Adenosine deaminase modulates metabolic remodeling and orchestrates joint destruction in rheumatoid arthritis.

Rheumatoid Arthritis (RA) is a chronic autoimmune disease associated with inflammation and joint remodeling. Adenosine deaminase (ADA), a risk factor in RA, degrades adenosine, an anti-inflammatory molecule, resulting in an inflammatory bias. We present an integrative analysis of clinical data, cytokines, serum metabolomics in RA patients and mechanistic studies on ADA-mediated effects on in vitro cell culture models. ADA activity differentiated patients into low and high ADA sets. The levels of the cytokines TNFα, IFNγ, IL-10, TGFß and sRANKL were elevated in RA and more pronounced in high ADA sets. Serum metabolomic analysis shows altered metabolic pathways in RA which were distinct between low and high ADA sets. Comparative analysis with previous studies shows similar pathways are modulated by DMARDs and biologics. Random forest analysis distinguished RA from control by methyl-histidine and hydroxyisocaproic acid, while hexose-phosphate and fructose-6-phosphate distinguished high ADA from low ADA. The deregulated metabolic pathways of High ADA datasets significantly overlapped with high ADA expressing PBMCs GEO transcriptomics dataset. ADA induced the death of chondrocytes, synoviocyte proliferation, both inflammation in macrophages and their differentiation into osteoclasts and impaired differentiation of mesenchymal stem cells to osteoblasts and mineralization. PBMCs expressing elevated ADA had increased expression of cytokines and P2 receptors compared to synovial macrophages which has low expression of ADA. Our data demonstrates increased cytokine levels and distinct metabolic signatures of RA based on the ADA activity, suggests an important role for ADA in the pathophysiology of RA joints and as a potential marker and therapeutic target in RA patients.

Periodontal disease is significantly higher in non-smoking treatment-naive rheumatoid arthritis patients: results from a case-control study.

OBJECTIVE: To find the strength of association between periodontal disease (PD) and rheumatoid arthritis (RA) in non-smoking, disease modifying antirheumatic drug (DMARD)-naive RA patients in a case-control design. METHODS: Patients of RA (DMARD-naive, non-smokers) satisfying the American college of Rheumatology 1987 criteria and healthy controls were included. PD was defined as present if the mean pocket depth (MPD) is ≥3 mm. Demographic data and disease specific variables were recorded for RA patients and healthy controls. Titres of immunoglobulin M-rheumatoid factor (IgM-RF) and anticitrullinated peptide antibodies (ACPAs) were measured using ELISA. RESULTS: Patients with RA (n=91) had a 4.28 (CI 2.35 to 7.38) higher odds of PD (64.8% vs 28%, p<0.001) compared with healthy controls (n=93). The MPD was 3.61±1.22 mm in cases and 2.46±0.74 mm in controls (p<0.001). IgM-RF titres (110.56±95.81 vs 66.53±70.29; p=0.02) and ACPA titres (753.05±1088.27 vs 145.15±613.16, p=0.001) were significantly higher in RA patients with PD than those without PD. The MPD positively correlated with titres of ACPAs in RA patients (r=0.24; p=0.02). CONCLUSIONS: PD is more frequent and severe in non-smoking DMARD-naive RA patients compared with healthy controls. PD in RA is associated with high titres of ACPAs.