AB0052 INFLAMMATORY PROTEOMIC SIGNATURE RELATED TO DECREASED FERTILITY IN WOMEN WITH RHEUMATOID ARTHRITIS
Authors: M. Bongenaar, H. T. Smeele, E. Lubberts, R. Dolhain
Journal: Annals of the Rheumatic Diseases (2021)

Background: Fertility issues are common in women with rheumatoid arthritis (RA). Decreased fertility in these patients is associated with high disease activity and the use of certain medication [1]. However, immunological mechanisms behind this phenomenon remain unresolved. Objectives: This study aims to identify inflammation-related proteins associated with decreased fertility in women with rheumatoid arthritis and a wish to conceive. Methods: Patients were derived from the PARA-study, a prospective cohort on RA and pregnancy. High-multiplex immunoassay technology with qPCR readout (Olink Proteomics, Uppsala, Sweden) was used to assess 92 inflammation-related proteins in serum obtained before pregnancy of 186 women with RA and a wish to conceive. Measured protein levels were imputed into multivariable cox regression models with time to pregnancy (TTP) as dependent variable. This model was corrected for known confounders age, nulliparity, NSAID use, prednisone use and past methotrexate use [2]. Results: Our analyses show prolonged TTP to be associated with increased expression of pro-inflammatory cytokines (TNF, IL-6, IL-18), chemokines (CCL23, CCL19, CXCL10, MCP-3, CXCL9) and T cell stimulating factors (TNFRSF9, CDCP-1). Furthermore, increased factors associated with angiogenesis (VEGF-A) and bone and collagen damage (RANKL, MMP-1) were found. Lastly, decreased fertility is associated with increased immune regulatory factors (IL-10, IL10RB, PD-L1). After false discovery rate (FDR) correction for multiple testing, IL-10, CCL23, MCP-3 and CDCP-1 remained statistically significant (adjusted P&lt;0.05). Results are depicted in table 1. Conclusion: This study shows a pro-inflammatory proteomic signature, including a counterbalance of increased immune regulatory proteins, to be associated with prolonged TTP. These findings provide more insight into the immunological pathways involved in fertility in RA patients. References: [1]Smeele HTW, Dolhain R. Current perspectives on fertility, pregnancy and childbirth in patients with Rheumatoid Arthritis. Semin Arthritis Rheum. 2019;49(3S):S32-S5. [2]Brouwer J, Hazes JM, Laven JS, Dolhain RJ. Fertility in women with rheumatoid arthritis: influence of disease activity and medication. Ann Rheum Dis. 2015;74(10):1836-41. Table 1. Significant multivariable cox regression results with time to pregnancy as dependent variable, corrected for age, nulliparity, NSAID use, prednisone use and past MTX use. HR = hazard ratio, FDR = false discovery rate. Protein HR P P FDR adjusted Function IL-10 0,64 0,001 0,026 Immune regulatory CCL23 0,51 0,001 0,026 T cell/monocyte migration MCP-3 0,74 0,001 0,026 Monocyte migration CDCP1 0,56 0,002 0,039 T cell migration CCL19 0,77 0,005 0,077 DC/T cell/B cell migration TNFRSF9 0,63 0,007 0,090 T cell costimulator VEGF-A 0,7 0,014 0,154 Angiogenesis CXCL10 0,82 0,021 0,185 T cell/monocyte/NK/DC migration RANKL 0,76 0,022 0,185 Osteoclast activation, DC survival IL-6 0,88 0,024 0,185 Pro-inflammatory cytokine, stimulation of acute phase response PD-L1 0,55 0,027 0,189 Immune suppression IL-18 0,7 0,035 0,193 Type 1 response activator IL-7 0,69 0,038 0,208 Lymphocyte maturation IL-10RB 0,48 0,039 0,208 IL-10 receptor MMP-1 0,73 0,045 0,208 Collagen breakdown TNF 0,44 0,048 0,208 Pro-inflammatory cytokine, necrosis CXCL9 0,26 0,049 0,208 Th1 polarization Acknowledgements: The authors are grateful to all patients who participated in the PARA study. Additionally, they thank Yaël de Man, Fleur van de Geijn, Esther Gasthuis, Florentien de Steenwinkel, Jenny Brouwer and all laboratory workers and research assistants for their contribution to the data collection. Disclosure of Interests: Margot Bongenaar: None declared, Hieronymus TW Smeele: None declared, Erik Lubberts Grant/research support from: CHDR, Galapagos, Radboud Dolhain Speakers bureau: Yes, for UCB, Roche, Abbvie, Genzyme, Novartis, Consultant of: Yes, Galapagos, Grant/research support from: Yes, UCB