Patients with rheumatoid arthritis in clinical remission and ultrasound-defined active synovitis exhibit higher disease activity and increased serum levels of angiogenic biomarkers

Abstract

IntroductionThe aim of this study was to identify and characterize subclinical synovitis in patients with rheumatoid arthritis (RA) in clinical remission using power Doppler ultrasound (PDUS) and serum levels of biomarkers of inflammation and/or angiogenesis.MethodsWe selected patients with RA in clinical remission defined as a Disease activity score of 28 joints (DAS28)-erythrocyte sedimentation rate (ESR) <2.6 for more than six months tested by two independent rheumatologists. Clinical, epidemiological, demographic and serological data were analyzed. PDUS of knees and hands was performed by a sonographer. Synovial hypertrophy (SH) and PDUS signal were scored (grades 0 to 3). SH ≥2 and a PDUS signal was classified as active synovitis. Serum levels of biomarkers of inflammation/angiogenesis were determined by Quantibody® Human Array.ResultsThis study included 55 patients, of whom 25 (45.4%) met criteria for ultrasound-defined active synovitis. Patients with active synovitis had higher DAS28-C reactive protein (P = 0.023), DAS28-ESR (P = 0.06), simplified disease activity score, SDAI (P = 0.064), and only 12% were taking oral glucocorticoids (≤5 mg/day) compared with 40% of patients without active synovitis (P = 0.044). Patients with synovitis also had significantly higher serum levels of the angiogenic biomarkers angiopoietin-2 (P = 0.038), vascular endothelial growth factor-D (P = 0.018), placental growth factor (P = 0.043), stromal cell-derived factor-1 (P = 0.035), matrix metallopeptidase-2 (P = 0.027) and basic fibroblast growth factor (bFGF) (P = 0.007), but not of pro-inflammatory cytokines.In the multivariate logistic regression model used to explore prognostic biomarkers for active synovitis, serum levels of bFGF, DAS28-ESR and not receiving glucocorticoids were the best predictors of active synovitis. The predictive indexes provided by the model were specificity 73.3%, sensitivity 72%, and area under the curve in receiver operating characteristic 81.5% (95% CI: 70.1% to 92.8%).ConclusionsNearly half of the patients with RA in clinical remission had ultrasound-defined active synovitis, higher disease activity and less frequent oral glucocorticoid consumption than patients without active synovitis. This clinical situation was associated with a specific biological profile characterized by an excess of angiogenic mediators rather than persistent proinflammatory cytokine responses.

The MRI Features in Patients with Rheumatoid Arthritis Treated with Tocilizumab, in Clinical Remission or Low Disease Activity State

“…Inoue et al found DAS28-CRP 2.3 matched DAS28-ESR remission in Japanese patients [10].The present study suggests that composite scores overestimate remission and patients retain subclinical inflammation found on MRI. Our results join the various studies that have proven the dissociation between clinical remission according different composite scores and remission in imaging either by ultrasound (Ramirez J et al [11]) or MRI (Gandjbakhch F et al [12]) or both (Foltz V et al [13]). …”

“…With recent improvements in the treatment of rheumatoid arthritis, remission has become an achievable goal for a large proportion of RA patients, and remission is now a defined target in current RA guidelines. However, there is concern about whether current criteria reflect true remission characterized by the abrogation of synovitis and consequently, a lack of radiographic progression [5,6].…”

“…In recent years, ultrasound and magnetic resonance imaging techniques have revealed that a significant percentage of patients classified as being in clinical remission exhibit different grades of synovitis, and a subgroup of these patients suffer flares and/or joint damage during follow-up [6].…”

Joint Ultrasonography in Rheumatoid Arthritis: Pathogenetic Rationale, Possible Use in Diagnosis, Therapy Efficiency Evaluation, and Outcome Prediction

“…Ramirez и соавт. [19] изучали субклинический сино-вит у пациентов с РА в клинической ремиссии с помощью УЗИ и уровней сывороточных биомаркеров воспаления и ангиогенеза. Пациенты с активным синовитом (45,4% от общего числа включенных пациентов) имели более высокие показатели DAS28-СРБ, DAS28-СОЭ, SDAI, и только 12% из них принимали глюкокортикоиды (≤5 мг/сут), по срав-нению с 40% пациентов без активного синовита (р=0,044).…”

“…В исследовании J. Ramires и соавт. [19] у 55 пациентов с длительно текущим РА, находившихся в клинической ре-миссии, отмечена корреляция между активностью субкли-нического синовита по данным ЭД, значениями DAS28-СРБ, DAS28-СОЭ, SDAI и уровнем проангиогенных био-маркеров, таких как MMП2, ТФРβ1 и ANG. При этом кор-реляции между УЗ-признаками синовита и концентрацией провоспалительных цитокинов (ФНОα, ИЛ6, ИЛ8, ИЛ17A, ИЛ17F, ИЛ18, ИЛ20, ИЛ23 и ИЛ33) также не отме-чено.…”