Several potential biomarkers of therapy change and disease flare in patients with remitted rheumatoid arthritis (RA) were identified in a study published in Rheumatology. Treatment changes were independently associated with body mass index (BMI), not using biological disease-modifying anti-rheumatic drugs (DMARDs), progression of erosion score in the first year of diagnosis, and calprotectin serum levels.

This 5-year prospective cohort study recruited patients with RA in remission from an arthritis clinic in Barcelona, Spain. Remission was defined as having a Disease Activity Score-28 with Erythrocyte Sedimentation Rate (DAS28-ESR) <2.6. Patients underwent clinical and biological assessment at 4-month intervals until month 60. Serum levels of angiogenic and inflammatory biomarkers were measured at baseline and 12 months.

Magnetic resonance imaging (MRI) of the dominant hand and ultrasound of the hands and knees were performed at baseline and 12 months. Synovial biopsies were taken in patients with Power Doppler signal. Radiographic images of the hand and feet were taken at baseline at month 60. Disease flares and therapy change were assessed at each follow-up interval. Radiographic progression was defined by change in modified Sharp van der Heijde score between baseline and 5 years. Logistic regression was performed to identify correlates of therapy change.

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The cohort comprised 81.6% patients, among whom 13 (21.6%) were men. Mean age at enrollment was 53.0 years. Just under half (45%) were taking DMARDs at baseline, and 81.6% were positive for anti-citrullinated protein antibodies. Additionally, 66.6% had Power Doppler signal at baseline. At 5 years, 73.3% of patients remained in remission according to DAS28-ESR. Twenty patients (33.3%) experienced loss of clinical remission and changed treatment regimen at some point during follow-up. Therapy change was independently associated with higher BMI (odds ratio [OR], 1.3; 95% confidence interval [CI], 1.0-1.7), lack of biological DMARD therapy (OR, 24.7; 95% CI, 2.3-257.2), first-year erosion progression on MRI (OR, 1.2; 95% CI, 1-1.3), and first-year progression of calprotectin serum levels (OR, 2.8; 95% CI, 1.0-8.2). Radiographic progression was relatively rare, detected in just 6 patients (10%).

Radiographic progression was associated with first-year progression of MRI erosions (P =.03) and bone edema (P =.04). A total of 23 patients underwent synovial biopsy at baseline, among whom 10 later experienced a flare. Mast cell density was significantly higher in patients who experienced a flare than patients who did not (P =.02). In a logistic regression model adjusted for BMI, infiltration of mast cells in synovium was independently correlated with flares (OR, 1.1; 95% CI, 1.0-1.4).

Limitations of the study include small sample size and all patients had established disease, impeding conclusions being applied to early RA cohorts. Additionally, a pre-established treatment protocol was not utilized.

These data identify potential biomarkers of flare or progression in patients with remitted RA. The small number of patients with radiographic progression prevented a more precise analysis of risk factors. Further research in a larger cohort is necessary to confirm the utility of these potential biomarkers. “[O]ur findings support [a multi-dimensional] approach to define durable remission,” investigators wrote. “Patients in remission with normal BMI, on bDMARDs and with normal serum calprotectin levels have significantly lower risk of flare of the disease and change of treatment.”


Ramírez J, Cuervo A, Celis R, et al. Biomarkers for treatment change and radiographic progression in patients with rheumatoid arthritis in remission: a 5 year follow-up study. Rheumatology. Published online July 12, 2020. doi:10.1093/rheumatology/keaa258