CCL21 as a Potential Serum Biomarker for Pulmonary Arterial Hypertension in Systemic Sclerosis

Hoffmann-Vold, A. M.; Hesselstrand, Roger; Fretheim, H.; Ueland, Thor; Andreassen, Arne K.; Brunborg, Cathrine; Palchevskiy, Vyacheslav; Midtvedt, Øyvind; Garen, Torhild; Aukrust, Pål; Belperio, John A.; Molberg, Øyvind

doi:10.1002/art.40534

Cited by 34 publications

(35 citation statements)

References 49 publications

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“…Interestingly, when expressed on non-immune cells, CCR7 is a chemokine receptor heavily involved in the development of fibrosis following stimulation by its ligands, CCL19, and CCL21. 94,102,103 Taken together, [92][93][94] these in vitro data fulfill in part pathogenicity criterion no.…”

Section: Topoisomerase I Is a Bifunctional Aag That Interacts With Ccmentioning

confidence: 54%

Pathogenic roles of autoantibodies in systemic sclerosis: Current understandings in pathogenesis

Senécal

Hoa

Yang

et al. 2019

Journal of Scleroderma and Related Disorders

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The potential pathogenic role for autoantibodies in systemic sclerosis has captivated researchers for the past 40 years. This review answers the question whether there is yet sufficient knowledge to conclude that certain serum autoantibodies associated with systemic sclerosis contribute to its pathogenesis. Definitions for pathogenic, pathogenetic and functional autoantibodies are formulated, and the need to differentiate these autoantibodies from natural autoantibodies is emphasized. In addition, seven criteria for the identification of pathogenic autoantibodies are proposed. Experimental evidence is reviewed relevant to the classic systemic sclerosis antinuclear autoantibodies, anti-topoisomerase I and anticentromere, and to functional autoantibodies to endothelin 1 type A receptor, angiotensin II type 1 receptor, muscarinic receptor 3, platelet-derived growth factor receptor, chemokine receptors CXCR3 and CXCR4, estrogen receptor α, and CD22. Pathogenic evidence is also reviewed for anti-matrix metalloproteinases 1 and 3, anti-fibrillin 1, anti-IFI16, anti-eIF2B, anti-ICAM-1, and anti-RuvBL1/RuvBL2 autoantibodies. For each autoantibody, objective evidence for a pathogenic role is scored qualitatively according to the seven pathogenicity criteria. It is concluded that anti-topoisomerase I is the single autoantibody specificity with the most evidence in favor of a pathogenic role in systemic sclerosis, followed by anticentromere. However, these autoantibodies have not been demonstrated yet to fulfill completely the seven proposed criteria for pathogenicity. Their contributory roles to the pathogenesis of systemic sclerosis remain possible but not yet conclusively demonstrated. With respect to functional autoantibodies and other autoantibodies, only a few criteria for pathogenicity are fulfilled. Their common presence in healthy and disease controls suggests that major subsets of these immunoglobulins are natural autoantibodies. While some of these autoantibodies may be pathogenetic in systemic sclerosis, establishing that they are truly pathogenic is a work in progress. Experimental data are difficult to interpret because high serum autoantibody levels may be due to polyclonal B-cell activation. Other limitations in experimental design are the use of total serum immunoglobulin G rather than affinity-purified autoantibodies, the confounding effect of other systemic sclerosis autoantibodies present in total immunoglobulin G and the lack of longitudinal studies to determine if autoantibody titers fluctuate with systemic sclerosis activity and severity. These intriguing new specificities expand the spectrum of autoantibodies observed in systemic sclerosis. Continuing elucidation of their potential mechanistic roles raises hope of a better understanding of systemic sclerosis pathogenesis leading to improved therapies.

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Section: Topoisomerase I Is a Bifunctional Aag That Interacts With Ccmentioning

confidence: 54%

Pathogenic roles of autoantibodies in systemic sclerosis: Current understandings in pathogenesis

Senécal

Hoa

Yang

et al. 2019

Journal of Scleroderma and Related Disorders

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“…At the Oslo University Hospital (OUH), all SSc patients were enrolled in the prospective Oslo SSc cohort. Patients were followed annually, and data were recorded in the Norwegian Systemic Connective Tissue Disease and Vasculitis Registry (NOSVAR) . Echocardiographies are performed annually in order to screen for pulmonary hypertension (PH).…”

Section: Methodsmentioning

confidence: 99%

Systolic Dysfunction in Systemic Sclerosis: Prevalence and Prognostic Implications

Tennøe

Murbræch

Andreassen

et al. 2019

ACR Open Rheumatology

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Objective. Primary cardiac involvement is presumed to account for a substantial part of disease-related mortality in systemic sclerosis (SSc). Still, there are knowledge gaps on the evolution and total burden of systolic dysfunction in SSc. Here we evaluated prospective left ventricular (LV) and right ventricular (RV) systolic function in an unselected SSc cohort and assessed the burden of systolic dysfunction on mortality.Methods. From the Oslo University Hospital cohort, 277 SSc patients were included from 2003-2016 and compared with healthy controls. Serial echocardiographies were reevaluated in order to detect change in systolic function. Right heart catheterization was performed on patients suspected of pulmonary hypertension. Descriptive and regression analyses were conducted.Results. At baseline, LV systolic dysfunction by ejection fraction less than 50%, or a global longitudinal strain greater than −17.0%, was found in 12% and 24%, respectively. RV systolic dysfunction measured by tricuspid annular plane systolic excursion (TAPSE) less than 17 mm was evident in 10%. Follow-up echocardiography was performed after a median of 3.3 years (interquartile range [IQR] 1.5-5.6). At follow-up, LV systolic function remained stable, whereas RV function evaluated by TAPSE deteriorated (mean 23.1 to 21.7 mm, P = 0.005) equaling a 15% prevalence of RV systolic dysfunction. RV systolic function predicted mortality in multivariable models (hazard ratio 0.41, 95% confidence interval [CI] 0.19-0.90, P value 0.027), whereas LV systolic function lost predictive significance when adjusted for TAPSE.Conclusion. In this unselected and prospective study, systolic dysfunction of the LV and RV was a frequent complication of SSc. LV systolic function remained stable across the observation period, whereas RV function deteriorated and predicted mortality.

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“…There are several interesting and novel potential blood biomarkers for PAH in SSc that reflect endothelial dysfunction, inflammation, autoimmunity, epigenetic changes, extracellular matrix deposition and metabolite changes, which have recently been extensively reviewed by ODLER et al [102]. For example, one recent study found that levels of chemokine CCL21, which is involved in T-cell differentiation, were higher in patients with SSc-PAH from two independent cohorts versus controls, patients with SSc and interstitial lung disease, patients with SSc without PH and idiopathic PAH [103]. Furthermore, CCL21 levels were elevated years prior to the PAH diagnosis and were associated with survival after diagnosis.…”

Section: Considerations For Future Screening Studiesmentioning

confidence: 99%

Screening for pulmonary arterial hypertension in systemic sclerosis

et al. 2019

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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.

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CCL21 as a Potential Serum Biomarker for Pulmonary Arterial Hypertension in Systemic Sclerosis

Abstract: 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.

Cited by 34 publications

References 49 publications

Pathogenic roles of autoantibodies in systemic sclerosis: Current understandings in pathogenesis

Pathogenic roles of autoantibodies in systemic sclerosis: Current understandings in pathogenesis

Systolic Dysfunction in Systemic Sclerosis: Prevalence and Prognostic Implications

Screening for pulmonary arterial hypertension in systemic sclerosis

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