Prediction of flare following remission and treatment withdrawal in early rheumatoid arthritis: post hoc analysis of a phase IIIb trial with abatacept

Abstract

Background: Drug-free remission is a desirable goal in rheumatoid arthritis (RA) for both patients and clinicians. The aim of this post hoc analysis was to investigate whether clinical and magnetic resonance imaging (MRI) variables in patients with early RA who achieved remission with methotrexate and/or abatacept at 12 months could predict disease flare following treatment withdrawal.

Methods: In the AVERT study of abatacept in early RA, patients with low disease activity at month 12 entered a 12-month period with all treatment discontinued (withdrawal, WD). This post hoc analysis assessed predictors of disease flare at WD+6months (mo) and WD+12mo of patients with Disease Activity Score in 28 joints (DAS28)-defined remission (DAS28[C-reactive protein (CRP)] <2.6) at withdrawal using univariate and multivariable regression models. Predictors investigated included the Health Assessment Questionnaire-Disability Index (HAQ-DI), pain, Patient Global Assessment; MRI synovitis, erosion, bone edema, and combined (synovitis + bone edema) inflammation scores.

Results: Remission was achieved by 172 patients; 100 (58%) and 113 (66%) patients had experienced a flare at WD+6mo and WD+12mo, respectively. In univariate analyses, higher HAQ-DI and MRI synovitis, erosion, bone edema, and combined inflammation scores at WD were identified as potential predictors of flare (P ≤ 0.01). In multivariable analysis, high scores at WD for HAQ-DI and MRI erosion were confirmed as independent predictors of flare at WD+6mo and WD+12mo (P < 0.01).

Conclusion: In patients with early RA achieving clinical remission, patient function (HAQ-DI), and MRI measures of bone damage (erosion) predicted disease flare 6 and 12 months after treatment withdrawal. These variables may help identify patients with early RA in clinical remission as candidates for successful treatment withdrawal.

Trial registration: ClinicalTrials.gov, NCT01142726 (date of registration: June 11, 2010).

Keywords: Abatacept; Disease-modifying antirheumatic drugs (DMARDs); Flare; Magnetic resonance imaging (MRI); Rheumatoid arthritis.

Conflict of interest statement

Professor Conaghan has received grant/research support from Bristol Myers Squibb, consulting fees from AbbVie, GlaxoSmithKline, Eli Lilly, Novartis, Pfizer, and Roche, and speaking fees from AbbVie, Bristol Myers Squibb, and Novartis. Professor Emery has received consulting fees from AbbVie, Bristol Myers Squibb, Eli Lilly, Merck, Novartis, Pfizer, Roche, and Samsung Bioepis. Professor Huizinga has received grant/research support from the EU & Dutch Arthritis Foundation, consulting fees from Abbott Laboratories, Biotest AG, Bristol Myers Squibb, Crescendo Biosciences, Eli Lilly, Novartis, Pfizer, Roche, Sanofi-Aventis, Schering-Plough, and UCB, and speaking fees from Abbott Laboratories, Biotest AG, Bristol Myers Squibb, Novartis, Pfizer, Pharmaceuticals Corporation, Roche, Sanofi-Aventis, and Schering-Plough. Mr. Elbez received consulting fees from Bristol Myers Squibb. Dr. Banerjee is an employee of and shareholder in Bristol Myers Squibb. Professor Østergaard has received grant/research support from AbbVie, Bristol Myers Squibb, Janssen, and Merck, and speaking fees from AbbVie, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Centocor, Eli Lilly, GlaxoSmithKline, Hospira, Janssen, Merck, Mundipharma, Novartis, Novo Nordisk, Orion, Pfizer, Regeneron, Roche, Schering-Plough, Takeda, UCB, and Wyeth.

Dr. Ahmad is an employee of Bristol Myers Squibb. Dr. Baker has received consulting fees from Bristol Myers Squibb.

© 2022. The Author(s).

Figures

Fig. 1

Standardized estimated difference between patients with flare versus no flare for clinical and MRI variables. Data are shown for patients with and without flare at A WD+6months (mo) and B WD+12mo. Data from WD (or at baseline for age, weight, and duration of rheumatoid arthritis [RA]) were standardized to have a mean equal to zero and a standard deviation (SD) equal to one and were compared by the estimated differences between flare versus no flare groups. Vertical line indicates limit of effect: positive data indicate effect, negative data or data that cross 0 indicate absence of effect. P values of comparison were calculated from Student’s t test; values in bold indicate statistical significance. *Number of subjects with WD data available. †Higher SF-36 scores denote improvement in quality of life. ‡Synovitis score + edema score. §Synovitis score + 2x edema score. CI confidence interval, CRP C-reactive protein, DAS28 Disease Activity Score in 28 joints, HAQ-DI Health Assessment Questionnaire–Disability Index, OR odds ratio, PGA Physician Global Assessment, PRO patient-reported outcomes, PtGA Patient Global Assessment, SF36 Short Form-36, SJC(28) Swollen 28-Joint Count, TJC(28) Tender 28-Joint Count, VAS visual analog scale, WD withdrawal

Fig. 2

Clinical and MRI variables at WD and associated ORs for flare versus no flare. Data are shown for flare versus no flare at A WD+6mo and B WD+12mo. Data from WD were standardized (mean equal to zero and SD equal to one). Vertical line indicates limit of effect: positive data indicate effect, negative data or data that cross 1 indicate absence of effect. ORs (per one unit) and P values are from a univariate logistic regression model with scores at WD as the independent variables and flare at WD+6mo and WD+12mo as the dependent variable; bold P values indicate statistical significance. *HAQ-DI: n = 94 for flare at WD+6mo and n = 65 at WD+12mo; pain: n = 94 for flare at WD+6mo and n = 66 at WD+12mo; MRI: n = 92 for flare at WD+6mo and n = 63 at WD+12mo. †Synovitis score + edema score. ‡Synovitis score + 2x edema score. §HAQ-DI: n = 107 for flare at WD+6mo and n = 52 at WD+12mo; pain: n = 107 for flare at WD+6mo and n = 52 at WD+12mo; MRI: n = 103 for flare at WD+6mo and n = 52 at WD+12mo. OR odds ratio. See Fig. 1 for other definitions

Fig. 3

Multivariable logistic regression analysis assessing the value of cut-off scores for predicting flare. Analysis was performed for flare status at WD+6mo and WD+12mo. A multivariable logistic regression model, adjusted for treatment arm, determined whether patient-reported outcome (PRO) and MRI measures at WD were independent predictors of flare at WD+6mo and WD+12mo. P values in bold type indicate statistical significance. Vertical line indicates limit of effect: positive data indicate effect, negative data or data that cross 1 indicate absence of effect. *Synovitis score + (2x bone edema score). MTX methotrexate, SC subcutaneous. See Fig. 1 for other definitions