Abstract
Key challenges in the management of spondyloarthritis focus on the lack of availability of measures of disease activity and the inability to predict joint damage or response to treatment, which is expensive and associated with potentially serious toxicity. Recent studies have focused on the possible contribution of soluble biomarkers, which have been selected based on current understanding of their role in inflammation and/or their association with turnover of joint matrix. Emerging candidates for disease activity markers include interleukin-6 and soluble cytotoxic T lymphocyte associated molecule-4. Potential predictors of damage include metalloproteinase-3 and sclerostin. Acute-phase reactants C-reactive protein and serum amyloid A and interleukin-6 are currently the best predictors of treatment response. Significant study limitations are small sample size and the lack of multivariate analyses that can determine whether the biomarker contributes information that is independent of other clinical and laboratory variables used in routine care.
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van der Heijde DM, Wanders A, Mielants H, et al.: Prediction of progression of radiographic damage over 4 years in patients with ankylosing spondylitis [abstract]. Ann Rheum Dis 2004, 63:OP132.
Maksymowych WP, Chiowchanwisawakit P, Clare T, et al.: Inflammatory lesions of the spine on MRI predict the development of new syndesmophytes in ankylosing spondylitis: evidence for coupling between inflammation and ankylosis. Arthritis Rheum 2009, 60:93–102.
•• Rudwaleit M, Claudepierre P, Wordsworth P, et al.: Effectiveness, safety, and predictors of good clinical response in 1250 patients treated with adalimumab for active ankylosing spondylitis. J Rheumatol 2009, 36:801–808. This was a large, open-label analysis of the efficacy and safety of adalimumab in real world practice that also examined clinical and laboratory parameters used in routine care as predictors of treatment response.
Rudwaleit M, Listing J, Brandt J, et al.: Prediction of a major clinical response (BASDAI 50) to tumor necrosis factor a blockers in ankylosing spondylitis. Ann Rheum Dis 2004, 63:665–670.
• Rudwaleit M, Schwarzlose S, Hilgert ES, et al.: MRI in predicting a major clinical response to anti-tumor necrosis factor treatment in ankylosing spondylitis. Ann Rheum Dis 2008, 67:1276–1281. This is one of the few studies that has incorporated MRI data for inflammation into a prediction model for treatment response.
van der Heijde D, Kivitz A, Schiff MH, et al.: Efficacy and safety of adalimumab in patients with ankylosing spondylitis: results of a multicenter, randomized, double-blind, placebo-controlled trial. Arthritis Rheum 2006, 54:2136–2146.
Bollow M, Fischer T, Reisshauer H, et al.: Quantitative analyses of sacroiliac biopsies in spondylarthropathies: T cells and macrophages predominate in early and active sacroiliitis—cellularity correlates with the degree of enhancement detected by magnetic resonance imaging. Ann Rheum Dis 2000, 59:135–140.
Appel H, Loddenkemper C, Grozdanovic Z, et al.: Correlation of histopathological findings and magnetic resonance imaging in the spine of patients with ankylosing spondylitis. Arthritis Res Ther 2006, 8:R143.
Lambert RGW, Salonen D, Rahman P, et al.: Adalimumab significantly reduces both spinal and sacroiliac joint inflammation in patients with ankylosing spondylitis. Arthritis Rheum 2007, 56:4005–4014.
Jung SY, Park MC, Park YB, Lee SK: Serum amyloid a as a useful indicator of disease activity in patients with ankylosing spondylitis. Yonsei Med J 2007, 48:218–224.
Poddubnyy DA, Rudwaleit M, Listing J, et al.: Comparison of a high sensitivity and standard C reactive protein measurement in patients with ankylosing spondylitis and non-radiographic axial spondyloarthritis. Ann Rheum Dis 2010, 69:1338–1341.
Bal A, Unlu E, Bahar G, et al.: Comparison of serum IL-1 beta, sIL-2R, IL-6, and TNF-alpha levels with disease activity parameters in ankylosing spondylitis. Clin Rheumatol 2007, 26:211–215.
Keller C, Webb A, Davis J: Cytokines in the seronegative spondyloarthropathies and their modification by TNF blockade: a brief report and literature review. Ann Rheum Dis 2003, 62:1128–1132.
• Visvanathan S, Wagner C, Marini JC, et al.: Inflammatory biomarkers, disease activity and spinal disease measures in patients with ankylosing spondylitis after treatment with infliximab. Ann Rheum Dis 2008, 67:511–517. This is one of the larger studies in the field and includes a multivariate analysis of cytokines and other biomarkers as predictors of treatment response. The latter is defined according to both MRI and clinical parameters of inflammation.
• Melis L, Vandooren B, Kruithof E, et al.: Systemic levels of IL-23 are strongly associated with disease activity in rheumatoid arthritis but not spondyloarthritis. Ann Rheum Dis 2010, 69:618–623. This study compared synovial and peripheral blood expression of IL-17/23 in RA, psoriatic arthritis, and SpA. Cytokines are examined for their associations with disease activity.
Wendling D, Cedoz JP, Racadot E: Serum and synovial fluid levels of p40 IL12/23 in spondyloarthropathy patients. Clin Rheumatol 2009, 28:187–190.
Rihl M, Kellner H, Kellner W, et al.: Identification of interleukin-7 as a candidate disease mediator in spondylarthritis, Arthritis Rheum 2008, 58:3430–3435.
Haroon N, Tsui FWL, O’Shea FD, et al.: From gene expression to serum proteins: biomarker discovery in ankylosing spondylitis. Ann Rheum Dis 2010, 69:297–300.
Maksymowych WP, Landewé R, Conner-Spady B, et al.: Serum matrix metalloproteinase 3 is an independent predictor of structural damage progression in patients with ankylosing spondylitis. Arthritis Rheum 2007, 56:1846–1853.
• Maksymowych WP, Rahman P, Shojania K, et al.: Beneficial effects of adalimumab on biomarkers reflecting structural damage in patients with ankylosing spondylitis. J Rheumatol 2008, 35:2030–2037. This report describes the associations between several biomarkers and disease activity in a placebo-controlled trial of adalimumab in AS. Disease activity is assessed according to clinical, laboratory, and MRI parameters.
Woo JH, Lee HJ, Sung IH, Kim TH: Changes of clinical response and bone biochemical markers in patients with ankylosing spondylitis taking etanercept. J Rheumatol 2007, 34:1753–1759.
• Appel H, Janssen L, Listing J, et al.: Serum levels of biomarkers of bone and cartilage destruction and new bone formation in different cohorts of patients with axial spondyloarthritis with and without tumor necrosis factor-alpha blocker treatment. Arthritis Res Ther 2008, 10:R125. This is one of the few studies comparing biomarker levels over time in patients on standard therapy and those receiving a TNF blocker.
Vandooren B, Kruithof E, Yu DT, et al.: Involvement of matrix metalloproteinases and their inhibitors in peripheral synovitis and down-regulation by tumor necrosis factor alpha blockade in spondylarthropathy. Arthritis Rheum 2004, 50:2942–2953.
Maksymowych WP, Poole AR, Hiebert L, et al.: Etanercept exerts beneficial effects on articular cartilage biomarkers of degradation and turnover in patients with ankylosing spondylitis. J Rheumatol 2005, 32:1911–1917.
Kim TH, Stone M, Payne U, et al.: Cartilage biomarkers in ankylosing spondylitis: relationship to clinical variables and treatment response. Arthritis Rheum 2005, 52:885–891.
• Vosse D, Landewé R, Garnero P, et al.: Association of markers of bone- and cartilage-degradation with radiological changes at baseline and after 2 years follow-up in patients with ankylosing spondylitis. Rheumatology (Oxford) 2008, 47:1219–1222. This prospective study examined biomarkers of cartilage turnover in a multivariate analysis of AS patients on standard therapies to determine their ability to predict joint damage.
Toussirot E, Wendling D: Bone mass in ankylosing spondylitis. Clin Exp Rheumatol 2000, 18(Suppl 21):S16–S20.
Mitra D, Elvins DM, Collins AJ: Biochemical markers of bone metabolism in mild ankylosing spondylitis and their relationship with bone mineral density and vertebral fractures. J Rheumatol 1999, 26:2201–2204.
Toussirot E, Ricard-Blum S, Dumoulin G, et al.: Relationship between urinary pyridinium crosslinks, disease activity and disease subsets of ankylosing spondylitis. Rheumatology 1999, 38:21–27.
Franck H, Meurer T, Hofbauer LC: Evaluation of bone mineral density, hormones, biochemical markers of bone metabolism, and osteoprotegerin serum levels in patients with ankylosing spondylitis. J Rheumatol 2004, 31:2236–2241.
Visvanathan S, van der Heijde D, Deodhar A, et al.: Effects of infliximab on markers of inflammation and bone turnover and associations with bone mineral density in patients with ankylosing spondylitis. Ann Rheum Dis 2009, 68:175–182.
Toussirot E, Dumoulin G, Saas P, et al.: Increased tartrate-resistant acid phosphatase serum levels in ankylosing spondylitis and relationship with the inflammatory process. Ann Rheum Dis 2008, 67:430–431.
Kim HR, Kim HY, Lee SH: Elevated serum levels of soluble receptor activator of nuclear factors-kappa B ligand (sRANKL) and reduced bone mineral density in patients with ankylosing spondylitis (AS). Rheumatology (Oxford) 2006, 45:1197–1200.
Vis M, Havaardsholm EA, Haugeberg G, et al.: Evaluation of bone mineral density, bone metabolism, osteoprotegerin and receptor activator of the NF kappa B ligand serum levels during treatment with infliximab in patients with rheumatoid arthritis. Ann Rheum Dis 2006, 65:1495–1499.
Diarra D, Stolina M, Polzer K, et al.: Dickkopf-1 is a master regulator of joint remodeling. Nat Med 2007, 13:156–163.
Wang N, Morrow S, Mallon C, Maksymowych WP: DKK-1 levels are comparably increased in patients with AS and RA, show similar decreases with anti-TNF therapy, and are not associated with markers of bone remodeling [abstract]. Ann. Rheum Dis 2008, 67(Suppl II):129.
• Daoussis D, Liossis SN, Solomou EE, et al.: Evidence that Dkk-1 is dysfunctional in ankylosing spondylitis. Arthritis Rheum 2010, 62:150–158. In contrast to the Diarra et al. report [34], this study reported higher levels of DKK-1 in AS but also provided evidence that DKK-1 may be dysfunctional. Furthermore, it showed that this may be an important factor in driving new bone formation through inhibition of signalling through wingless proteins.
Choi ST, Kim JH, Kang EJ, et al.: Osteopontin might be involved in bone remodelling rather than in inflammation in ankylosing spondylitis. Rheumatology (Oxford) 2008, 47:1775–1779.
•• Toussirot E, Saas P, Deschamps M, et al.: Increased production of soluble CTLA-4 in patients with spondyloarthropathies correlates with disease activity. Arthritis Res Ther 2009, 11:R101. This study reported for the first time that a biomarker reflecting regulation of T-cell costimulation may reflect disease activity in SpA.
Chen CH, Liao HT, Chen HA, et al.: Soluble triggering receptor expressed on myeloid cell-1 (sTREM-1): a new mediator involved in early ankylosing spondylitis. J Rheumatol 2008, 35:1846–1848.
O’Shea FD, Haroon N, Riarh R, Inman RD: A prediction model for future radiologic damage in ankylosing spondylitis based on a prospective cohort analysis [abstract]. Arthritis Rheum 2009, 60(Suppl):1797.
Maksymowych WP, Morency N, Wichuk S, et al.: Multiplex assay of a panel of 58 biomarkers in ankylosing spondylitis: identification of high priority candidates for prediction of structural damage [abstract]. Ann Rheum Dis 2010, 69(Suppl 3):428.
Baraliakos X, Landewe RB, van der Heijde D, et al.: The relationship of biomarkers and radiographic progression in patients with ankylosing spondylitis treated with TNF-blockers [abstract]. Ann Rheum Dis 2010, 69(Suppl 3):105.
Sieper J, Appel H, Rudwaleit M, et al.: Inverse correlation between serum levels of dickkopf 1 (DKK1) and new bone formation in ankylosing spondylitis patients [abstract]. Ann Rheum Dis 2010, 69(Suppl 3):442.
•• Appel H, Ruiz-Heiland G, Listing J, et al.: Altered skeletal expression of sclerostin and its link to radiographic progression in ankylosing spondylitis. Arthritis Rheum 2009, 60:3257–3262. This study described the first evaluation of sclerostin as a biomarker for predicting radiographic progression in SpA. It also described the immunohistochemical localization data of this molecule in SpA as compared with RA patients and those with osteoarthritis.
Park MC, Park YB, Lee SK: Relationship of bone morphogenetic proteins to disease activity and radiographic damage in patients with ankylosing spondylitis. Scand J Rheumatol 2008, 37:200–204.
• de Vries MK, van Eijk IC, van der Horst-Bruinsma IE, et al.: Erythrocyte sedimentation rate, C-reactive protein level, and serum amyloid a protein for patient selection and monitoring of anti-tumor necrosis factor treatment in ankylosing spondylitis. Arthritis Rheum 2009, 61:1484–1490. This was a large prospective study analyzing clinical and laboratory parameters used in routine care as predictors of treatment response to anti–TNF-α therapy.
Luc M, Gossec L, Ruyssen-Witrand A, et al.: C-reactive protein predicts tumor necrosis factor-alpha blocker retention rate in axial ankylosing spondylitis. J Rheumatol 2007, 34:2078–2081.
Romero-Sánchez C, Robinson WH, Tomooka BH, et al.: Identification of acute phase reactants and cytokines useful for monitoring infliximab therapy in ankylosing spondylitis. Clin Rheumatol 2008, 27:1429–1435.
Stone MA, Payne U, Pacheco-Tena C, Inman RD: Cytokine correlates of clinical response patterns to infliximab treatment of ankylosing spondylitis. Ann Rheum Dis 2004, 63:84–87.
Disclosure
Dr. Maksymowych has received honoraria from Merck & Co., Pfizer, and Abbott Laboratories.
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Maksymowych, W.P. Biomarkers in Spondyloarthritis. Curr Rheumatol Rep 12, 318–324 (2010). https://doi.org/10.1007/s11926-010-0127-9
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DOI: https://doi.org/10.1007/s11926-010-0127-9