A predominant involvement of the triple seropositive patients and others with rheumatoid factor in the association of smoking with rheumatoid arthritis

Abstract

The major environmental risk factor for rheumatoid arthritis (RA) is smoking, which according to a widely accepted model induces protein citrullination in the lungs, triggering the production of anti-citrullinated protein antibodies (ACPA) and RA development. Nevertheless, some research findings do not fit this model. Therefore, we obtained six independent cohorts with 2253 RA patients for a detailed analysis of the association between smoking and RA autoantibodies. Our results showed a predominant association of smoking with the concurrent presence of the three antibodies: rheumatoid factor (RF), ACPA and anti-carbamylated protein antibodies (ACarPA) (3 Ab vs. 0 Ab: OR = 1.99, p = 2.5 × 10^-8). Meta-analysis with previous data (4491 patients) confirmed the predominant association with the concurrent presence of the three antibodies (3 Ab vs. 0 Ab: OR = 2.00, p = 4.4 ×10^-16) and revealed that smoking was exclusively associated with the presence of RF in patients with one or two antibodies (RF⁺₁₊₂ vs. RF^-₀₊₁₊₂: OR = 1.32, p = 0.0002). In contrast, no specific association with ACPA or ACarPA was found. Therefore, these results showed the need to understand how smoking favors the concordance of RA specific antibodies and RF triggering, perhaps involving smoking-induced epitope spreading and other hypothesized mechanisms.

Figure 1

Smoking association with seropositivity for different numbers of autoantibodies in the combined meta-analysis. Forest plots showing the fixed-effect meta-analysis involving the RA patients that were positive for (A) one, (B) two, and (C) three autoantibodies. The patients without antibodies (0 Ab) were taken as reference. The OR corresponding to each cohort (Study) and its 95%-CI are provided and shown by a vertical tick and the length of a horizontal line, respectively. The area of the square around the tick is proportional to the size of the study. Summary OR and 95% CI are given in bold and represented as a vertical dashed line and a diamond, respectively. The OR scale is logarithmic.

Figure 2

Association of smoking with the presence of RF in the RA patients carrying one or two antibodies. Forest plots showing the comparison of: (A) RF⁺ patients that were positive for one or two antibodies (RF⁺₁₊₂) with the patients without antibodies (0); and (B) the comparison of RF⁺ patients that were positive for one or two antibodies (RF⁺₁₊₂) with all the RF⁻ patients (RF⁻₀₊₁₊₂). No cohort-specific information was available for the three cohorts in van Wesemael et al. Plots follow Fig. 1 conventions.

Figure 3

Smoking frequency in the patients stratified by the presence of the three autoantibodies. The double-decker plot divides the patients in rectangles proportional to the frequency in each subgroup. The width is proportional to the size of the antibody-defined patient subgroups, whereas the height of the red rectangles is proportional to the ever smokers within the antibody subgroups.

Figure 4

Classification tree of the patients by the presence of antibodies according to smoking. Each node shows its number (upper left corner), the percentage of ever smokers (upper right corner), and an histogram representing the frequency of ever smokers (continuous line) and never smokers (dotted line). Decision nodes are in blue whereas terminal nodes are in red. The splitting conditions are displayed below the node with indication of the value determining each side of the split and the number of subjects sent to the child node.