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Introduction: Haemophilia (HA) and rheumatoid arthritis (RA) patients may develop joint damage caused by recurrent joint bleedings in HA or by chronic inflammation in RA. Only few data exist for biomarker studies in these patients.
Aim: The objective of the present study is to assess a large array of biomarkers in peripheral blood samples obtained from HA patients without or with arthropathy and to compare pattern to RA patients and healthy controls.
Methods: A panel of biomarkers was assessed in 129 men (40 HA patients without arthropathy, 23 HA patients with arthropathy, 23 RA patients and 43 control subjects). 37 different biomarkers (cytokines, angiogenesis‐related proteins) were analysed using a multiple analyte profiling technology and supplemented by acute phase proteins, coagulation and immunological parameters.
Results: Evidence for systemic inflammation was obtained by increased acute phase reactants in all patient groups. 13 or 14 from 42 soluble parameters demonstrated significant differences (p < .05) between HA patients without arthropathy and healthy controls, or between HA patients with arthropathy and healthy controls, respectively. Largely overlapping patterns were obtained except for interleukin‐7 being increased in HA patients without arthropathy and being decreased in HA in the presence of arthropathy.
Conclusions: In addition to data supporting systemic inflammation, we provide evidence for a common biomarker profile in HA patients and RA patients compared to healthy controls. A distinctive biomarker profile for HA patients with arthropathy did not appear except for interleukin‐7 demonstrating specific changes depending on the absence or presence of arthropathy in HA patients.
Background: Synovial fibroblasts (SF) play a major role in the pathogenesis of rheumatoid arthritis (RA) and develop an aggressive phenotype destroying cartilage and bone, thus termed RASF. JAK inhibitors have shown to be an efficient therapeutic option in RA treatment, but less is known about the effect of JAK inhibitors on activated RASF. The aim of the study was to examine the effects of JAK inhibitors on activated RASF.
Methods: Synovium of RA patients was obtained during knee replacement surgeries. Synoviocytes were isolated and pretreated with JAK inhibitors. Pro-inflammatory cytokines and matrix degrading proteinases were measured by ELISA in supernatant after stimulation with oncostatin M or IL-1β. The proliferation of RASF was measured by BrdU incorporation. Cell culture inserts were used to evaluate cell migration. For adhesion assays, RASF were seeded in culture plates. Then, plates were extensively shaken and adherent RASF quantified. Cell viability, cytotoxicity and apoptosis were measured using the ApoTox-Glo™ Triplex and the CellTox™ Green Cytotoxicity Assay.
Results: Tofacitinib and baricitinib decreased the IL-6 release of RASF stimulated with oncostatin M. JAK inhibition attenuated the IL-6 release of IL-1β activated and with soluble IL-6 receptor treated RASF. In contrast, only peficitinib and filgotinib decreased the IL-6 release of RASF activated with IL-1β. Peficitinib decreased also the MMP-3, CXCL8, and CXCL1 release at 5 μM. Moreover, peficitinib was the only JAK inhibitor suppressing proliferation of activated RASF at 1 μM. Peficitinib further decreased the migration of RASF without being cytotoxic or pro-apoptotic and without altering cell adhesion.
Conclusions: JAK inhibitors effectively suppress the inflammatory response induced by oncostatin M and by transsignaling of IL-6 in RASF. Only peficitinib modulated the IL-1β-induced response of RASF and their proliferation in vitro at concentrations close to reported Cmax values of well tolerated doses in vivo. In contrast to filgotinib, peficitinib also highly suppressed RASF migration showing the potential of peficitinib to target RASF.
An excess of the proinflammatory substance IL-18 is present in joints of patients with rheumatoid arthritis (RA), and expression of IL-18 receptor (IL-18R) regulates IL-18 bioactivity in various cell types. We examined the expression of IL-18R alpha-chain and beta-chain and the biologic effects of IL-18 in fibroblast-like synoviocytes (FLS) after long-term culture. The presence of both IL-18R chains was a prerequisite for IL-18 signal transduction in FLS. However, all FLS cultures studied were either resistant or barely responsive to IL-18 stimulation as regards cell proliferation, expression of adhesion molecules ICAM-1 and vascular cell adhesion molecule (VCAM)-1, and the release of interstitial collagenase and stromelysin, IL-6 and IL-8, prostaglandin E2, or nitric oxide. We conclude that the presence of macrophages or IL-18R+ T cells that can respond directly to IL-18 is essential for the proinflammatory effects of IL-18 in synovitis in RA. Open Access: Published: 14 November 2001 © 2002 Möller et al., licensee BioMed Central Ltd (Print ISSN 1465-9905; Online ISSN 1465-9913)