To evaluate interstitial lung disease associated with systemic sclerosis (SSc-ILD) and its changes during treatment by using quantitative analysis (QA) compared to semi-quantitative analysis (semiQA) ...of chest computed tomography (CT) scans. To assess the prognostic value of QA in predicting functional changes.
We retrospectively selected 35 consecutive patients with SSc-ILD with complete pulmonary functional evaluation, Doppler-echocardiography, immunological tests, and chest CT scan at both baseline and follow-up after immunosuppressive therapy. CT images were analyzed by two chest radiologists for semiQA and by a computational platform for texture analysis of ILD patterns (CALIPER) for QA. Concordance between semiQA and QA was tested. Traction bronchiectasis severity was scored. Analysis of ROC curves was performed.
Seventy CT scans were analyzed and QA failed in 4/70 scans. Thus, the final population included 31/35 patients (51.3±12.1 years). QA had a weak-to-good concordance with semiQA (ICC reticular:0.275; ICC ground-glass:0.667) and QA correlated better than semiQA (r = -0.3 to -0.74 vs r = -0.3 to -0.4) with functional parameters. Both methods correlated with traction bronchiectases score and pulmonary artery diameter at CT. A pulmonary artery diameter ≥29mm distinguished patients with lower lung volumes and ILD extent greater than 39% (p<0.001). Changes in QA patterns during treatment were not accurate (AUC: 0.50 to 0.70; p>0.05) in predicting disease progression as assessed by functional parameters, whereas variation in total lung volume at QA accurately predicted changes in the composite functional respiratory endpoint with FVC% and DLco% (AUC = 0.74; 95%CI: 0.54 to 0.93; p = 0.03).
Pulmonary QA of CT images can objectively quantify specific patterns of ILD changes during treatment in patients with SSc-ILD. Changes in QA patterns do not correlate with functional changes, but variation in total lung volume at QA accurately predicted changes in the composite functional respiratory endpoint with FVC% and DLco%. Pulmonary artery diameter at CT reflects the interstitial involvement, identifying patients with more severe prognosis.
Systemic sclerosis-associated interstitial lung disease (SSc-ILD) is the most frequent cause of death for SSc but there is still no sufficient treatment available. Although cyclophosphamide (CYC) ...therapy is a common treatment which has shown statistical efficacy against SSc-ILD to date, its effects are temporary and not enough. Rituximab (RTX), the anti-CD20 monoclonal antibody, has recently shown efficacy in many autoimmune diseases. In SSc-ILD, RTX is also considered to be one of the novel treatment candidates. However, studies of SSc-ILD in Japanese treated with RTX have only a few case reports. Therefore, in this study, we retrospectively compared nine patients treated with RTX and 30 patients treated with CYC to investigate the efficacy of RTX treatment for Japanese anti-topoisomerase I-positive SSc-ILD patients. At the 24-month evaluation, the improvement rates of percent predicted of forced vital capacity and percent predicted of diffusing capacity of the lung carbon monoxide in the RTX-treated group were significantly higher than those in the CYC-treated group (20.6 ± 8.8% vs 1.1 ± 3.9%; P < 0.05 and 34.0 ± 6.0% vs -1.5 ± 2.8%; P < 0.01, respectively). In addition, skin thickness scores also showed a marked improvement from 13.5 points before the start of treatment to 5.8 points after 24 months by RTX therapy (P < 0.05). These results suggest that RTX treatment is more effective for Japanese SSc-ILD patients than CYC treatment. In the future, it is expected that large-scale clinical trials will show the usefulness of RTX treatment for SSc-ILD.
Cardiac rhythm disturbances constitute the most frequent cardiovascular cause of death in SSc. However, electrocardiographic findings are not a part of risk stratification in SSc. We aimed to ...translate 24 h Holter findings into a tangible risk prediction score using cardiovascular magnetic resonance.
The Scleroderma Arrhythmia Clinical Utility Study (SAnCtUS) was a prospective multicentre study including 150 consecutive SSc patients from eight European centres, assessed with 24 h Holter and cardiovascular magnetic resonance, including ventricular function, oedema (T2 ratio) and late gadolinium enhancement (%LGE). Laboratory/clinical parameters were included in multivariable corrections. A combined endpoint of sustained ventricular tachycardia requiring hospitalization and sudden cardiac death at a median (interquartile range) follow-up of 1 (1.0-1.4) year was generated.
Only T2 ratio and %LGE were significant predictors of ventricular rhythm disturbances, but not of supraventricular rhythm disturbances, after multivariable correction and adjustment for multiple comparisons. Using decision-tree analysis, we created the SAnCtUS score, a four-category scoring system based on T2 ratio and %LGE, for identifying SSc patients at high risk of experiencing ventricular rhythm disturbance at baseline. Increasing SAnCtUS scores were associated with a greater disease and arrhythmic burden. All cases of non-sustained ventricular tachycardia (n = 7) occurred in patients with the highest SAnCtUS score (=4). Having a score of 4 conveyed a higher risk of reaching the combined endpoint in multivariable Cox regression compared with scores 1/2/3 hazard ratio (95% CI): 3.86 (1.14, 13.04), P = 0.029 independently of left ventricular ejection fraction and baseline ventricular tachycardia occurrence.
T2 ratio and %LGE had the greatest utility as independent predictors of rhythm disturbances in SSc patients.
Systemic sclerosis (SSc) is an autoimmune disease characterized by vascular injury and inflammation, followed by excessive fibrosis of the skin and other internal organs, including the lungs. CX3CL1 ...(fractalkine), a chemokine expressed on endothelial cells, supports the migration of macrophages and T cells that express its specific receptor CX3CR1 into targeted tissues. We previously reported that anti-CX3CL1 monoclonal antibody (mAb) treatment significantly inhibited transforming growth factor (TGF)-β1-induced expression of type I collagen and fibronectin 1 in human dermal fibroblasts. Additionally, anti-mouse CX3CL1 mAb efficiently suppressed skin inflammation and fibrosis in bleomycin- and growth factor-induced SSc mouse models. However, further studies using different mouse models of the complex immunopathology of SSc are required before the initiation of a clinical trial of CX3CL1 inhibitors for human SSc.
To assess the preclinical utility and functional mechanism of anti-CX3CL1 mAb therapy in skin and lung fibrosis, a sclerodermatous chronic graft-versus-host disease (Scl-cGVHD) mouse model was analyzed with immunohistochemical staining for characteristic infiltrating cells and RNA sequencing assays.
On day 42 after bone marrow transplantation, Scl-cGVHD mice showed increased serum CX3CL1 level. Intraperitoneal administration of anti-CX3CL1 mAb inhibited the development of fibrosis in the skin and lungs of Scl-cGVHD model, and did not result in any apparent adverse events. The therapeutic effects were correlated with the number of tissue-infiltrating inflammatory cells and α-smooth muscle actin (α-SMA)-positive myofibroblasts. RNA sequencing analysis of the fibrotic skin demonstrated that cGVHD-dependent induction of gene sets associated with macrophage-related inflammation and fibrosis was significantly downregulated by mAb treatment. In the process of fibrosis, mAb treatment reduced cGVHD-induced infiltration of macrophages and T cells in the skin and lungs, especially those expressing CX3CR1.
Together with our previous findings in other SSc mouse models, the current results indicated that anti-CX3CL1 mAb therapy could be a rational therapeutic approach for fibrotic disorders, such as human SSc and Scl-cGVHD.
Systemic sclerosis is an autoimmune disorder characterized by inflammation and a progressive fibrosis affecting the skin and visceral organs. Over the last two decades, it became clear that oxidative ...stress plays a key role in its pathogenesis. In this review, we highlighted the role of ROS in the various pathological components of systemic sclerosis, namely the inflammatory, the autoimmune and the fibrotic processes. We also discussed how these pathological processes can induce ROS overproduction, thus maintaining a vicious circle. Finally, we summarized the therapeutic approaches targeting oxidative stress tested in systemic sclerosis, in cells, animal models and patients.
Context:
Systemic sclerosis (SSc) is a connective tissue disease of unknown etiology, and several studies reported its association with thyroid autoimmune disorders. No study has evaluated ...longitudinally the incidence of new cases of thyroid autoimmunity and dysfunction in patients with SSc.
Objective:
The purpose of this study was to evaluate the incidence of new cases of clinical and subclinical thyroid dysfunction in a wide group of women with SSc vs an age- and sex-matched control group from the same geographic area.
Design and Patients or Other Participants:
After exclusion of sclerodermic patients with thyroid dysfunction (n = 55) at the initial evaluation, the appearance of new cases of thyroid disorders was evaluated in 179 patients and 179 matched control subjects, with similar iodine intake (median follow-up 73 months in patients with SSc vs 94 months in control subjects).
Results:
A high incidence (P < .05) of new cases of hypothyroidism, thyroid dysfunction, anti–thyroperoxidase antibody positivity, and appearance of a hypoechoic thyroid pattern in sclerodermic patients (15.5, 21, 11, and 14.6 of 1000 patients per year; respectively) vs that in control subjects was shown. A logistic regression analysis showed that in patients with SSc, the appearance of hypothyroidism was related to a borderline high initial TSH level, anti–thyroperoxidase antibody positivity, and a hypoechoic and small thyroid.
Conclusions:
Our study shows a high incidence of new cases of hypothyroidism and thyroid dysfunction in female sclerodermic patients. Female sclerodermic patients, who are at high risk (a borderline high even if in the normal range TSH value, anti–thyroperoxidase antibody positivity, and a hypoechoic and small thyroid) should have periodic thyroid function follow-up.
Fibrosis is a pathological process characterized by excessive accumulation of connective tissue components in an organ or tissue. Fibrosis is produced by deregulated wound healing in response to ...chronic tissue injury or chronic inflammation, the hallmarks of rheumatic diseases. Progressive fibrosis, which distorts tissue architecture and results in progressive loss of organ function, is now recognized to be one of the major causes of morbidity and mortality in individuals with one of the most lethal rheumatic disease, systemic sclerosis (SSc). In this Review, we discuss the pathological role of fibrosis in SSc. We discuss the involvement of endothelium and pericyte activation, aberrant immune responses, endoplasmic reticulum stress and chronic tissue injury in the initiation of fibrosis in SSc. We then discuss fibroblast activation and myofibroblast differentiation that occurs in response to these initiating processes and is responsible for excessive accumulation of extracellular matrix. Finally, we discuss the chemical and mechanical signals that drive fibroblast activation and myofibroblast differentiation, which could serve as targets for new therapies for fibrosis in SSc.
Systemic sclerosis (SSc) is a multi-organ fibrotic disease with few treatment options. Activated fibroblasts are the key effector cells in SSc responsible for the excessive production of collagen and ...the development of fibrosis. Platelet-derived growth factor (PDGF), a potent mitogen for cells of mesenchymal origin, has been implicated in the activation of SSc fibroblasts. Our aim was to examine the therapeutic potential of crenolanib, an inhibitor of PDGF receptor signaling, in cultured fibroblasts and in angiotensin II-induced skin and heart fibrosis. Crenolanib effectively inhibited proliferation and migration of SSc and healthy control fibroblasts and attenuated basal and transforming growth factor-β–induced expression of CCN2/CTGF and periostin. In contrast to healthy control fibroblasts, SSc fibroblasts proliferated in response to PDGFAA, whereas a combination of PDGFAA and CCN2 was required to elicit a similar response in healthy control fibroblasts. PDGF receptor α mRNA correlated with CCN2 and other fibrotic markers in the skin of SSc patients. In mice challenged with angiotensin II, PDGF receptor α-positive cells were increased in the skin and heart. These PDGF receptor α-positive cells co-localized with PDGF receptor β, procollagen, and periostin. Treatment with crenolanib attenuated the skin and heart fibrosis. Our data indicate that inhibition of PDGF signaling presents an attractive therapeutic approach for SSc.
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