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. 2017 Dec 1;56(12):2145-2153.
doi: 10.1093/rheumatology/kex340.

The risk of individual autoantibodies, autoantibody combinations and levels for arthritis development in clinically suspect arthralgia

Robin M Ten Brinck  1 , Hanna W van Steenbergen  1 , Myrthe A M van Delft  1 , Marije K Verheul  1 , Rene E M Toes  1 , Leendert A Trouw  1 , Annette H M van der Helm-van Mil  1
Affiliations

The risk of individual autoantibodies, autoantibody combinations and levels for arthritis development in clinically suspect arthralgia

Robin M Ten Brinck et al. Rheumatology (Oxford). .

Abstract

Objectives: Autoantibody testing is helpful for predicting the risk of progression to clinical arthritis in subjects at risk. Previous longitudinal studies have mainly selected autoantibody-positive arthralgia patients, and consequently the predictive values of autoantibodies were evaluated relative to one another. This study assessed the risks for arthritis development of ACPA, RF and/or anti-carbamylated protein antibodies (anti-CarP) in arthralgia patients considered at risk for RA by rheumatologists, based on clinical characteristics (clinically suspect arthralgia, CSA).

Methods: The baseline ACPA, RF and anti-CarP autoantibody status of 241 patients, consecutively included in the CSA cohort, was studied for risk of developing clinical arthritis during a median follow-up of 103 (interquartile range: 81-114) weeks.

Results: Univariable associations for arthritis development were observed for ACPA, RF and anti-CarP antibodies; hazard ratios (HRs) (95% CI) were 8.5 (4.7-15.5), 5.1 (2.8-9.3) and 3.9 (1.9-7.7), respectively. In multivariable analysis, only ACPA was independently associated (HR = 5.1; 2.0-13.2). Relative to autoantibody-negative CSA patients, ACPA-negative/RF-positive patients had HRs of 2.6 (1.04-6.6), ACPA-positive/RF-negative patients 8.0 (2.4-27.4) and ACPA-positive/RF-positive patients 10.5 (5.4-20.6). Positive predictive values for development of clinical arthritis within 2 years were: 38% for ACPA-negative/RF-positive, 50% for ACPA-positive/RF-negative and 67% for ACPA-positive/RF-positive patients. Higher ACPA levels were not significantly associated with increased progression to clinical arthritis, in contrast to higher RF levels. Autoantibody levels were stable during follow-up.

Conclusion: ACPA conferred the highest risk for arthritis development and had an additive value to RF. However, >30% of ACPA-positive/RF-positive CSA patients did not develop arthritis during the 2-year follow-up. Thus, CSA and information on autoantibodies is insufficient for accurately identifying imminent autoantibody-positive RA.

Keywords: autoantibodies; autoantigens; biomarkers; epidemiology; inflammation; rheumatoid arthritis.

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Conflict of interest statement

Competing Interests

All authors declare no conflicts of interest relevant to the presented manuscript.

Figures

Figure 1
Figure 1. Flowchart of the patient flow and development of clinical arthritis during two-year follow-up period of the present study.
Flowchart of the patient flow and development of clinical arthritis during two-year follow-up period of the present study.
Figure 2
Figure 2. Kaplan-Meier One Minus Survival plots with combinations of Anti-Citrullinated Protein antibodies (ACPA) and Rheumatoid Factor (RF) and associated risks for progression to clinical arthritis over time.
With autoantibody-negative CSA-patients as reference (N=184), ACPA-negative/RF-positive patients (N=25) had a HR of 2.6 (1.04-6.6), ACPA-positive/RF-negative (N=6) a HR of 8.0 (2.4-27.4) and ACPA-positive/RF-positive patients (N=26) a HR of 10.5 (5.4-20.6) for progression to clinical arthritis.
Figure 3
Figure 3. Kaplan-Meier One Minus Survival plots with (A) ACPA-levels in ACPA-positive CSA patients and (B) RF-levels in RF-positive CSA-patients and associated risks for progression to clinical arthritis over time.
A. The ACPA-positive patients in the second tertile (levels 96–325 U/ml, N=11) had a HR of 1.2 for progression to clinical arthritis (95%CI=0.39–3.9) compared to the patients in the lowest tertile (N=10). The ACPA-positive patients in the third and highest tertile (levels ≥326 U/ml, N=11) had a HR of 1.6 for progression to clinical arthritis (95%CI=0.50–4.8) compared to the patients in the lowest ACPA-level tertile. B. The RF-positive patients in the second tertile (levels 11-40 IU/ml, N=17) had a HR of 1.6 for progression to clinical arthritis (95%CI=0.50–5.0) compared to the patients in the lowest tertile (N=17). The RF-positive patients in the third and highest tertile (levels ≥41 IU/ml, N=17) had a HR of 3.3 for progression to clinical arthritis (95%CI=1.1–9.6) compared to the patients in the lowest RF-level tertile.
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References

    1. Gan RW, Trouw LA, Shi J, et al. Anti-carbamylated Protein Antibodies Are Present Prior to Rheumatoid Arthritis and Are Associated with Its Future Diagnosis. J Rheumatol. 2015 Apr;42(4):572–9. - PMC - PubMed
    1. Nielen MMJ, Van Schaardenburg D, Reesink HW, et al. Specific autoantibodies precede the symptoms of rheumatoid arthritis: A study of serial measurements in blood donors. Arthritis Rheum. 2004 Feb;50(2):380–6. - PubMed
    1. Rantapää-Dahlqvist S, De Jong BA, Berglin E, et al. Antibodies against cyclic citrullinated peptide and IgA rheumatoid factor predict the development of rheumatoid arthritis. Arthritis Rheum. 2003 Oct;48(10):2741–9. - PubMed
    1. Rakieh C, Nam JL, Hunt L, et al. Predicting the development of clinical arthritis in anti-CCP positive individuals with non-specific musculoskeletal symptoms: a prospective observational cohort study. Ann Rheum Dis. 2015 Sep;74(9):1659–66. - PubMed
    1. Bos WH, Wolbink GJ, Boers M, et al. Arthritis development in patients with arthralgia is strongly associated with anti-citrullinated protein antibody status: a prospective cohort study. Ann Rheum Dis. 2010 Mar;69(3):490–4. - PubMed

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