Can anti-cyclic citrullinated peptide antibody-negative RA be subdivided into clinical subphenotypes?

Abstract

Introduction: Studies investigating genetic risk factors for susceptibility to rheumatoid arthritis (RA) studied anti-citrullinated peptide antibody (CCP)-positive RA more frequently than anti-CCP-negative RA. One of the reasons for this is the perception that anti-CCP-negative RA may include patients that fulfilled criteria for RA but belong to a wide range of diagnoses. We aimed to evaluate the validity of this notion and explored whether clinical subphenotypes can be discerned within anti-CCP-negative RA.

Methods: The 318 patients with anti-CCP-negative RA (1987 ACR criteria), included in the Leiden Early Arthritis Clinic between 1993 and 2006, were studied for baseline characteristics and radiologic progression data during a mean follow-up of 5 years. Grouping was studied both at variable and patient levels. Principal components analysis and partial least-squares regression were applied to study for clustering of variables. A cluster analysis was performed to look for clustering of patients.

Results: The simultaneous presence of patient characteristics at disease presentation was observed for several groups; however, the three largest groups of patients' characteristics explained only 26.5% of the total variance. Plotting the contribution of each patient to these three groups did not reveal clustering of patients. Comparable observations were made when data on progression of joint destruction were studied in relation to baseline clinical data. A cluster analysis, evaluating whether patients resemble each other, revealed no grouping of patients. Altogether, no clinically distinguishable subphenotypes were observed.

Conclusions: The current data provide evidence that, for risk-factor studies, anti-CCP-negative RA patients can be studied as one group.

Figure 1

Plots of the most important component loadings from PCA and PLS on 318 anti-CCP-negative RA patients. In these plots, each dot indicates one single patient. Component scores indicate how strongly each component is represented in each patient. For example, in (a), a dot indicates how much the variance in an individual patient is being described by factor 1 on the x-axis (age, gender, and the presence of baseline erosions) in relation to factor 2 on the y-axis (involvement of small joints versus the involvement of large joints or both SJC and CRP). If a concurrence of components was found, clustering of patients would be visible. In the PCA, clinical variables at disease onset were explored. The same applies for the factors in PLS regression. In the PLS regression, the clinical variables at disease onset were explored together with radiologic data on progression of joint destruction during a mean of 5 years of disease. CRP, C-reactive protein; PCA, principal components analysis; PLS, partial least squares regression; RA, rheumatoid arthritis; SJC, swollen joint count.

Figure 2

Plots of the two major component loadings from PLS on the whole Leiden Early Arthritis Clinic (n = 704). Each dot indicates one patient. Component scores indicate how strongly each component is represented in each patient. Patients positive for anti-CCP antibodies are blue, whereas negative patients are red. CCP, citrullinated peptide antibody; PLS, partial least squares regression.

Figure 3

Heat map of the cluster analysis of 318 anti-CCP-negative RA patients. Heat map representing the presence or absence of disease characteristics in individual patients. To make variables comparable, all values were transformed into binary values. For those variables on a continuous scale, the following cut-offs were made: Morning Stiffness, ≤60 minutes; Fatigue, fatigue rated more than mean (45.1) on Visual Analogue Scale; symptom duration more than or ≤12 weeks age at inclusion, age greater than mean age (59.2 years); swollen joint count, more than four swollen joints; CRP, CRP greater than reference value (10 mg/L). The dendrograms depict the relative strength of correlations between the variables and the patients, respectively. CCP, citrullinated peptide antibody; CRP, C-reactive protein; RA, rheumatoid arthritis; SJC, swollen joint count; VAS, visual analogue scale.