ReviewClosing the serological gap: promising novel biomarkers for the early diagnosis of rheumatoid arthritis
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
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Several novel biomarkers have been described showing promising results.
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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.
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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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