Background Rheumatoid arthritis (RA) is a chronic systemic inflammatory disease which is associated with increased mortality, mostly because of a higher incidence of cardiovascular disease (CVD), which cannot be explained by traditional risk factors alone. (1,2) Also studies showed that the cardiovascular events can already occur at a higher than expected rate shortly after the first symptoms of RA. (3)This raises the question if individuals with clinical suspect arthralgia (CSA) but not yet diagnosed with RA, already have an increased risk for developing cardiovascular disease compared to healthy controls and if this is also true for ACPA positive individuals without symptoms of clinical suspect arthralgia.

In our study we used skin autofluorescence (SAF), measured with the AGE reader, as an early non-invasive tool to identify subjects who are at increased risk for developing cardiovascular disease. (4) SAF measures the accumulation of AGEs in the skin and thereby offers a simple alternative to invasive measurement of AGE accumulation. (5)

Objectives To investigate skin autofluorescence (SAF) levels, as an early indicator for cardiovascular disease, in relation to the presence of anticitrullinated protein antibodies (ACPA), clinical suspect arthralgia (CSA) and rheumatoid arthritis (RA) in a large population-based cohort.

Methods Cross-sectional data were used from 17346 participants of the Dutch Lifelines Cohort Study, of whom baseline SAF and ACPA levels were available. The presence of CSA was determined using EULAR questions from the connective tissue disease screening questionnaire (CSQ). Individuals were divided into four groups: ACPA negative controls (n=17211), ACPA positive without CSA (n=49), ACPA positive with CSA (n=31) and defined RA (n=52). Multinomial regression was used to compare SAF levels and correct for potential confounders.

Results SAF levels were higher in the ACPA positive with CSA group (OR 2.04, p=0.034) and the defined RA group (OR 3.10, p<0.001) compared to controls, but not in the ACPA positive without CSA group (OR 1.07, p=0.875). The difference in SAF levels remained statistically significant in the defined RA group after adjusting for age (OR 2.09, p=0.011), smoking status, renal function or HbA1c. In the ACPA positive with CSA group, the effect was found to be comparable (corrected for age: OR 2.09).

Conclusion Our results indicate that ACPA positive individuals with CSA have elevated SAF levels, which is regarded as an early marker for oxidative stress and a possible indicator for development of cardiovascular disease. Therefore it is important to conduct further studies to explore if, in individuals with clinical suspect arthralgia, cardiovascular risk management should be considered in future clinical practice.

References [1]Wolfe F, Mitchell DM, Sibley JT, Fries JF, Bloch DA, Williams CA, et al. The mortality of rheumatoid arthritis. Arthritis Rheum 1994 Apr;37(4):481-494.

[2]Symmons DP, Jones MA, Scott DL, Prior P. Longterm mortality outcome in patients with rheumatoid arthritis: early presenters continue to do well. J Rheumatol 1998 June 01;25(6):1072-1077.

[3]Kerola AM, Kauppi MJ, Kerola T, Nieminen TV. How early in the course of rheumatoid arthritis does the excess cardiovascular risk appear? Ann Rheum Dis 2012 October 01;71(10):1606-1615.

[4]Stirban A, Heinemann L. Skin Autofluorescence - A Non-invasive Measurement for Assessing Cardiovascular Risk and Risk of Diabetes. Eur Endocrinol 2014 August 01;10(2):106-110.

[5]Meerwaldt R, Graaff R, Oomen PHN, Links TP, Jager JJ, Alderson NL, et al. Simple non-invasive assessment of advanced glycation endproduct accumulation. Diabetologia 2004 July 01;47(7):1324-1330.

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Figure 1.

The top chart shows SAF levels measured with the AGE reader in the 4 groups: ACPA negative controls, ACPA positive without CSA group, APCA positive with CSA group and defined RA group.

The lower picture shows the AGE reader we used from DiagnOptics Technologies BV, Groningen, the Netherlands: https://www.diagnoptics.com/

Acknowledgements The Lifelines initiative has been made possible by subsidy from the Dutch Ministry of Health, Welfare and Sport, the Dutch Ministry of Economic Affairs, the University Medical Center Groningen (UMCG), Groningen University and the Provinces in the North of the Netherlands (Drenthe, Friesland, Groningen).

Disclosure of Interests None declared.