Abstract
ObjectiveTo investigate whether calprotectin (S100A8/A9 or MRP8/14), an inflammatory complex released by monocytes, could indicate residual subclinical inflammation in rheumatoid arthritis (RA) patients who are in stable remission on disease-modifying anti-rheumatic drugs (DMARDs) and serve as a marker for disease flare after DMARD tapering.MethodsWe used data from two trials. Patients from the IMPROVED study had early (< 2 years) RA, and when they achieved disease activity score remission (DAS44 < 1.6), they stopped methotrexate to attempt drug-free remission. Patients from the RETRO study had established RA in stable remission (DAS28 < 2.6) and either tapered by 50% or stopped (biological or conventional) DMARDs. Circulating calprotectin at the tapering time point was determined by ELISA, and its predictive value for flare (loss of remission) within 12 months of DMARD tapering/stopping was determined.ResultsIn both IMPROVED (n = 104) and RETRO (n = 57), patients that flared within 12 months had higher calprotectin at the moment of DMARD tapering/stopping. Twofold higher calprotectin at the moment of DMARD tapering/stopping was associated with an increased risk (odds ratio) of flare of 1.07 (95% CI 0.98–1.18, p = 0.14) in the IMPROVED and 3.62 (95% CI 1.76–7.46, p < 0.001) in the RETRO. Correcting for clinical predictors of flare (DAS at study inclusion, anti-CCP2 positivity, gender) did not change these estimates. The area under the receiver operating curve of calprotectin levels for predicting flare within 12 months was 0.63 (95% CIs 0.51–0.76) in the IMPROVED study and 0.80 (95% CIs 0.69 to 0.92) in the RETRO study.ConclusionCirculating calprotectin levels in RA patients in remission on DMARDs are higher in patients that will flare upon DMARD tapering/stopping. Since the differences between the cohorts precluded definitive conclusions, more research is needed to determine whether calprotectin has prognostic value in predicting flare after attempting drug tapering in RA.Trial registrationIMPROVED, ISRCTN11916566. RETRO, 2009-015740-42.
Highlights
In rheumatoid arthritis (RA), improvements in the control of inflammation by conventional synthetic and biologic disease-modifying antirheumatic drugs (DMARDs) are slowly shifting therapeutic goals from preventing damage by suppressing disease activity to tapering DMARDs in patients in stable remission to achieve drug-free remission (DFR)
DFR will not be reached by all RA patients in remission, and the disease flare that can occur after unsuccessful DMARD tapering can increase disease burden that could have been avoided if the DMARDs had not been interrupted
Calprotectin levels were not correlated with acute-phase reactants (ESR, C-reactive protein (CRP)), disease activity scores (DAS), or physical function as measured by the Health Assessment Questionnaire (HAQ) in either cohort, most likely due to the low variability of these parameters in these patients in remission (Additional file 1: Figure S1), and baseline demographics did not differ between patients with high vs. low calprotectin levels (Additional file 1: Table S2)
Summary
In rheumatoid arthritis (RA), improvements in the control of inflammation by conventional synthetic and biologic disease-modifying antirheumatic drugs (DMARDs) are slowly shifting therapeutic goals from preventing damage by suppressing disease activity to tapering DMARDs in patients in stable remission to achieve drug-free remission (DFR). Identifying factors associated with increased risk of disease flare after tapering DMARDs would aid clinical decision-making. Residual subclinical inflammation has been proposed to be a major predictor of flare, prompting multiple studies to identify biomarkers sensitive in detecting residual inflammation at the moment of tapering, including multibiomarker disease activity scores [3] and inflammation on imaging [1]. These markers are limited by variable associations and lack of replication
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