Abstract
BackgroundRheumatoid arthritis (RA) is a heterogeneous disease, as evidenced by the differences in long-term outcomes. This applies especially to anti-citrullinated protein antibodies (ACPA)-negative RA, where a proportion achieves sustained DMARD-free remission (SDFR; sustained absence of synovitis after DMARD cessation). Differentiation of RA patients who will achieve SDFR can guide personalized treatment/tapering strategies. Although this subgroup remains scarcely discerned, previous research demonstrated that these RA patients are characterized by an early clinical response (DAS remission after 4 months) after DMARD start. We studied whether, in addition to this clinical response, a specific biomarker response can further distinguish the subgroup of RA patients most likely to achieve SDFR.MethodsIn 266 RA patients, levels of 12 biomarkers (SAA/CRP/MMP-1/MMP-3/resistin/leptin/IL-6/TNF-R1/YKL-40/EGF/VEGF/VCAM-1), in the first 2 years after diagnosis, were studied in relation to SDFR, stratified for ACPA status. Subsequently, biomarkers associated with SDFR development were combined with early DAS remission to study its additional value in defining subgroups. Since most biomarker levels are not routinely measured in clinical practice, we explored how this subgroup can be clinically recognized.ResultsACPA-negative RA patients achieving SDFR were characterized by high baseline levels and stronger decline in MMP-1/MMP-3/SAA/CRP after DMARD-start, respectively 1.30×/1.44×/2.12×/2.24× stronger. This effect was absent in ACPA-positive RA. In ACPA-negative RA, a strong biomarker decline is associated with early DAS remission. The combination of both declines (clinical, biomarker) was present in a subgroup of ACPA-negative RA patients achieving SDFR. This subgroup can be clinically recognized by the combination of high baseline CRP levels (≥ 3 times ULN), and early DAS remission (DAS4 months < 1.6). This latter was replicated in independent ACPA-negative RA patients.ConclusionsACPA-negative RA patients with early DAS remission and a strong biomarker response (or baseline CRP levels ≥ 3× ULN) are most likely to achieve SDFR later on. This could guide personalized decisions on DMARD tapering/cessation in ACPA-negative RA.
Highlights
Rheumatoid arthritis (RA) is an auto-immune syndrome which, from a pathophysiological perspective, presumably consists of different disease entities
We addressed the following complementary hypotheses: (1) the biomarker response in Matrix metalloproteinase (MMP)-3, Serum amyloid A (SAA), and C-reactive protein (CRP) after disease-modifying antirheumatic drugs (DMARDs) initiation is stronger in anti-citrullinated protein antibodies (ACPA)-negative RA patients achieving sustained DMARD-free remission (SDFR); (2) a strong biomarker response in matrix metalloproteinase-3 (MMP-3), SAA, and CRP occurs in the same RA patients with high baseline levels of these biomarkers; and (3) a combination of a strong biomarker response and early Dis‐ ease activity score (DAS) remission occurs in ACPA-negative RA patients who achieve SDFR (Fig. 1)
Biomarker response combined with early DAS remission associated with SDFR in ACPA‐negative RA When exploring the relation between a strong biomarker response and early DAS remission, we found that early DAS remission tended to be associated with a stronger median decline in matrix metalloproteinase-1 (MMP-1), MMP-3, SAA, and CRP in ACPA-negative RA patients achieving SDFR (Figs. 4 and 5, S9)
Summary
Rheumatoid arthritis (RA) is an auto-immune syndrome which, from a pathophysiological perspective, presumably consists of different disease entities. Sustained DMARD-free remission (SDFR; sustained absence of synovitis after DMARD discontinuation) is prevalent within ACPA-negative RA (~ 40%), but other ACPA-negative RA patients have persisting disease, generally requiring life-long disease-modifying antirheumatic drugs (DMARDs) [3]. The course of this group of ACPA-negative RA patients resembles ACPA-positive RA, where SDFR can only be achieved by ~ 5–10%, and persistent or progressive disease is common [4, 5]. Rheumatoid arthritis (RA) is a heterogeneous disease, as evidenced by the differences in long-term outcomes This applies especially to anti-citrullinated protein antibodies (ACPA)-negative RA, where a proportion achieves sustained DMARD-free remission (SDFR; sustained absence of synovitis after DMARD cessation). In addition to this clini‐ cal response, a specific biomarker response can further distinguish the subgroup of RA patients most likely to achieve SDFR
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