Abstract and Introduction
Background: Reliable assessment of remission is important for the optimal management of rheumatoid arthritis (RA) patients. In this study, we used the multi-biomarker disease activity (MBDA) test to explore the role of biomarkers in predicting point remission and sustained remission.
Methods: RA patients on > 6 months stable therapy in stable low disease activity (DAS28-ESR ≤ 3.2) were assessed every 3 months for 1 year. Baseline, intermittent (IR) and sustained (SR) remission were defined by DAS28-ESR, DAS28-CRP, simple disease activity index (SDAI), clinical disease activity index (CDAI) and ACR/EULAR Boolean criteria. Patients not fulfilling any remission criteria at baseline were classified as 'low disease activity state' (LDAS). Patients not fulfilling any remission criteria over 1 year were classified as 'persistent disease activity' (PDA). MBDA score was measured at baseline/3/6 months. The baseline MBDA score, the 6-month time-integrated MBDA score and MBDA biomarkers were used for analyses. The area under the receiver operating characteristic curve (AUROC) assessed the ability of the MBDA score to discriminate between remission and non-remission. Biomarkers were analysed at baseline using the Mann-Whitney test and over time using the Jonckheere-Terpstra trend test.
Results: Of 148 patients, 27% were in the LDAS, 65% DAS28-ESR remission, 51% DAS28-CRP remission, 40% SDAI remission, 43% CDAI remission and 25% ACR/EULAR Boolean remission at baseline. Over 1 year, 9% of patients were classified as PDA. IR and SR were achieved in 42%/47% by DAS28-ESR, 46%/29% by DAS28-CRP, 45%/20% by SDAI, 44%/21% by CDAI and 35%/9% by ACR/EULAR Boolean criteria, respectively. By all remission criteria, baseline MBDA score discriminated baseline remission (AUROCs 0.68–0.75) and IR/SR (AUROCs 0.65–0.74). The 6-month time-integrated MBDA score discriminated IR/SR (AUROCs 0.65–0.79). Baseline MBDA score and concentrations of IL-6, leptin, SAA and CRP were significantly lower in all baseline remission criteria groups vs LDAS. They and the 6-month time-integrated values were lower among patients who achieved IR/SR vs PDA over 1 year.
Conclusions: This study demonstrated that the MBDA score and its biomarkers IL-6, leptin, SAA and CRP differentiated between small differences in disease activity (i.e. between low disease activity and remission states). They were also predictors of remission over 1 year.
Rheumatoid arthritis (RA) is a chronic disease with heterogeneous outcomes. Early treatment intervention, biologic therapies, and tight control treatment strategies have made achievement of low disease-activity, including remission states, increasingly common. The remission criteria that have evolved over the last two decades reflect a common underlying theme. These criteria include measurement of clinical variables assessed by clinicians and patients, such as joint counts and global scores, as well as inflammatory blood markers, such as the erythrocyte sedimentation rate (ESR) or C-reactive protein (CRP). Despite attempts to define remission in many different ways,[2–5] the definition of a true state of biological remission remains elusive. A substantial proportion of patients classified as being in clinical remission continue to develop radiographic progression.[6–9] In addition, imaging studies have shown that the majority of patients in remission, whether treated with conventional DMARDs or a biological agent, have evidence of active subclinical inflammation.[10,11] Flares can occur when DMARDs are tapered or stopped for patients in low disease activity or clinical remission. These findings indicate that a subset of patients in clinical remission have clinically significant disease despite displaying few clinical signs or symptoms.
The clinical components of the conventional disease activity assessments are subject to intra-assessor and inter-assessor variability[13,14] and can be confounded by co-morbidities such as fibromyalgia and joint damage. The biomarkers ESR or CRP have limitations because they are non-specific and can be elevated in a number of conditions, such as older age, anaemia, infection and malignancy, and they may also be normal in many patients with clinically active RA.[16,17] These considerations highlight the need for identifying novel measures to complement clinical assessment of remission status.
A multi-biomarker disease activity (MBDA) score measures 12 serum protein biomarkers and has been validated as an objective measure of disease activity across a range of disease activity states.[18,19] These 12 biomarkers reflect biological pathways involved in the pathogenesis of RA and can be broadly grouped as acute-phase reactants (SAA, CRP), hormones (leptin and resistin), growth factors (VEGF and EGF), adhesion molecules (VCAM1), skeletal-related proteins (YKL-40), matrix metalloproteinases (MMP-1, MMP-3) and cytokine-related proteins (IL-6, TNFR1). The MBDA score has been shown to predict risk for radiographic progression. Therefore, these objective markers may be useful for defining remission on a molecular level and may have potential for predicting sustained remission. In post hoc analysis of OPERA, a study of patients with active recent-onset RA who were treated with methotrexate alone or with adalimumab, changes in MBDA score from baseline to 3 months were associated with achieving clinical remission at 6 months. In contrast, the utility of the MBDA score for predicting outcomes in patients who are in stable low disease activity states while continuing a stable treatment has not been examined in depth.
Reliable assessment of remission is important for the optimal management of patients with RA to achieve the best clinical, radiographic and functional outcomes possible. We have addressed this need in the present study by evaluating a cohort of clinically similar patients in low disease activity or remission. We aimed to identify serum molecular markers of remission and to explore the role of these biomarkers in predicting point and sustained remission as defined by several clinical remission criteria.
Arthritis Res Ther. 2020;22(158) © 2020 BioMed Central, Ltd.
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