Autoantibody profiling as early diagnostic and prognostic tool for rheumatoid arthritis

Abstract

Background: Early treatment prevents progression of joint damage in rheumatoid arthritis (RA), but diagnosis in early disease is impeded by lack of appropriate diagnostic criteria.

Objective: To study the value of rheumatoid factor (RF), anti-cyclic citrullinated peptide autoantibodies (anti-CCP), and anti-RA33 autoantibodies for diagnosis of RA and prediction of outcome in patients with very early arthritis.

Methods: The prospective follow up inception cohort included 200 patients with very early (<3 months) inflammatory joint disease. Autoantibodies were measured at baseline and analysed in a tree based model which aimed at determining the added diagnostic value of testing for anti-CCP and anti-RA33 as compared with RF alone.

Results: RA was diagnosed in 102 patients, while 98 developed other inflammatory arthropathies. Receiver operator curve analysis showed an optimum cut off level for RF at 50 U/ml, above which anti-CCP and anti-RA33 had no additional diagnostic value. Remarkably, RF >or=50 U/ml and anti-CCP showed similar sensitivity and high specificity for RA, but overlapped considerably. Anti-RA33 was less specific and did not correlate with RF or anti-CCP. Among patients with RA, 72% showed at least one of these three autoantibodies, compared with 15% of non-RA patients. RF >or=50 U/ml and anti-CCP were predictors of erosive disease, whereas anti-RA33 was associated with mild disease.

Conclusions: Stepwise autoantibody testing in early inflammatory joint disease, starting with RF, followed by anti-CCP (in patients with RF <50 U/ml), and finally anti-RA33, should be used as a sensitive and effective strategy for distinguishing patients with RA at high risk for poor outcome.

Figure 1

ROC curve for the tree based model. Using a computer based tree model we obtained the optimum cut off value for RF above which determining anti-CCP and/or anti-RA33 would add no significant benefit in identifying patients with RA. This value was found at 49.75 IU/l (indicated by an arrow), and RF values ⩾50 U/ml were subsequently called "high titre" RF. The ROC curve shows an area under the curve for this model of 0.78.

Figure 2

High titre RF and anti-CCP are associated with rapid radiographic progression of RA. Box plots showing the difference in Larsen scores (grade 1 abandoned) in (A) patients with RA with high titre RF v low titre or negative RF; (B) patients with RA with low titre or negative RF, positive or negative for anti-CCP; and (C) anti-CCP negative patients with RA with high titre RF v low titre or negative RF. The box shows median values and 25th/75th centiles. P_sm values indicate differences in regression coefficients between the groups. Baseline values were similar in all groups, but Larsen score progression was significantly higher in patients with high titre RF than in patients with low titre or negative RF, and this both in the overall RA population (p_sm<0.0001; fig 2A), and also in the subpopulation of anti-CCP negative patients (p_sm = 0.0014; fig 2C); a significant difference in progression was also seen between anti-CCP positive and anti-CCP negative patients in the subpopulation of patients with low titre or negative RF (p_sm = 0.038; fig 2B).

Figure 3

Prognostic value of autoantibodies for predicting improvement of disease activity. Baseline disease activity (DAS28) was similar in all patient groups (dark grey columns). At the study end point, DAS28 (light grey columns) was significantly lower in patients with RF <50 U/ml than in patients with high titre RF. In patients with RF <50 U/ml the difference between anti-CCP positive and anti-CCP negative patients was not significant. DAS28 in anti-RA33 positive patients was markedly lower than in high titre RF or anti-CCP positive patients and even significantly lower than in patients negative for all three autoantibodies. p Values represent the difference in DAS28 at study end point between the autoantibody positive versus negative group.

Figure 4

Decision tree to determine risk of RA and erosive disease in patients with early arthritis. All patients with early arthritis are tested for RF. High titre RF (⩾50 U/ml) is highly predictive for the diagnosis of RA and for developing erosive disease, and there is no benefit from determining additional autoantibodies. In patients with low titre or negative RF, anti-CCP determination helps to identify additional patients with RA at high risk of developing erosive disease. In patients negative for RF and anti-CCP, anti-RA33 testing may allow identification of patients with a more favourable outcome. Percentages shown correspond to the total numbers of patients with RA and non-RA patients.