Serum IL-17, BMP-7, and bone turnover markers in patients with ankylosing spondylitis.

Metabolic and Renal Function Testing, University Teaching Hospital, Besançon, France
Joint, bone, spine: revue du rhumatisme (Impact Factor: 3.22). 06/2007; 74(3):304-5. DOI: 10.1016/j.jbspin.2006.11.005
Source: PubMed
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    ABSTRACT: Currently, there are only two effective drug classes approved for treatment of ankylosing spondylitis (AS)/axial spondyloarthritis (axSpA): non-steroidal anti-inflammatory drugs (NSAIDs) and, if NSAIDs fail, tumour necrosis factor (TNF)-α blockers. Although the majority of patients do respond well to these treatment options, there is certainly an unmet need for further therapeutic options for patients who do not respond to, do not tolerate or have contraindications for NSAIDs and TNF-α blockers. Blockade of the Th17 pathway that includes inhibition of interleukins (IL)-12/23 and to a further extent IL-17 represent currently the most promising therapeutic targets in axSpA. The first positive results on the blockade of IL-12/23 in active AS should be confirmed in larger placebo-controlled studies, ideally including the entire population of axSpA. It is very important to identify whether IL-12/23 and IL-17 blockade also works in TNF-α blocker non-responders and if there are specific predictors of response to one or another drug class. Also, effects of this therapy on long-term outcomes including progression of structural damage in the spine in AS/axSpA are of high importance and should be evaluated.
    06/2015; 1(2). DOI:10.1007/s40674-015-0021-8
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    ABSTRACT: Uveitis, or intraocular inflammatory disease, is a frequent extra-articular manifestation of several forms of arthritis. Despite the frequent co-occurrence of uveitis and arthritis, little is understood of the eye's predisposition to this disease. We recently described a previously unreported uveitis in a murine model of spondyloarthropathy triggered by autoimmunity to aggrecan, a prominent proteoglycan (PG) macromolecule in cartilage. In contrast to the joint and spine, wherein interferon-gamma (IFNγ) deficiency reduced disease, IFNγ deficiency worsened uveitis. Given the regulatory role of IFNγ on the Th17 response and the current focus of anti-interleukin-17 therapeutics in patients with uveitis and spondyloarthritis, we sought to determine the extent to which interleukin (IL)-17 mediates uveitis in the absence of IFNγ. Antigen specific T cell cytokine production was measured in splenocyte cultures using multiplex-ELISA. Transgenic (Tg) mice expressing the T cell receptor (TCR) recognizing the dominant arthritogenic epitope in the G1 domain of PG (TCR-Tg), also lacking IFNγ, were immunized with PG. Mice were then systemically administered an anti-IL-17 neutralizing antibody. The onset and severity of peripheral arthritis was evaluated by clinical scoring criteria and histology. Uveitis was assessed using intravital videomicroscopy, which visualizes leukocyte trafficking within the vasculature and tissue of the iris, and by histology. TCR-Tg splenocytes stimulated in vitro with recombinant G1 peptide demonstrated exacerbated production of cytokines, such as macrophage inflammatory protein (MIP)-1α, MIP-1β, IL-1β, and most notably IL-17A as a consequence of IFNγ deficiency. In vivo, IL-17 inhibition prevented the component of PG-induced arthritis that occurs independently of IFNγ. Blockade of IL-17 ameliorated the ongoing leukocyte trafficking responses within the iris vasculature and tissue, which coincided with reduced infiltration of leukocytes within the anterior and posterior eye segments. However, the anti-IL-17 treatment resulted in unanticipated photoreceptor toxicity. These data support a protective, regulatory role for IFNγ in suppression of IL-17-mediated intraocular disease and to a lesser extent, joint disease. The unanticipated photoreceptor toxicity raises some caution regarding the use of anti-IL-17 therapeutics until the mechanism of this potential effect is determined.
    Arthritis research & therapy 01/2012; 14(1):R18. DOI:10.1186/ar3697 · 4.12 Impact Factor
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    ABSTRACT: In this study, we analysed the number of IL-17(+) cells in facet joints, in the peripheral blood (PB) and synovial fluid (SF) of spondyloarthritis (SpA) patients and compared these results with those of patients with other rheumatic diseases and controls. Immunohistochemical analysis of IL-17(+) cells was performed in facet joints of 33 ankylosing spondylitis (AS) patients and compared with data from 20 osteoarthritis (OA) patients. The frequency of IL-17(+)CD4(+) T cells in PB and SF of SpA patients (PB n = 30, SF n = 11), rheumatoid arthritis (RA) patients (PB n = 14, SF n = 7), OA patients (PB n = 10) and healthy controls (PB n = 12) was analysed after stimulation with Staphylococcus aureus Enterotoxin B and phorbol 12-myristate 13-acetate/ionomycin and quantified by flow cytometry. In AS facet joints, the frequency of IL-17-secreting cells was significantly higher than in samples obtained from OA patients (P < 0.001), with a slight predominance of IL-17(+) cells among the mononuclear cells (61.5% ± 14.9%) compared to cells with polysegmental nuclei. Immunofluorescence microscopy revealed that the majority of IL-17(+) cells were myeloperoxidase-positive (35.84 ± 13.06/high-power field (HPF) and CD15(+) neutrophils (24.25 ± 10.36/HPF), while CD3(+) T cells (0.51 ± 0.49/HPF) and AA-1(+) mast cells (2.28 ± 1.96/HPF) were less often IL-17-positive. The frequency of IL-17(+)CD4(+) T cells in the PB and SF of SpA patients did not differ significantly compared to RA patients, OA patients or healthy controls. Our data suggest an important role for IL-17 in the inflammatory processes in AS. However, the innate immune pathway might be of greater relevance than the Th17-mediated adaptive immune response.
    Arthritis research & therapy 06/2011; 13(3):R95. DOI:10.1186/ar3370 · 4.12 Impact Factor


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