Background The Disease Activity Score in 28 joints (DAS28) is a scoring system used to measure the disease activity in patients with Rheumatoid Arthritis (RA). A complex calculation based on four parameters: Swollen and tender joint counts, C-reactive protein (CRP) and patient global assessment (VAS Global) result in the DAS28 value. In daily clinical practice DAS28 is used to guide treatment decisions. According to the EULAR DAS28 >5.1 indicate high disease activity, whereas a value <3.2 is indicative of low disease activity. If DAS28 is lower than 2.6 the patient is considered to be in remission. Response criteria have also been based on the DAS28 value, so when comparing a patient’s DAS28 score over two time points a DAS28 improvement >1.2 is considered as a good response to the treatment [1]. We will focus on the parameter CRP. The intraindividual biological variation of CRP in healthy subjects is about 42 % [2], while the analytical variation is below 10%. Intraindividual biological variability of CRP in patients with RA is unknown, however it must be expected to be at least in the same order of magnitude as for healthy individuals, and then it might have significant impact on DAS28 score and therefore on the overall treatment. This is becoming increasingly relevant as so called high-sensitivty C-reactive protein (hs-CRP) tests are available on routine basis in many hospitals [3].

Objectives The aim of this study was to investigate the theoretical influence of the variability in CRP at low/normal values on the DAS28 score

Methods We used Microsoft Excel to calculate DAS28 score by using following formula: DAS28=0.56*√(tender joints) + 0.28*√(swollen joints) + 0.36*ln(CRP+1) + 0.014*VAS Global + 0.96

Results Changes in CRP results below app. 10 mg/l that might be caused by biological variation can result in disproportionately great change in the DAS28 score and misclassification of patients. An example: A patient with five tender joints, one swollen joint, VAS 10 and CRP 1mg/l, DAS28 score is 2,9; if the CRP instead is tested to 7 mg/l which is possible if the patient’s true CRP-level is 4 mg/l DAS28 is calculated to 3,4. A figure with (non uploadable) DAS28 on the Y-axis and CRP mg/l on the X-axis shows a steep increase in the DAS28 at CRP values lower than 20mg/l, then the curve flattens significantly.

Conclusions The intraindividual biological variation of CRP in patients with RA with low disease activity is unknown, but if it is similar to the variation in healthy subjects you should be cautious to interpret the DAS28 score when CRP <10 mg/l because biological variation of CRP might cause relatively large fluctuations on the final DAS28 score, with consequences on patient classification and treatment.

1. G. Wells et al, Validation of the 28-joint Disease Activity Score (DAS28) and European League Against Rheumatism response criteria based on C-reactive protein against disease progression in patients with rheumatoid arthritis, and comparison with the DAS28 based on erythrocyte sedimentation rate, Ann Rheum Dis. 2009 June; 68(6): 954-960

2. Clark GH, Fraser CG. Biological variation of acute phase proteins. Ann Clin Biochem 1993; 30: 373-6

3. Rojo-Martinez G. et al, Factors determining high-sensitivity C-reactive protein values in the Spanish population. Di@bet.es study, Eur J Clin Invest 2013;43(1):1-10

Disclosure of Interest None Declared