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Dual seropositivity and shared epitopes in RA: friends or foes?

Dual seropositivity (rheumatoid factor (RF) and/or anti-citrullinated protein antibodies (ACPA) as well as shared epitope (SE) are known to be associated with poor prognosis and structural damage in RA.

In OP0104, Lend and colleagues aimed at investigating if RF, ACPA & SE could predict treatment response. In the NORD-STAR trial, 800+ naive RA pts were randomized with MTX in combination with csDMARDs, Abatactept (ABA), Tocilizumab (TCZ) or Certolizumab (CTZ). This abstract looked at treatment response in these 4 groups based on presence of RF, ACPA and/or SE. Efficacy in triple-positive patients was similar at at 48 weeks across groups. RF or ACPA positivity seems to predict a better response to MTX+ABA at 24 weeks, but this prediction was not sustained at week 48. The addition of SE did not improve the prediction.

These data contradict the results of the AMPLE study, a single blind head to head trial suggesting the superiority of ABA vs. ADA at week 24 & 48 in early RA patients with dual seropositivity, and more so in SE carriers, although due to a small sample size not all results reached statistical significance.

It seems in fact, that the AMPLE trial inspired the study presented in OP0007, by Maldonado et al. The AMPLIFIED Phase 3 RCT aimed at comparing head-to-head ABA vs ADA in pts with early (MTX-IR), dual seropositive RA & SE carriers. 300+ pts were recruited. ACR50 rates in both dual seropositive and in the SE+ subset were high in both groups, at week 24 59% ABA vs. 60% ADA; failing to show superiority of ABA in this subgroup of patients. Of interest, in this study the ACPA autoantibody titres seemed to decrease more notably in the ABA groupe. In addition, when stratifying by ACPA levels, patients with the highest anti-CCP2 levels trended towards a better response to ABA although this did not reach significance. Tolerance was similar across groups.

What to take home from this?

It would be very impactful for the field if such accessible biomarkers would help in prediction of response to treatment. Unfortunately, it does not seem in the current context that using dual seropositivity or SE as biomarkers has the power to direct the clinician towards one mechanism of action rather than another. There might be still hope for the very high ACPA positive subgroup, but one needs to be careful with trends and numerical superiority.


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