Conserved human effector Treg cell transcriptomic and epigenetic signature in arthritic joint inflammation

Treg cells are critical regulators of immune homeostasis, and environment-driven Treg cell differentiation into effector (e)Treg cells is crucial for optimal functioning. However, human Treg cell programming in inflammation is unclear. Here, we combine transcriptional and epigenetic profiling to identify a human eTreg cell signature. Inflammation-derived functional Treg cells have a transcriptional profile characterized by upregulation of both a core Treg cell (FOXP3, CTLA4, TIGIT) and effector program (GITR, BLIMP-1, BATF). We identify a specific human eTreg cell signature that includes the vitamin D receptor (VDR) as a predicted regulator in eTreg cell differentiation. H3K27ac/H3K4me1 occupancy indicates an altered (super-)enhancer landscape, including enrichment of the VDR and BATF binding motifs. The Treg cell profile has striking overlap with tumor-infiltrating Treg cells. Our data demonstrate that human inflammation-derived Treg cells acquire a conserved and specific eTreg cell profile guided by epigenetic changes, and fine-tuned by environment-specific adaptations.

Targeted apoptosis of macrophages and osteoclasts in arthritic joints is effective against advanced inflammatory arthritis

Insufficient apoptosis of inflammatory macrophages and osteoclasts (OCs) in rheumatoid arthritis (RA) joints contributes toward the persistent progression of joint inflammation and destruction. Here, we deliver celastrol (CEL) to selectively induce apoptosis of OCs and macrophages in arthritic joints, with enzyme-responsive nanoparticles (termed PRNPs) composed of RGD modified nanoparticles (termed RNPs) covered with cleavable PEG chains. CEL-loaded PRNPs (CEL-PRNPs) dually target OCs and inflammatory macrophages derived from patients with RA via an RGD-αvβ3 integrin interaction after PEG cleavage by matrix metalloprotease 9, leading to increased apoptosis of these cells. In an adjuvant-induced arthritis rat model, PRNPs have an arthritic joint-specific distribution and CEL-PRNPs efficiently reduce the number of OCs and inflammatory macrophages within these joints. Additionally, rats with advanced arthritis go into inflammatory remission with bone erosion repair and negligible side effects after CEL-PRNPs treatment. These findings indicate potential for targeting chemotherapy-induced apoptosis in the treatment of advanced inflammatory arthritis.

Musculoskeletal system

The chapter entitled ‘Musculoskeletal system’ summarizes the parts of the connective and skeletal tissues—connective tissue, cartilage, and bone—before looking in more detail at the anatomy of the upper and lower limbs and the spine, including the bones, joints, muscles, innervation, and blood vessels. The chapter provides comprehensive summaries of the bones of the skeleton, their function and anatomical arrangement as well as the muscles involved in movements of different joints and their innervation and anatomical arrangement. The pathology of the musculoskeletal system is discussed, including arthritic joint disease, muscular dystrophies, and atrophy due to disuse.

THU0441 DIAGNOSTIC ACCURACY OF THE NIJMENGEN SCORE FOR GOUTY ARTHRITIS IN PATIENTS HOSPITALIZED FOR ACUTE MONOARTHRITIS

Background:The gold-standard for diagnosis of gout is the identification of monosodium urate (MSU) crystal in joint fluid. However, the sensitivity, specificity, and reproducibility of such analysis are not excellent, and joint aspiration is sometimes difficult, or impossible. The Nijmengen score is an easy-to-use rule without joint fluid analysis with excellent validity, in primary as well as in secondary care (1, 2). However, it’s validity as not been evaluated in the particular situation of patients whose acute arthritis necessitates hospitalization.Objectives:The objective of the present study was to assess diagnosis performances of the score in patients hospitalized for acute monoarthritis.Methods:Inclusion: all patients hospitalized for acute monoarthritis in the rheumatology department of the Dijon University Hospital between 2016 and 2019.Assessment: 1- clinical examination by an experimented rheumatologist; 2- joint aspiration and synovial fluid analysis following aspiration; 3- ultrasound (US) examination of the knees, first metatarso-phalangeal joints, and arthritic joint by a trained rheumatologist; 4- dual-energy computed tomography (DECT) of the arthritic joint; 5- Nijmengen score (cutoff scores of ≥ 8 needed for diagnosis of gout, and ≤ 4 to rule out gout) and ACR/EULAR 2015 classification criteria (3) (cut-off score of ≥ 8 needed for diagnosis of gout).Analysis: positive and negative predictive values, and ROC curve analysis of the Nijmengen score, using as gold-standard on one hand the results of the MSU crystal research, on the other hand those of the ACR/EULAR criteria.Results:A total of 39 patients were included (mean age = 69.8 ± 15 years, 74.4 % males, mean BMI = 27.5 ± 4.6 Kg/m2, mean serum uric acid = 354.6 ± 117.5 µmol/l). The affected joints were the knee (n = 31), ankle (n = 3), hip (n = 2), wrist (n = 2), shoulder (n = 1). Joint fluid analysis revealed MSU crystal in 11 patients. The ACR/EULAR was ≥ 8 in 15 patients. The Nijmengen score was ≥ 8 in 11 patients, including 5 with MSU crystal on joint fluid analysis and 9 with an ACR/EULAR score ≥ 8. The Nijmengen score was ≤ 4 in 15 patients, including 14 with no MSU crystal on joint fluid analysis and 14 with an ACR/EULAR score < 8. The positive predictive values of a Nijmengen score ≥ 8 were 45 % (joint fluid analysis as gold standard) and 81.8 % (ACR/EULAR). The negative predictive values of a Nijmengen score ≤ 4 were 93.3 % (joint fluid analysis and ACR/EULAR as gold standard). On ROC curve analyses, the areas under the curve were 0.763 (95% CI = 0.612 – 0.914) using joint fluid analysis as gold standard (figure 1) and 0.908 (95% CI = 0.814 – 1.0) using the ACR/EULAR score as gold standard (figure 2).Fig. 1ROC curve (fluid analysis as gold standard)Fig. 2Roc curve (ACR/EULAR as gold standard)Conclusion:Although having been developed for use in primary-care, the Nijmengen score appears to be useful in patients hospitalized for acute monoarthritis in a rheumatology unit.References:[1]Janssens et al. A diagnostic rule for acute gouty arthritis in primary care without joint fluid analysis. Arch Intern Med 2010; 170:1120-6.[2]Kienhorst L et al. The validation of a diagnostic rule for gout without joint fluid analysis: a prospective study. Rheumatology 2015; 54:609-14.[3]Neogi T et al. 2015 Gout Classification Criteria: An American College of Rheumatology/European League Against Rheumatism Collaborative Initiative: ACR/EULAR CLASSIFICATION CRITERIA FOR GOUT. Arthritis and Rheumatology. oct 2015;67(10):2557-68.Disclosure of Interests: :marie Schmitt: None declared, André Ramon: None declared, Paul Ornetti: None declared, jean Francis Maillefert Grant/research support from: Abbot, shugai, Roche, pfiser, BMS,, Speakers bureau: Abbot, Shugai, Roche, Pfiser, BMS

Igniting the flame in arthritis: C5aR2 controls endothelial transcytosis of C5a

C5aR2 transports C5a generated in the arthritic joint to the blood vessel endothelium as the first step in C5aR1-driven neutrophil arrest and crawling.