SAT0081 FOOTPRINT OF THE BRAIN-DERIVED NEUROTROPHIC FACTOR ON PAIN AND MOOD PERCEPTION OF PATIENTS WITH RHEUMATOID ARTHRITIS
Authors: L. Leifsdottir, C. Wasen, M. C. Erlandsson, K. M. Andersson, R. Heckemann, M. I. Bokarewa
Journal: Annals of the Rheumatic Diseases (2020)

Background: Depression and cognitive impairment have been frequently reported in rheumatoid arthritis (RA) (1). Studies of the molecular mechanisms behind these phenomena attract increasing attention. We previously reported that signaling through the insulin-like receptor is impaired in RA and has consequences for pain processing (2). Objectives: We investigated the central and peripheral footprint of the major neurotrophin in the central nervous system, brain-derived neurotrophic factor (BDNF), on pain and mood perception of RA patients. Methods: Pain symptomatology was assessed in 216 female RA patients (mean age 52y, mean disease duration 10 years) by a visual analogue scale (VAS), 18 tender points count (TPC), and by pressure-induced pain threshold measurement. The mood was patient-reported based on the Hospital Anxiety and Depression Scale (HADS). Clinical RA activity was assessed by DAS28. Serum levels of BDNF, IL6, IL1b, IL10 and IFN-gamma were measured by ELISA. Transcription of FOXO1 and FOXO3 was measured by RT-PCR in whole-blood RNA. Effect of BDNF signaling in leukocytes was assessed by differentially expressed gene (DEG) analysis in RNAseq of 24 female RA patients (R-studio, Bioconductor). High-resolution brain MRI was performed in a representative selection of 16 patients. Brain volumes were analyzed with MAPER software for accurate measurement of 83 anatomical regions (3) and compared between two groups of patients with high and low serum BDNF, respectively. Results: In RA patients, high serum levels of BDNF were associated with low TPC (4.1 vs 5.3, p=0.04) and higher pain threshold (kPa, 416 vs 382, p=0.09). No connection between BDNF and mood measures was evident. High BDNF was associated with high serum VEGF (p&lt;0,001), IFNg (p=0.0004), IL1b (p=0.036) and serum insulin (p&lt;0,001), but low resistin (p=0.059). No correlation was found between BDNF with either serum IGF1 or inflammation parameters DAS28 and IL6. Serum BDNF was functional, since the RA patients with high BDNF had significantly larger brain volumes in specific regions and significantly lower FOXO1 mRNA in blood leukocytes (p=0.03). Specifically, structures of the limbic system, parahippocampus, lingual gyrus, nucleus accumbens and thalamus, key regions for the transmission of nociceptive information and central modulation of pain, were enlarged. BDNF production was measured in CD4-CD8- PBMC and was inversely related to expression of its high-affinity receptor TrkB in CD4+ PBMC. DEG analysis in CD4 T cells showed that low TrkB was associated with CD28+ transitional memory phenotype. Conclusion: We conclude that high serum BDNF was associated with larger volumes of nociception-related brain regions and lower pain perception, acting independently of IGF1 and systemic inflammation. References: [1] Dougados M, Curr OppRheumatol 2016 [2] Andersson, Wasen, PNAS2017 [3] Heckemann, NeuroImage 2010 Disclosure of Interests: None declared