What do biomarkers tell us about the pathogenesis of ankylosing spondylitis?
ABSTRACT Biomarkers may provide information that promotes understanding of prognosis, disease activity, and pathogenesis in ankylosing spondylitis. Biomarkers reflecting disease activity (metallo-proteinase-3) and inflammatory lesions on magnetic resonance imaging predict new bone formation and are ameliorated by anti-tumor necrosis factor therapy, yet this treatment may not prevent new bone formation. Moreover, elevated levels of biomarkers reflecting tissue repair (bone-specific alkaline phosphatase) post-treatment together with magnetic resonance imaging indicates such treatment may even promote repair through new bone formation. Tumor necrosis factor regulation of Dickkopf-1 may constitute a molecular brake that controls osteoblastogenesis through wingless and bone morphogenetic proteins in an established inflammatory lesion in ankylosing spondylitis.
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ABSTRACT: Ankylosing spondylitis (AS) is a chronic rheumatic disease associated with spinal inflammation that subsequently leads to progression of structural damage and loss of function. The fully human anti-tumor necrosis factor (anti-TNF) antibody adalimumab reduces the signs and symptoms and improves overall quality of life in patients with active AS; these benefits have been maintained through 2 years of treatment. Our objective was to compare the progression of structural damage in the spine in patients with AS treated with adalimumab for up to 2 years versus patients who had not received TNF antagonist therapy. Radiographs from patients with AS who received adalimumab 40 mg every other week subcutaneously were pooled from the Adalimumab Trial Evaluating Long-Term Efficacy and Safety for Ankylosing Spondylitis (ATLAS) study and a Canadian AS study (M03-606). Radiographic progression from baseline to 2 years in the spine of adalimumab-treated patients from these two studies (adalimumab cohort, n = 307) was compared with an historic anti-TNF-naïve cohort (Outcome in AS International Study [OASIS], n = 169) using the modified Stoke AS Spine Score (mSASSS) method. mSASSS results were not significantly different between the adalimumab cohort and the OASIS cohort, based on baseline and 2-year radiographs. Mean changes in mSASSS from baseline to 2 years were 0.9 for the OASIS cohort and 0.8 for the adalimumab cohort (P = 0.771), indicating similar radiographic progression in both groups. When results for patients in the OASIS cohort who met the baseline disease activity criteria for the ATLAS and Canadian studies (OASIS-Eligible cohort) were analyzed, there was no significant difference in mean change in mSASSS from baseline to 2 years between OASIS-Eligible patients and adalimumab-treated patients; the mean changes in mSASSS were 0.9 for the OASIS-Eligible cohort and 0.8 for the adalimumab cohort (P = 0.744). Two years of treatment with adalimumab did not slow radiographic progression in patients with AS, as assessed by the mSASSS scoring system, when compared with radiographic data from patients naïve to TNF antagonist therapy.Arthritis research & therapy 09/2009; 11(4). DOI:10.1186/ar2794 · 4.12 Impact Factor
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ABSTRACT: Dkk-1 is an inhibitory molecule that regulates the Wnt pathway, which controls osteoblastogenesis. This study was undertaken to explore the potential role of Dkk-1 in ankylosing spondylitis (AS), a prototypical bone-forming disease. Serum Dkk-1 levels were measured in 45 patients with AS, 45 patients with rheumatoid arthritis (RA), 15 patients with psoriatic arthritis (PsA), and 50 healthy subjects by sandwich enzyme-linked immunosorbent assay (ELISA). A functional ELISA was used to assess the binding of Dkk-1 to its receptor (low-density lipoprotein receptor-related protein 6). Furthermore, we studied the effect of sera from patients with AS and healthy subjects on the activity of the Wnt pathway in the Jurkat T cell model, with and without a neutralizing anti-Dkk-1 monoclonal antibody, by Western immunoblotting. Serum Dkk-1 levels were significantly increased in patients with AS (mean +/- SEM 2,730 +/- 135.1 pg/ml) as compared with normal subjects (P = 0.040), patients with RA (P = 0.020), and patients with PsA (P = 0.049). Patients with AS receiving anti-tumor necrosis factor alpha (anti-TNFalpha) treatment had significantly higher serum Dkk-1 levels than patients with AS not receiving such treatment (P = 0.007). Patients with AS studied serially prior to and following anti-TNFalpha administration exhibited a significant increase in serum Dkk-1 levels (P = 0.020), in contrast to patients with RA, who exhibited a dramatic decrease (P < 0.001). Jurkat cells treated with serum from AS patients exhibited increased Wnt signaling compared with cells treated with control serum. In that system, Dkk-1 blockade significantly enhanced Wnt signaling in control serum-treated, but not AS serum-treated, Jurkat T cells. Our findings indicate that in patients with AS, circulating bone formation-promoting factors functionally prevail. This can be at least partially attributed to decreased Dkk-1-mediated inhibition.Arthritis & Rheumatology 01/2010; 62(1):150-8. DOI:10.1002/art.27231 · 7.87 Impact Factor
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ABSTRACT: Spondyloarthritis (SpA) refers to a spectrum of immune-mediated inflammatory diseases with overlapping features, which differ from other types of inflammatory arthritis in genetic predisposition, pathogenesis and outcome. SpA frequently involves the axial skeleton, and can result in abnormal bone formation with eventual ankylosis of the spine, resulting in substantial disability. SpA often begins as an 'undifferentiated' disease, the presentation of which differs in children and adults; most notably, spinal involvement is uncommon, while hip arthritis and enthesitis are frequently seen in juvenile-onset disease. Currently, the classification of SpA in adults and children is approached differently. Using the International League of Associations for Rheumatology (ILAR) system for juvenile idiopathic arthritis, most childhood SpA is classified as enthesitis-related arthritis. However, in contrast to adult SpA classification, the presence of, or a family history of, psoriasis dictates a separate category of juvenile idiopathic arthritis. More importantly, the ILAR system does not specifically recognize the presence of axial disease in juvenile SpA. Resolution of these issues will improve communication and the transitioning of patients from pediatric to adult clinics, will facilitate research in genetics and pathogenesis, and will be particularly important in the evaluation of tumor necrosis factor inhibitors and other biologic agents for early, axial SpA.Nature Reviews Rheumatology 08/2010; 6(8):477-85. DOI:10.1038/nrrheum.2010.103 · 10.25 Impact Factor