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The combination of three autoantibodies, ACPA, RF and anti-CarP antibodies is highly specific for rheumatoid arthritis: implications for very early identification of individuals at risk to develop rheumatoid arthritis

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Verheul MK1, Böhringer S2, van Delft MAM1, Jones JD3, Rigby WFC3, Gan RW4, Holers VM5, Edison JD6, Deane KD5, Janssen KMJ7, Westra J8, Brink M9, Rantapää-Dahlqvist S9, Huizinga TWJ1, van der Helm-van Mil AHM1, van der Woude D1, Toes REM1, Trouw LA1,10. Arthritis Rheumatol. 2018 May 21. doi: 10.1002/art.40562. [Epub ahead of print]


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1 Department of Rheumatology, Leiden university medical center, Leiden, the Netherlands.

2 Department of Medical Statistics, Leiden university medical center, Leiden, the Netherlands.

3 Division of Rheumatology, Department of Medicine, Geisel School of Medicine at Dartmouth, Lebanon, New Hampshire, USA.

4 Department of Epidemiology, Colorado School of Public Health, Aurora, Colorado, USA.

5 Division of Rheumatology, University of Colorado, Aurora, Colorado, USA.

6 Walter Reed National Military Medical Center, Bethesda, Maryland, USA.

7 Department of Oral and Maxillofacial Surgery, University of Groningen and University Medical Center Groningen, Groningen, The Netherlands.

8 Department of Rheumatology and Clinical Immunology, University of Groningen and University Medical Center Groningen, Groningen, The Netherlands.

9 Department of Public Health and Clinical Medicine / Rheumatology, Umeå University, Umeå, Sweden.

10 Department of Immunohematology and Blood Transfusion, Leiden university medical center, Leiden, the Netherlands.


OBJECTIVE: In rheumatoid arthritis(RA), the autoantibodies anti-citrullinated protein antibodies(ACPA) and rheumatoid factor(RF) are commonly used to aid RA diagnosis. Although these autoantibodies are mainly found in RA, their specificity is not optimal. It is therefore difficult to identify RA patients, especially in very early disease, based on the presence of ACPA and RF alone. Also, anti-carbamylated protein(anti-CarP) antibodies have diagnostic and prognostic value as the presence of anti-CarP antibodies associates with joint damage in RA patients and with future RA development in arthralgia patients. Therefore, we aimed to investigate the value of combined antibody testing in relation to prediction and diagnosis of (early) RA.

METHODS: A literature search resulted in twelve studies, consisting of RA patients, pre-RA individuals, disease controls, healthy first-degree relatives of RA patients or healthy controls, in which data on RF, ACPA and anti-CarP antibody-status was available. Random effects meta-analyses were carried out for several antibody combinations.

RESULTS: The individual antibodies are highly prevalent in RA(34%-80%) compared to the control groups, but are also present in non-RA controls(0%-23%). To classify most people correctly as RA or non-RA, the combination of ACPA and/or RF often performs well(specificity:65-100, sensitivity:59-88). However, triple positivity for ACPA, RF and anti-CarP antibodies results in a higher specificity(98-100) (accompanied by a lower sensitivity(11-39)).

CONCLUSIONS: As the rheumatology field is moving towards very early identification of RA and possible screening for individuals at maximum risk in populations with a low pre-test probability, triple positivity provides interesting information on individuals at risk to develop RA.