc, greater age at onset, lower forced vital capacity and DLco, and the presence of anti–topoisomerase I antibody, while the presence of anticentromere antibody was protective. There was no difference in cumulative incidence of PH between the 2 subsets—24% in lcSSc and 18% in dcSSc (P = 0.558). Incidence rates were 1–2% per year. The PH prediction model demonstrated that greater age at onset, increase in serum creatinine levels, lower DLco, and the presence of anti–RNA polymerase III or anti–U3 RNP antibodies were associated with increased risk of PH, while anti–topoisomerase I antibody positivity reduced the hazard.
Conclusion
Our study provides data on long‐term outcome of SSc and the timing and frequency of major organ complications. The predictive models we present could be used as clinical tools for patient risk stratification and could facilitate cohort enrichment for event‐driven studies.
Objective Markers for early identification of progressive interstitial lung disease (ILD) in systemic sclerosis (SSc) are in demand. Chemokine CCL18, which has been linked to pulmonary inflammation, ...is an interesting candidate, but data have not been consistent. We aimed to assess CCL18 levels in a large, prospective, unselected SSc cohort with longitudinal, paired data sets on pulmonary function and lung fibrosis. Methods Sera from the Oslo University Hospital SSc cohort (n = 298) and healthy control subjects (n = 100) were analyzed for CCL18 by enzyme immunoassay. High CCL18 (>53 ng/mL) was defined using the mean value plus 2 SD in sera obtained from healthy control subjects as the cutoff. Results High serum CCL18 was identified in 35% (105 of 298). Annual decline in FVC differed significantly between high and low CCL18 subsets (13.3% and 4.7%; P = .016), as did the annual progression rate of lung fibrosis (0.9% SD, 2.9 and 0.2% SD, 1.9). Highest rates of annual FVC decline > 10% (21%) and annual fibrosis progression (1.2%) were seen in patients with high CCL18 and early disease (< 3 years). In multivariate analyses, CCL18 was associated with annual FVC decline > 10% (OR, 1.1; 95% CI, 1.01-1.11) and FVC < 70% at follow-up (OR, 3.1; 95% CI, 1.08-8.83). Survival analyses showed that patients with high CCL18 had reduced 5- and 10-year cumulative survival compared with patients with low CCL18 (85% and 74%, compared with 97% and 89%, respectively; P = .001). Conclusions The results from this prospective cohort reinforce the notion that high CCL18 may serve as a marker for early identification of progressive ILD in SSc.
Pulmonary arterial hypertension (PAH) is a dreaded complication of systemic sclerosis (SSc) that occurs in ∼10% of patients. Most individuals present with severe symptoms, significant functional ...impairment and severe haemodynamics at diagnosis, and survival after PAH diagnosis is poor. Therefore, early diagnosis through systematic screening of asymptomatic patients has the potential to identify PAH at an early stage. Current evidence suggests that early diagnosis and treatment of PAH in patients with SSc may lead to better clinical outcomes. Annual screening may include echocardiography, but this can miss some patients due to suboptimal visualisation or insufficient tricuspid regurgitation. Other options for screening include the DETECT algorithm or the use of a combination of pulmonary function testing (forced vital capacity/diffusing capacity of the lung for carbon monoxide ratio) and N-terminal-pro-brain natriuretic peptide levels. Symptomatic patients, those with an elevated tricuspid regurgitation velocity on echocardiogram with or without secondary echocardiographic features of PAH, and those who screen positive on the DETECT or other pulmonary function test algorithms should undergo right heart catheterisation. Exercise echocardiography or cardiopulmonary exercise testing, nailfold capillaroscopy and molecular biomarkers are promising but, as yet, unproven potential options. Future screening studies should employ systematic catheterisation to define the true predictive values for PAH.
The factors responsible for maintaining persistent organ fibrosis in systemic sclerosis (SSc) are not known but emerging evidence implicates toll-like receptors (TLRs) in the pathogenesis of SSc. ...Here we show the expression, mechanism of action and pathogenic role of endogenous TLR activators in skin from patients with SSc, skin fibroblasts, and in mouse models of organ fibrosis. Levels of tenascin-C are elevated in SSc skin biopsy samples, and serum and SSc fibroblasts, and in fibrotic skin tissues from mice. Exogenous tenascin-C stimulates collagen gene expression and myofibroblast transformation via TLR4 signalling. Mice lacking tenascin-C show attenuation of skin and lung fibrosis, and accelerated fibrosis resolution. These results identify tenascin-C as an endogenous danger signal that is upregulated in SSc and drives TLR4-dependent fibroblast activation, and by its persistence impedes fibrosis resolution. Disrupting this fibrosis amplification loop might be a viable strategy for the treatment of SSc.
Systemic sclerosis (SSc) is a rare systemic autoimmune disease characterized by skin and organ fibrosis. The pathogenesis of SSc and its progression are poorly understood. The SSc intrinsic gene ...expression subsets (inflammatory, fibroproliferative, normal-like, and limited) are observed in multiple clinical cohorts of patients with SSc. Analysis of longitudinal skin biopsies suggests that a patient's subset assignment is stable over 6-12 months. Genetically, SSc is multi-factorial with many genetic risk loci for SSc generally and for specific clinical manifestations. Here we identify the genes consistently associated with the intrinsic subsets across three independent cohorts, show the relationship between these genes using a gene-gene interaction network, and place the genetic risk loci in the context of the intrinsic subsets. To identify gene expression modules common to three independent datasets from three different clinical centers, we developed a consensus clustering procedure based on mutual information of partitions, an information theory concept, and performed a meta-analysis of these genome-wide gene expression datasets. We created a gene-gene interaction network of the conserved molecular features across the intrinsic subsets and analyzed their connections with SSc-associated genetic polymorphisms. The network is composed of distinct, but interconnected, components related to interferon activation, M2 macrophages, adaptive immunity, extracellular matrix remodeling, and cell proliferation. The network shows extensive connections between the inflammatory- and fibroproliferative-specific genes. The network also shows connections between these subset-specific genes and 30 SSc-associated polymorphic genes including STAT4, BLK, IRF7, NOTCH4, PLAUR, CSK, IRAK1, and several human leukocyte antigen (HLA) genes. Our analyses suggest that the gene expression changes underlying the SSc subsets may be long-lived, but mechanistically interconnected and related to a patients underlying genetic risk.
Systemic sclerosis (scleroderma) leads to morbidity and mortality through a combination of inflammation, fibrosis and vascular damage leading to internal organ complications affecting the heart, ...lung, kidneys and bowel. More than half of those diagnosed ultimately die from the disease. Current treatments focus on broad spectrum immunosuppression or organ-based therapy for complication such as lung fibrosis, pulmonary or systemic hypertension. Targeting peptide mediators such as endothelin-1 have already led to licensed effective therapies for SSc vasculopathy. Outcomes are improving but as well as providing a major clinical challenge there are great opportunities for research translation that can be expected to improve understanding of the pathogenesis of SSc and also develop better and more targeted therapy. Key pathways and mediators can be identified within the skin and blood vessels and these are now being examined in early stage clinical trials. Promising results are emerging from targeting cytokine signalling, including IL-6, and from other immune-inflammatory therapies including lipid mediators such as LPA1. Other approaches to modulate TGFbeta and other profibrotic pathways also have potential although safety and toxicity remain to be determined. Since many profibrotic pathways have important physiological roles the assessment of safety and toxicity will be paramount. Nevertheless, advances in understanding the interplay between different pathological processes and progress in clinical trial design and patients stratification mean that targeted therapies are emerging and likely to be further developed and refined to have application in other important clinical contexts such as lung fibrosis.
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