Elsevier

Autoimmunity Reviews

Volume 12, Issue 2, December 2012, Pages 318-322
Autoimmunity Reviews

Review
Closing the serological gap: promising novel biomarkers for the early diagnosis of rheumatoid arthritis

https://doi.org/10.1016/j.autrev.2012.05.007Get rights and content

Abstract

Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by inflammation and damage of the joints affecting about 0.5% of the general population. Early treatment in RA is important as it can prevent disease progression and irreversible damage of the joints. Despite the high diagnostic value of anti-citrullinated protein antibodies (ACPA) and rheumatoid factor (RF), there is a strong demand for novel serological biomarkers to further improve the diagnosis of this abundant disease. During the last decades, several autoantigens have been described in RA including Ra33 (hnRNP A2), fibrinogen, fibronectin, alpha-enolase, type II collagen, immunoglobulin binding protein (BiP), annexins and viral citrullinated peptide (VCP) derived from Epstein Barr Virus-encoded protein (EBNA-2). More recent discoveries include antibodies to carbamylated antigens (anti-CarP), to peptidyl arginine deiminase type 4 (PAD4), to BRAF (v raf murine sarcoma viral oncogene homologue B1) and to 14 autoantigens identified by phage display technology. This review provides a current overview of novel biomarkers for RA and discusses their future potential to improve the diagnosis of the disease.

Section snippets

Rheumatoid arthritis (RA)

Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by inflammation and damage of the joints affecting about 0.5% of the general population [1]. Early treatment in RA is important as it can prevent irreversible damage of the joints. Despite the strong diagnostic value of anti-citrullinated protein antibodies (ACPA) and rheumatoid factor (RF), there is a strong demand for novel serological biomarkers to further improve the early diagnosis of this abundant disease. During the

Anti-citrullinated protein antibodies (ACPA)

ACPA are an important serological marker in the diagnosis of RA [2], [3]. ACPA can be detected up to 10 years before RA patients first present to a clinician, predicting the future development of RA [4]. In addition, the presence of ACPA is associated with a specific disease course [5]. Historically, a combination of several serologic markers, including RF, anti-perinuclear factor (APF) and anti-keratin antibody (AKA), has been used to aid in the diagnosis of RA [2]. With the discovery in 1998

Additional autoantigens recognized by autoantibodies in sera from RA patients

Following the success of the CCP test, several alternative methods for detecting ACPA have been developed, including assays based on citrullinated proteins instead of peptides, such as mutated citrullinated vimentin (MCV; Orgentec, Mainz, Germany) [21], filaggrin (CPA; Genesis, London, UK). In addition, a viral citrullinated peptide has been discovered (VCP; VCP1 and VCP2) [9], [21], [22]. The limited data and contradictory results from comparative studies on anti-MCV autoantibodies [23], [24],

Recent discoveries of novel markers for early RA diagnosis

Although, ACPA have significantly improved the diagnosis of RA, it is unquestionable that novel biomarkers are required for a better diagnosis of early and seronegative RA. Recently, such autoantigens have been described mainly by three research groups [31], [32], [33], [34], [35], [36]. Despite all of these biomarkers are very promising, none has yet been transferred into commercial/clinical use.

Comparison of different markers

Since none of the novel markers have the clinical utility of ACPA, it is unlikely that they will replace ACPA. Therefore, the novel markers or combination of different markers (UH.RA 11 plex and UH.RA 14 plex) were compared in the CCP‐negative RA patient cohort (see Fig. 1). Sensitivities in this important group of patients ranged from 16% to 40% (BRAF p10) for a single marker and up to 67% using the UH.RA 14 plex [31]. Following the CCP3.1 approach [40], an IgA/IgG screening test for anti-CarP

Future perspectives

Once more diagnostically relevant biomarkers will be established, modern multiplexing techniques for the simultaneous detection of a wide spectrum of markers may provide additional benefit in diagnosis as much as in classification of RA subtypes [41]. The novel biomarkers presented and discussed here have the potential to become part of the diagnostic algorithm and multiplex approaches for the diagnosis of RA in the near future.

Competing interest

Leendert A. Trouw has no competing interest to declare. Michael Mahler is employed at INOVA Diagnostics, Inc. selling autoimmune diagnostic assays.

Abbreviations

    ACPA

    anti-citrullinated protein antibodies

    AUC

    area under the curve

    BiP

    immunoglobulin binding protein

    CCP

    cyclic citrullinated peptide

    LR

    likelihood ratio

    MCV

    mutated citrullinated vimentin

    RF

    rheumatoid factor

    VCP

    viral citrullinated peptide

    SARD

    systemic autoimmune rheumatic disease

Take-home messages

  • Several novel biomarkers have been described showing promising results.

  • Individual biomarkers might detect up to 40% of ACPA-negative patients. Combinations of different novel biomarkers might have the potential to detect even up to 70% of ACPA-negative RA patients.

  • Further studies are necessary to clearly define the clinical utility of novel biomarkers for the early diagnosis of RA.

Acknowledgements

We thank Brian McEvilly (INOVA Diagnostics) for proofreading and valuable suggestions. The work of Dr. Trouw is supported by FP7 project Masterswitch as well as the IMI JU-funded project BeTheCure (contract no. 115142-2).

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