Despite most previous studies analyzing the association of antibodies to anti-TNF response have used similar or smaller sample sizes, the number of patients used in our prospective study is relatively modest
Despite most previous studies analyzing the association of antibodies to anti-TNF response have used similar or smaller sample sizes, the number of patients used in our prospective study is relatively modest. these AZD7687 markers has not been evaluated yet. Our aim was to analyze the interaction between these four antibodies in relation to the response to anti-TNF therapy. Methods For this objective, a prospective cohort of methotrexate; conventional synthetic DMARDs; interquartile range; standard deviation Association of antibodies with anti-TNF response Multivariate linear regression was used to simultaneously test for association between anti-CCP, RF, anti-CarP and anti-PAD4 antibodies and treatment response. At the single-marker level, none of the autoantibodies were found to be significantly associated with an improvement in the DAS28 (Supplementary Table S1). We next tested for the presence of interaction effects between all six pairwise antibody combinations in relation to treatment response. We found a highly significant antibody interaction between anti-CarP and anti-PAD4 (values for association are shown for the interaction term (first column) and for the independent effect of each antibody (second and third columns). In bold, interaction P-values that are significant after correcting for multiple testing. A highly significant interaction was found for anti-CCP:RF and anti-PAD4:anti-CarP interactions with anti-TNF response. None of the remaining four antibody interactions showed a significant association, even at the nominal (P?0.05) level Using an independent cohort of 199 RA patients, we replicated the interaction between anti-CCP and RF (P?=?0.044, Fig.?1). Like in the prospective cohort, the interaction was also found PJS to be positive, indicating that the simultaneous presence AZD7687 of both antibodies is associated with a better response to anti-TNF therapy. Open in a separate window Fig. 1 Validation study of the anti-CCP and RF interaction and anti-TNF response in RA. Forest plot showing the regression coefficients and 95% confidence intervals of the variables in the linear model testing the association of the two antibody combination with the response to anti-TNF therapy at week 12. Like in the prospective patient cohort, the interaction between anti-CCP and RF is statistically significant and positively associated with anti-TNF response (Beta:1.06 (0.03 to 2.10); P?0.05). Anti-CCP:RF: regression coefficient capturing the interaction effect Discussion The identification AZD7687 of factors associated with the response to anti-TNF therapy is AZD7687 a major objective for treatment personalization in RA. Diagnostic autoantibodies, like rheumatoid factor and anti-CCP, are appealing for this task since they are already integrated into the standard clinical routine. However, conflicting results have been reported and their association to treatment response to anti-TNF is yet not clear. We hypothesized that this inconsistency could be due to the presence of interaction effects between the autoantibodies. In the present study we have tested this hypothesis for the first time. Using a prospective cohort of RA patients starting anti-TNF therapy, we have found that the interaction between anti-CCP and RF and the interaction between anti-CarP and anti-PAD4 antibodies are both strongly associated with the clinical response at week 12. The present results suggest that interactions between antibodies are important in the response to anti-TNF therapy, and provide an explanation for the previous conflicting evidence. Our study shows that the presence of both anti-CCP and RF antibodies is needed for a favorable response to anti-TNF therapy. Several previous studies have analyzed the association of either antibody in relation with the response to anti-TNF drugs. The results, however, have been largely inconsistent or inconclusive [16]. In those few studies where both antibodies were determined, the presence of interactions was not evaluated. Here we show that, when the interaction is considered, a strong and positive association between these two classic antibodies and the clinical response emerges. From a statistical perspective, when interaction effects are present and are strong, not taking them into account in the association model can lead to inconsistent findings [17]. Failing to take this into account could therefore explain the lack of reproducibility of previous studies with anti-CCP AZD7687 and RF and treatment response. The interaction association identified between anti-CCP and RF with the response to anti-TNF therapy is in accordance with recent findings at the functional level. In a recent study, macrophages -the main producers of TNF in the RA joint- have been shown to secrete much higher TNF cytokine levels when stimulated.