Clinical Correlates of CENP-A and CENP-B Antibodies in a Large Cohort of Patients with Systemic Sclerosis

Hudson, Marie; Mähler, Michael; Pope, Janet; You, Daniel; Tatibouet, Solène; Steele, Russell; Baron, Murray; Fritzler, Marvin J.

doi:10.3899/rheum.111133

Cited by 50 publications

(38 citation statements)

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“…Existing clinical data were used to score patients on the 9 domains of Medsger et al disease severity scale, [24] where a score of 0 indicates normal findings while 4 indicates end-stage organ damage. In addition, we analyzed data pertinent to disease severity scale subitems for lung and heart, namely FVC, DLCO, estimated sPAP, presence of ILD (ILD; diagnosed with high-resolution CT and using Steele at al clinical decision rule), [12,28] left ventricular ejection fraction, and presence of electrocardiogram abnormalities. Finally, we obtained information on whether they had undergone right heart catheterization resulting in a diagnosis of precapillary pulmonary arterial hypertension (PAH) (mean ≥25 mm Hg and pulmonary artery wedge pressure ≤15 mm Hg).…”

Section: Methodsmentioning

confidence: 99%

“…[5–8] For instance, patients with anti-DNA topoisomerase I antibodies are more likely to have interstitial lung disease (ILD) and musculoskeletal and myocardial involvement; anti-RNA polymerase III positivity is associated with scleroderma renal crisis; and anti-CENP-positive patients are at greater risk of precapillary pulmonary arterial hypertension (PAH) without fibrosis. [3,9–12] The reason for these clinical associations is still largely unknown, just as it is unknown why some patients progress to more severe stages of the disease. In particular, it is not known why only about 10% to 20% of anti-CENP-positive patients develop PAH, one of the major causes of death from SSc.…”

Section: Introductionmentioning

confidence: 99%

“…[19] Although these chromatin-binding proteins are unrelated, patients often have antibodies to both. [3] As differences in disease features were not found between CENP-A-positive and CENP-B-positive patients, [12,20] it is important to examine the fine specificities within these antibody populations.…”

Section: Introductionmentioning

confidence: 99%

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Subspecificities of anticentromeric protein A antibodies identify systemic sclerosis patients at higher risk of pulmonary vascular disease

et al. 2016

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Patients with systemic sclerosis (SSc) who express autoantibodies to centromeric proteins (CENPs) are at risk of developing pulmonary vascular disease and pulmonary arterial hypertension without fibrosis. Currently no biomarkers are available to predict these complications. We previously characterized the fine specificity of anti-CENP-A antibodies in SSc by screening a phage display library (expressing random 12-mer peptides), and identified phage clones whose peptides were differentially recognized by patients’ autoantibodies. Here, we examined if subgroups of SSc patients with different anti-CENP-A antibody subspecificities also differ clinically, and if serum reactivity to phage-displayed peptides can predict pulmonary vascular disease.Clinical data and serum samples were collected from 84 anti-CENP-A-positive SSc patients. Indirect ELISAs were used to test serum reactivity. Pulmonary vascular disease was defined as high systolic pulmonary arterial pressure (sPAP) and low diffusing lung capacity for carbon monoxide (DLCO; percent of predicted values).Sera were screened for reactivity to peptides expressed by phage clones pc4.2 and pc14.1, confirming our earlier observation of differential specificities. Linear regression showed that the levels of antibodies specific for the 2 phage clones were associated with clinical features of pulmonary vascular disease, but in opposite ways: anti-pc4.2 antibodies were positively associated with sPAP and inversely associated with DLCO, whereas anti-pc14.1 antibodies were inversely associated with sPAP and positively associated with DLCO. Anti-pc4.2 and anti-pc14.1 antibody levels predicted sPAP independently of DLCO. These associations were confirmed by logistic regression using antibodies as predictors and dichotomized sPAP (cutoff, 45 mm Hg) as outcome. The ratio of the 2 antibody levels was a useful marker in predicting high sPAP.This study demonstrates that some SSc clinical features associate with subspecificities of anti-CENP-A antibodies. Moreover, it shows that a simple, inexpensive phage-based assay can predict which SSc patients have high sPAP and low DLCO, hence who are at greater risk of developing pulmonary arterial hypertension. The ability to identify these at-risk patients can contribute to clinical efficiency and effectiveness. Further research into the peptides expressed by the phage clones may reveal the molecular mechanisms that put some anti-CENP-A-positive patients at greater risk than others for pulmonary vascular disease.

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Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Subspecificities of anticentromeric protein A antibodies identify systemic sclerosis patients at higher risk of pulmonary vascular disease

et al. 2016

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“…[8] и наиболее часто описывались при лимитированной форме ССД, в особенности с чертами CREST-синдрома (кальциноз, синдром Рейно, эзофагит, склеродактилия, телеангиэктазии) и дигитальными ишемическими язва-ми [9][10][11]. При данной форме ССД АЦА ассоциированы с более низким риском возникновения интерстициаль-ного поражения легких и острой склеродермической почки, но более высоким риском возникновения легоч-ной артериальной гипертензии (ЛАГ) в сравнении с диффузной формой ССД [9][10][11].…”

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“…При данной форме ССД АЦА ассоциированы с более низким риском возникновения интерстициаль-ного поражения легких и острой склеродермической почки, но более высоким риском возникновения легоч-ной артериальной гипертензии (ЛАГ) в сравнении с диффузной формой ССД [9][10][11]. Также АЦА описаны при БШ, ПБЦ, СКВ, РА, феномене Рейно и опухолях [12].…”

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Primary Sjogren's Syndrome Associated With Anticentromere Antibodies

Чальцев¹

2018

rsp

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Prediction of Pulmonary Complications and Long‐Term Survival in Systemic Sclerosis

Nihtyanova

Schreiber

Ong

et al. 2014

Arthritis & Rheumatology

405

293

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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 antitopoisomerase I antibody positivity reduced the hazard.Conclusion. Our study provides data on longterm 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.

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Clinical Correlates of CENP-A and CENP-B Antibodies in a Large Cohort of Patients with Systemic Sclerosis

Abstract: Clinical immunology laboratories are increasingly using high-throughput ELISA tests for CENP antibodies, with or without ACA detected by indirect immunofluorescence. The phenotype of CENP-A and/or B-positive patients is generally similar to that associated with ACA.

Cited by 50 publications

References 23 publications

Subspecificities of anticentromeric protein A antibodies identify systemic sclerosis patients at higher risk of pulmonary vascular disease

Subspecificities of anticentromeric protein A antibodies identify systemic sclerosis patients at higher risk of pulmonary vascular disease

Primary Sjogren's Syndrome Associated With Anticentromere Antibodies

Prediction of Pulmonary Complications and Long‐Term Survival in Systemic Sclerosis

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