ALTERED SERUM INFLAMMATORY AND ANGIOGENIC SIGNATURES IN REFRACTORY RHEUMATOID ARTHRITIS

Background: Despite adhering to suggested treatment modifications, a considerable proportion of individuals with rheumatoid arthritis (RA) still endure symptoms, giving rise to the concept of “refractory RA.” It is imperative to gain a deeper comprehension of the pathogenesis of refractory RA to promptly identify and improve therapeutic interventions for these patients, and analyzing serum may be a relevant strategy to identify new relevant markers. Objectives: This study aimed to pinpoint serum biomarkers distinctive to refractory rheumatoid arthritis (RA), a condition marked by an intricate pathogenesis encompassing both inflammation and angiogenesis. Methods: Between 2019 and 2022, we enrolled 211 RA patients and categorized them into three groups: a) those with active and refractory RA, defined by a DAS28 score > 3.2 and resistance to at least two lines of targeted therapy, b) patients with active but non-refractory disease, and c) those in remission or exhibiting low disease activity (DAS28 ≤ 3.2). We used Luminex technology to measure the concentrations of 17 serum markers, including angiopoietin-1, neuropilin-1, Tie-2, endostatin, CXCL4, VCAM-1, VEGF, PlGF, interferon-gamma, IL-2, IL-4, IL-6, IL-8, IL-10, TNF-alpha, MMP-1, and BAFF. Results: In comparison to controls, RA patients displayed a proinflammatory and proangiogenic profile characterized by elevated levels of VCAM-1, PlGF, Endostatin, TNFα, IFNγ, IL-6, IL-4, and IL-10, along with decreased levels of IL-8. Further analysis within RA subgroups revealed that refractory and non-refractory active RA patients differed primarily in disease duration (18±11 years vs. 11±12 years, p<0.001) and the utilization of biologic therapy (78% vs. 19%, p<0.001) (Table 1). The concentrations of the 17 markers failed to distinguish refractory from non-refractory RA patients. Non-refractory active RA patients exhibited a robust proinflammatory and proangiogenic serum signature (Figure 1A) with 12 markers correlating with inflammation markers (CRP or ESR) or disease activity. In contrast, active refractory RA patients presented a poor serum signature with only 3 correlations with disease activity markers (Figure 1B). Unexpectedly, the serum profile of refractory RA did not differ from the profile of non-active RA, (Figure 1C). Conclusion: The serum profile observed in refractory RA closely resembles that of non-active RA, despite the existence of clinical and biological signs of disease activity. These results highlight the potential constraints of serum analysis in refractory RA. The lack of correlations between serum markers, CRP, and DAS28, in contrast to active non-refractory RA, may provide insights into the treatment resistance observed in refractory RA, especially in the context of therapies targeting angiogenesis and inflammation molecules. Figure 1. Serum signature in rheumatoid arthritis subgroups. Correlograms of angiogenic and inflammatory markers and clinico-biological data in active non refractory RA (n=85) (A), refractory RA (n=59) (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. Table 1. Patient characteristics. Refractory RA (n=59) Active non refractory RA (n=85) Non active RA (n=67) Age (years), mean ± SD 58 (13) 60 (14) 61 (15) Females, n (%) 51 (86) 65 (76) 48 (72) Disease duration (years), mean ± SD 18 (11 ) 11 (12 ) 14 (14) Positive rheumatoid factor, n (%) 46 (78) 63 (74) 58 (76) Positive anti-CCP antibodies, n (%) 48 (81) 68 (80) 59 (78) Erosions on hand/foot x-rays, n (%) 43 (73 ) 38 (45 ) 39 (51) Treatment Corticosteroid use, n (%) 39 (66) 44 (52) 35 (46) Methotrexate use, n (%) 29 (49) 50 (59) 45 (60) Biological treatment use, n (%) 46 (78 ) 16 (19 ) 28 (42 ) CRP (mg/L), median (IQR) 9 (2,2-22,5 ) 5,8 (1,5-12,6 ) 2,3 (1-5,4) ESR (mm), median (IQR) 35 (16-69) 29 (14-44) 13 (5,3-23) DAS28-CRP, median (IQR) 4,3 (3,8-5,6) 4,2 (3,7-5) 2 (1,5-2,4) DAS28-ESR, median (IQR) 4,9 (4,3-5,7) 4,7 (4,4-5,4) 2,5 (2-2,9) Ultrasound synovitis, n (%) 32/40 (80) 61/77 (79) 17/46 (37) Ultrasoud positive doppler signal, n (%) 31/40 (78) 60/77 (78) 12/46 (26) REFERENCES: NIL. Acknowledgements: We thank all the patients, physicians and nurses of Cochin hospital (Rheumatology department) who helped with the study. We thank the Luminex facilities of the Institut Mondor de Recherche Biomédicale. Disclosure of Interests: None declared. DOI: 10.1136/annrheumdis-2024-eular.2856 Keywords: Biomarkers, Cytokines and Chemokines, Prognostic factors Citation: , volume 83, supplement 1, year 2024, page 1665Session: Rheumatoid arthritis (Publication Only)

Biomarkers, Cytokines and Chemokines, Prognostic factors