Identification of urinary peptide biomarkers associated with rheumatoid arthritis.

Julie Klein,Paul Proost,Holger Husi,Hanna Johnsson,Angelique Stalmach,Mohammed Dakna,Duncan Porter,William Mullen,Harald Mischak,Iain B Mcinnes

doi:10.1371/journal.pone.0104625

Abstract

Early diagnosis and treatment of rheumatoid arthritis are associated with improved outcomes but current diagnostic tools such as rheumatoid factor or anti-citrullinated protein antibodies have shown limited sensitivity. In this pilot study we set out to establish a panel of urinary biomarkers associated with rheumatoid arthritis using capillary electrophoresis coupled to mass spectrometry. We compared the urinary proteome of 33 participants of the Scottish Early Rheumatoid Arthritis inception cohort study with 30 healthy controls and identified 292 potential rheumatoid arthritis-specific peptides. Amongst them, 39 were used to create a classifier model using support vector machine algorithms. Specific peptidic fragments were differentially excreted between groups; fragments of protein S100-A9 and gelsolin were less abundant in rheumatoid arthritis while fragments of uromodulin, complement C3 and fibrinogen were all increasingly excreted. The model generated was subsequently tested in an independent test-set of 31 samples. The classifier demonstrated a sensitivity of 88% and a specificity of 93% in diagnosing the condition, with an area under the receiver operating characteristic curve of 0.93 (p<0.0001). These preliminary results suggest that urinary biomarkers could be useful in the early diagnosis of rheumatoid arthritis. Further studies are currently being undertaken in larger cohorts of patients with rheumatoid arthritis and other athridities to assess the potential of the urinary peptide based classifier in the early detection of rheumatoid arthritis.

Highlights

Rheumatoid arthritis (RA) is a systemic autoimmune condition that primarily affects the joints and can lead to joint damage, disability and premature mortality
A preliminary analysis investigating the correlation between DAS28, health assessment questionnaire (HAQ) and C-reactive protein (CRP) revealed a poor correlation between CRP and DAS28, and CRP and HAQ
In order to establish potential urinary biomarkers associated with RA, urines samples from 33 RA patients and 30 healthy volunteers were run using coupled to mass spectrometry (CE-MS) and analysed for their peptidomic profile

Summary

Introduction

Rheumatoid arthritis (RA) is a systemic autoimmune condition that primarily affects the joints and can lead to joint damage, disability and premature mortality. In 2010, the American College of Rheumatology and European League Against Rheumatism (ACR/EULAR) developed a new approach to classifying RA based on scoring criteria [4]. This classification system improves sensitivity for the early detection of the disease compared to the former ACR 1987 classification criteria. Novel biomarkers which could assist in accurate, early diagnosis would facilitate more effective early intervention whilst limiting exposure to disease modifying therapy in patients otherwise destined to remit spontaneously. None of these approaches have yet yielded combinations of biomarkers with better specificity and sensitivity than ACPA used alone

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