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Introduction: Spondyloarthritis (SpA) is characterized by inflammation, articular bone erosions and pathologic new bone formation. Targeting TNFα or IL-17A with current available therapies reduces inflammation in SpA, however, treatment of the bone pathology in SpA remains an unmet clinical need. Activation of the mammalian target Of rapamycin (mTOR) promotes IL-17A expression and osteogenesis. Therefore, the inhibition of mTOR (with rapamycin) could be a promising therapeutic avenue in SpA. Objectives: To investigate the effect of blocking mTOR on inflammation, bone erosions and new bone formation in SpA. Methods: Peripheral blood mononuclear cells (PBMCs) from patients with SpA were stimulated with anti-CD3/CD28 in the presence or absence of rapamycin and the resulting cytokine expression was assessed. Fibroblast-like synoviocytes (FLS) from SpA patients were assessed for osteogenic differentiation potential in conditions with TNFα, IL-17A, or TNFα plus IL-17A, in the presence or absence of rapamycin. HLA-B27/Huβ2m transgenic rats were immunized with low dose heat-inactivated Mycobacterium tuberculosis (M. tub), treated with 1.5 mg/kg rapamycin prophylactically or therapeutically and monitored for arthritis and spondylitis. Histology and mRNA analysis were performed after 5 weeks of treatment to assess inflammation and bone pathology. Results: In vitro TNFα and IL-17A protein production by SpA PBMCs was inhibited in the presence of rapamycin. Rapamycin also inhibited osteogenic differentiation of human SpA FLS. Ex vivo analysis of SpA synovial biopsies indicated activation of the mTOR pathway in the synovial tissue of SpA patients. In vivo, prophylactic treatment of HLA-B27/Huβ2m transgenic rats with rapamycin significantly inhibited the development and severity of inflammation in peripheral joints and spine (arthritis and spondylitis), with histological evidence of reduced bone erosions and new bone formation around peripheral joints. In addition, therapeutic treatment with rapamycin significantly decreased severity of arthritis and spondylitis, with peripheral joint histology showing reduced inflammation, bone erosions and new bone formation. IL-17A mRNA expression was decreased in the metacarpophalangeal joints after rapamycin treatment. Conclusion: mTOR blockade inhibits IL-17A and TNFα production by PBMCs, and osteogenic differentiation of FLS from patients with SpA in vitro. In the HLA-B27 transgenic rat model of SpA, rapamycin inhibits arthritis and spondylitis development and severity, reduces articular bone erosions, decreases pathologic new bone formation and suppresses IL-17A expression. These results may support efforts to evaluate the efficacy of targeting the mTOR pathway in SpA patients.

We aimed to assess the mRNA expression of MHC class 1-related molecules in ankylosing spondylitis (AS) patients vs healthy controls (HCs) and, subsequently, if the absence of HLA-C*07 is associated with genetic susceptibility to axial spondyloarthritis (axSpA). HLA-C*07 was assessed in (a) an exploratory cohort of 24 AS patients vs 40 HCs, (b) a confirmatory cohort of 113 AS patients and 83 non-radiographic axSpA patients from the GErman SPondyloarthritis Inception Cohort (GESPIC) vs 134,528 German potential stem cell donors, and (c) an early back pain cohort with 94 early axSpA patients vs 216 chronic back pain (CBP) patients from the SPondyloArthritis Caught Early (SPACE) cohort. In the exploratory cohort, 79% of the AS patients were HLA-C*07 negative compared to 35% of the HCs (p < 0 .001). This difference was confirmed in GESPIC with 73% of AS patients being HLA-C*07 negative compared to 50% of the controls (p < 0.0001); 59% of the nr-axSpA patients were HLA-C*07 negative. In the SPACE cohort, 70% of the axSpA patients were HLA-C*07 negative compared to 44% of CBP patients (p < 0.0001); the association between HLA-C*07 negativity and a diagnosis of axSpA was independent from HLA-B*27. In conclusion, the absence of HLA-C*07 is associated with genetic susceptibility to axSpA.

Objectives Epigenetic modifications play an important role in the regulation of gene transcription and cellular function. Here, we examined if pro-inflammatory factors present in the inflamed joint of patients with rheumatoid arthritis (RA) could regulate histone deacetylase (HDAC) expression and function in fibroblast-like synoviocytes (FLS). Methods Protein acetylation in synovial tissue was assessed by immunohistochemistry. The mRNA levels of HDAC family members and inflammatory mediators in the synovial tissue and the changes in HDAC expression in RA FLS were measured by quantitative (q) PCR. FLS were either transfected with HDAC5 siRNA or transduced with adenoviral vector encoding wild-type HDAC5 and the effects of HDAC5 manipulation were examined by qPCR arrays, ELISA and ELISA-based assays. Results Synovial class I HDAC expression was associated with local expression of tumour necrosis factor (TNF) and matrix metalloproteinase-1, while class Ila HDAC5 expression was inversely associated with parameters of disease activity (erythrocyte sedimentation rate, C-reactive protein, Disease Activity Score in 28 Joints). Interleukin (IL)-1 beta or TNF stimulation selectively suppressed HDAC5 expression in RA FLS, which was sufficient and required for optimal IFNB, CXCL9, CXCL10 and CXCL11 induction by IL-1 beta, associated with increased nuclear accumulation of the transcription factor, interferon regulatory factor 1(IRF1). Conclusions Inflammatory cytokines suppress RA FLS HDAC5 expression, promoting nuclear localisation of IRF1 and transcription of a subset of type I interferon response genes. Our results identify HDAC5 as a novel inflammatory mediator in RA, and suggest that strategies rescuing HDAC5 expression in vivo, or the development of HDAC inhibitors not affecting HDAC5 activity, may have therapeutic applications in RA treatment

To investigate whether seemingly healthy first-degree relatives of patients with ankylosing spondylitis (AS) have clinical, laboratory, or imaging features of spondyloarthritis (SpA).First-degree relatives (ages 18-40 years) of HLA-B27-positive AS patients were included in the pre-spondyloarthritis (Pre-SpA) cohort, a prospective inception cohort study. Clinical, biologic, and imaging features were recorded. First-degree relatives were classified according to several sets of SpA classification criteria.We report baseline features of 51 first-degree relatives included in this study. Twenty-nine (57%) had back pain, 2 (4%) had psoriasis, 1 (2%) had inflammatory bowel disease, and 1 (2%) had uveitis. Three (6%) had low-grade sacroiliitis, 1 (2%) had cervical syndesmophytes on radiography, and 10 (20%) had bone marrow edema on magnetic resonance imaging of the sacroiliiac joints. Seventeen of 51 first-degree relatives (33%) fulfilled SpA classification criteria: 7 (14%) fulfilled both Assessment of SpondyloArthritis international Society (ASAS) axial SpA and European Spondylarthropathy Study Group (ESSG) classification criteria, 6 (12%) fulfilled only ASAS axial SpA classification criteria, and 4 (8%) fulfilled only ESSG classification criteria; 3 (6%) also fulfilled the Amor criteria. None fulfilled other SpA classification criteria. First-degree relatives fulfilling the ASAS axial SpA and/or ESSG classification criteria had more frequent inflammatory back pain, had a higher level of disease activity, and had more psoriasis. No differences were found in parameters of inflammation, peripheral and extraarticular disease other than psoriasis, and HLA-B27 positivity between those who did and those who did not fulfill the ASAS axial SpA and/or ESSG classification criteria. Four first-degree relatives (12%) who did not fulfill the ASAS axial SpA and/or ESSG classification criteria had imaging abnormalities suggestive of SpA.A substantial proportion of seemingly healthy first-degree relatives of HLA-B27-positive AS patients have clinical and/or imaging abnormalities suggestive of SpA. Thirty-three percent could be classified as having SpA. Further follow-up will show which first-degree relatives will develop clinically manifest SpA.

To examine whether the citrullinated chemokines epithelial neutrophil-activating peptide 78 (ENA-78)/CXCL5, macrophage inflammatory protein 1α/CCL3, and monocyte chemotactic protein 1/CCL2 are detected in the biologic fluid of patients with rheumatoid arthritis (RA), and if so, to determine the biologic activities of these chemokines.Recombinant human chemokines were citrullinated by peptidylarginine deiminase. Enzyme-linked immunosorbent assays were performed to measure the concentrations of citrullinated chemokines in sera from patients with rheumatoid arthritis (RA) and normal individuals and in synovial fluid from patients with RA, patients with osteoarthritis (OA), and patients with other inflammatory rheumatic diseases. The correlation between the citrullinated chemokine levels and clinical data was analyzed. Monocyte and neutrophil chemotaxis assays were performed, and native (noncitrullinated) or citrullinated ENA-78/CXCL5 was injected into mouse knees to evaluate the biologic activities of these chemokines.The concentration of citrullinated ENA-78/CXCL5 was significantly higher in RA sera and SF than in normal sera and in SF from patients with other rheumatic diseases including OA. In RA SF, a strong correlation between the amount of citrullinated ENA-78/CXCL5 and the C-reactive protein level or the erythrocyte sedimentation rate was observed. Citrullinated ENA-78/CXCL5 induced monocyte chemotaxis via CXCR1 and CXCR2, while noncitrullinated ENA-78/CXCL5 did not. In a mouse model of inflammatory arthritis, citrullinated ENA-78/CXCL5 induced more severe inflammation and recruited more monocytes than did noncitrullinated ENA-78/CXCL5.Citrullinated ENA-78/CXCL5 is highly correlated with RA disease activity and, unlike noncitrullinated ENA-78/CXCL5, recruits monocytes. These results indicate that citrullinated ENA-78/CXCL5 may exert previously unrecognized inflammatory properties in RA by recruiting monocytes to inflamed joint tissue.