Flare during tapering of biological DMARDs in patients with rheumatoid arthritis in routine care: characteristics and predictors

Abstract

Objective: To identify predictors of flare in a 2-year follow-up study of patients with rheumatoid arthritis (RA) in sustained clinical remission tapering towards withdrawal of biological disease-modifying anti-rheumatic drugs (bDMARDs).

Methods: Sustained clinical remission was defined as Disease Activity Score for 28 joints (DAS28)-C reactive protein (CRP) ≤2.6 without radiographic progression for >1 year. bDMARDs were tapered according to a mandatory clinical guideline to two-thirds of standard dose at baseline, half of dose at week 16 and discontinuation at week 32. Prospective assessments for 2 years included clinical evaluation, conventional radiography, ultrasound and MRI for signs of inflammation and bone changes. Flare was defined as DAS28-CRP ≥2.6 with ∆DAS28-CRP ≥1.2 from baseline. Baseline predictors of flare were assessed by logistic regression analyses.

Results: Of 142 included patients, 121 (85%) flared during follow-up of which 86% regained remission within 24 weeks after flare. Patients that flared were more often rheumatoid factor positive, had tried more bDMARDs and had higher baseline ultrasound synovitis sum scores than those not flaring. For patients on standard dose, predictors of flare within 16 weeks after reduction to two-thirds of standard dose were baseline MRI-osteitis (OR 1.16; 95% CI 1.03 to 1.33; p=0.014), gender (female) (OR 6.71; 95% CI 1.68 to 46.12; p=0.005) and disease duration (OR 1.06; 95% CI 1.01 to 1.11; p=0.020). Baseline predictors for flare within 2 years were ultrasound grey scale synovitis sum score (OR 1.19; 95% CI 1.02 to 1.44; p=0.020) and number of previous bDMARDs (OR 4.07; 95% CI 1.35 to 24.72; p=0.007).

Conclusion: The majority of real-world patients with RA tapering bDMARDs flared during tapering, with the majority regaining remission after stepwise dose increase. Demographic and imaging parameters (MR-osteitis/ultrasound greyscale synovitis) were independent predictors of immediate flare and flare overall and may be of importance for clinical decision-making in patients eligible for tapering.

Keywords: Magnetic Resonance Imaging; arthritis, rheumatoid; inflammation; ultrasonography.

Figure 1

Number of patients flaring within 16 weeks after dose reduction of bDMARDS (n=142 patients with RA in sustained clinical remission). Group A (A1) including patients tapered from standard dose: 121 of which 95 had no flare and 26 had flare. Group B (B1+B2) including patients tapering from two-thirds of dose: 104 of which 79 had no flare and 25 had flare. Group C (C1+C2+C3) including patients tapered from half of dose: 84 of which 41 had no flare and 43 had flare. Seven patients did not follow the tapering Four patients did not flare in A1, but they were not included in B2. Similarly, two patients did not flare in B2, but they were not included in C3, while one patient did not flare in B1, but he/she was not included in C2. bDMARDS, biological disease-modifying antirheumatic drugs; RA, rheumatoid arthritis

Figure 2

Heatmaps of predicted probabilities for (A): Flare from baseline to 2 years and (B): Flare within 16 weeks when tapering from standard dose to two-thirds of dose, stratified by gender. Predicted probabilities were derived based on logistic regression models including MRI and ultrasound component scores (table 3) with disease duration shown in years. bDMARD, biological disease-modifying antirheumatic drug.

Figure 3

Clinical and imaging measures stratified by regaining remission at 16 and 8 weeks before flare, flare, and 8, 16 and 24 weeks after flare −16 w: 16 weeks before flare; −8 w: 8 weeks before flare; F: flare; +8 w: 8 weeks after flare; +16 w: 16 weeks after flare; +24 w: 24 weeks after flare. Mann-Whitney U test, χ² test or Fisher’s exact test (as appropriate) was used for analysing between-group differences. *p<0.05, **p<0.01, ***p<0.001. ACR, American College of Rheumatology; CDAI, Clinical Disease Activity Index; CRP, C reactive protein; DAS28, Disease Activity Score for 28 joints; EULAR, European Alliance of Associations for Rheumatology; GLOESS, Global OMERACT-EULAR Composite Score; HAQ, Health Assessment Questionnaire; SJC, swollen joint count; TJC, tender joint count.