No financial relationships with ineligible companies to disclose
Manon Lesturgie-Talarek1, Virginie Gonzalez2, ALICE COMBIER3, Marion THOMAS4, Margaux Boisson5, Sandrine Carves3, Sarah Wanono3, Lucie Poiroux3, Anne Cauvet1, Sophie Hecquet6, Yannick Allanore7 and Jérôme Avouac8, 1Université de Paris, Institut Cochin, INSERM U1016 CNRS UMR8104, Paris, France, 2Université de Paris, Institut Cochin, INSERM U1016 CNRS UMR8104, Paris, Ile-de-France, France, 3Hôpital Cochin - Université Paris Cité, Paris, France, 4APHP, Paris, France, 5Hôpital Cochin - Université Paris Cité, Paris, 6Cochin Hospital, Paris, France, 7Université Paris Cité, Paris, France, 8Rheumatology A Department, Hôpital Cochin, AP-HP Centre - Université Paris Cité, Paris, France Background/Purpose: Despite the emergence of new therapies, a considerable proportion of individuals with rheumatoid arthritis (RA) still endure symptoms, giving rise to the concept of "refractory RA". This concept reflects the complex pathogenesis of this autoimmune disease, in which both inflammation and angiogenesis play a key role. This study aimed to pinpoint specific circulating angiogenic and inflammatory markers of refractory and active RA.
Methods: We used Luminex technology to measure the concentrations of 17 serum angiogenic (angiopoietin-1, neuropilin-1, Tie-2, endostatin, CXCL4, VCAM-1, VEGF, PlGF) and inflammatory (interferon-gamma, IL-2, IL-4, IL-6, IL-8, IL-10, TNF-alpha, MMP-1, and BAFF) markers in 211 RA patients. RA patients were categorized into three groups: - Refractory (failure of 2 or more targeted therapies) active (persistence of objective signs of disease activity) RA - Non-refractory (failure of ≥1 csDMARDs or a first line of targeted therapy) active RA - Non-active RA (DAS28≤3.2). The main objective was the identification of circulating markers that would differ specifically in the active and refractory RA population. Secondary outcomes were the detection of markers associated with disease activity and identification of correlations between the various markers and disease activity indicators.
Results: Refractory and non-refractory active RA patients differed in disease duration (18 years in refractory active RA versus 11 years non-refractory active, p< 0.001), structural damages (73% in refractory and active versus 45% in non-refractory active, p< 0.001) and the utilization of biologic therapy (78% in refractory and active versus 19% in non-refractory active, p< 0.001) (Table 1). The concentrations of the 17 markers failed to distinguish refractory from non-refractory RA patients. The comparison of active and non-active RA only revealed a strong increase of IL-6 concentration in active RA.
Then, correlograms were conducted to examine the relationships between angiogenic and inflammatory markers with RA disease characteristics. Refractory active RA exhibited a limited correlation profile showing only three correlations (VEGF, Neuropilin-1 and IL-6) with markers of disease activity (CRP or DAS28 CRP). By contrast, in non-refractory active RA patients, correlograms revealed an extensive proinflammatory and proangiogenic correlation profile with 12 markers correlating with inflammation markers or disease activity (Figure 1B). Refractory active RA showed a serum profile closer and even poorer than that of non-active in which 6 biomarkers correlated with CRP. (Figure 1C).
Conclusion: No classical marker of RA emerged as specific for refractory disease in this study. Moreover, refractory and active RA patients exhibited only few correlations with disease activity markers, despite the persistence of clinical and biological signs of disease activity. This may suggest that additional molecules may be implicated in refractory disease outside those herein selected. These findings also highlight the potential limitations of serum analysis in refractory active RA.
Table 1. Patient characteristics. CRP: C-Reactive Protein ; DAS: Disease Activity Score ; ESR: Erythrocytes Sedimentation Rate ; IQR: Interquartile Range ; JAK: Janus Kinase ; RA: Rheumatoid Arthritis ; TNF: Tumor Necrosis Factor ; SD: Standard Deviation.
Figure 1. Serum signature in rheumatoid arthritis subgroups. Correlograms of angiogenic and inflammatory markers and clinico-biological data in refractory active RA (n=59) (A), non-refractory active RA (n=85) (B) and non-active RA (n=67) (C). Only significant Spearman’s correlation coefficients are represented by colour intensity and square size. Red: positive correlation. Blue: negative correlation.
M. Lesturgie-Talarek: None; V. Gonzalez: None; A. COMBIER: None; M. THOMAS: None; M. Boisson: None; S. Carves: None; S. Wanono: None; L. Poiroux: None; A. Cauvet: Corvus, 12, Research grant given by Corvus; S. Hecquet: None; Y. Allanore: Corvus, 12, Research grant given by Corvus; J. Avouac: AbbVie, 1, 2, 4, 6, BMS, 4, 5, 6, Fresenius Kabi, 4, 5, Galapagos, 1, 2, 5, 6, Lilly, 6, Novartis, 6, Pfizer, 5, 6, Sanofi, 4, 6.