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[1451] - Multiplex Assay of a Panel of 58
Biomarkers in Ankylosing Spondylitis: Identification of High
Priority Candidates for Prediction of Structural
Damage.
Walter P
Maksymowych, MD, FRCPC1,Nathalie Morency,
F.R.C.P.(C)2,Stephanie Wichuk, BSc2,Proton
Rahman, MD3,Dafna D Gladman, MD,
FRCPC4,Robert D Inman5. 1Medical
Research Centre, University of Alberta, Edmonton,
AB,2University of Alberta, Edmonton,
Alberta,3Rheumatology, Memorial University Newfoundland,
St Johns, NL,4Ctr for Prognosis Studies, Toronto Western
Hospital, Toronto, ON,5Dept of Medicine/Rheumatology,
Toronto Western Hospital, Toronto, ON
Purpose: Radiographic progression in ankylosing spondylitis
(AS) requires 2 years before it can be reliably detected and
prospective studies have consistently identified only baseline
radiographic damage as an independent predictor of radiographic
progression in AS. This presents a major challenge to the study of
disease modifying therapies and to the identification of patients
at risk for damage progression. We aimed to simultaneously analyze
a large panel of serologic biomarkers reflecting pathophysiological
processes in AS as potential predictors of radiographic
progression.
Method: We used multiplexed sandwich immunoassays (Eve
Technologies) to simultaneously quantify a panel of 58 biomarkers
that comprised 8 markers reflecting bone turnover, calcium
homeostasis and osteoclasis, 8 metalloproteinases (MMP), 6 joint
tissue growth factors, 23 cytokines known to regulate inflammation,
9 chemokines, and 4 factors reflecting miscellaneous immunological
processes such as T-cell co-stimulation and enthothelial
activation. Serum was obtained at a single time point from 60
patients with AS and 60 age- and sex-matched controls. Selection of
30 AS patients was based on phenotypic characterization of their
progression status as measured by the modified Stoke AS Spine Score
(mSASSS) after patients had been followed for at least 2 years.
Progressors were defined as those patients where the baseline
mSASSS was at least 10 units, progression over 2 years was at least
5 units, and included at least one new syndesmophyte.
Non-progressors were patients meeting all 3 of the following:
disease duration at baseline of at least 10 years, baseline mSASSS
of less than 5 units, and no change in mSASSS over 2 years.
Unpaired t-test analyses were stratified according to radiographic
phenotype.
Results: A total of 23 biomarkers demonstrated significant
differences between AS patients and controls, the most significant
being osteocalcin and Rantes (both p<0.0001). Ten
biomarkers only demonstrated significant differences from controls
when analysis was stratified according to radiographic phenotype:
in the progressor subgroup MMP-9, transforming growth factor alpha,
and tumor necrosis factor alpha were significantly elevated
compared to controls (all p<0.0001) while eotaxin,
interferon alpha-2, and monocyte chemotactic protein-3 were
significantly increased in the non-progressor subgroup. Three
biomarkers, interleukin-17, interferon-gamma, and macrophage
inhibitory protein-beta, demonstrated significantly increased
levels in AS patients that were further increased in the progressor
subgroup. Six biomarkers were significantly increased only in male
patients and particularly the progressor subgroup, especially
macrophage derived chemokine and CD40 ligand (both
p<0.0001).
Conclusion: Multiplexed assay of an extensive panel of
biomarkers reflecting pathophysiological processes implicated in AS
has identified several biomarkers as high priority candidates for
prospective validation studies aimed at predictors of structural
damage in AS.
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从58个生物标记物中筛选AS结构破坏的预测因素
Maksymowych WP, et al. ACR 2010. Present No:
1451.
目的：AS放射学进展需要2年才能准确检测出来，若干前瞻性研究都发现只有基线期放射学损害是AS放射学进展的独立预测因素。这给研究改善病情治疗和明确出现损害进展的高危患者带来困难。本研究同时分析多种反映AS病理生理过程的血清学生物标记物，以期发现放射学进展的预测因素。
方法：我们采用多重免疫夹心方法同时对58种生物标记物进行定量，包括8种反映骨转换、钙稳态和骨破折的标记物，8种金属蛋白酶（MMP），6种关节组织生长因子，23种调节炎症的细胞因子，9种趋化因子，4种反映多种免疫过程（如T细胞共刺激、内皮细胞活化）的因子。在单个时间点采取60例AS患者和60例年龄、性别匹配的对照者的血清。随访2年以上后，根据修订的Stoke AS脊柱评分（mSASSS）评估30例AS患者的进展状况，研究其表型特征。进展者定义为基线期mSASSS≥10单位，2年后进展≥5单位，至少有一个新发韧带骨赘。非进展者符合以下3项：基线期病程≥10年，基线期mSASSS＜5单位，2年后mSASSS无变化。根据放射学表型，采用非配对t检验进行分层。
结果：共有23个生物标记物在AS患者与对照者存在显著性差异，其中差异最大的是骨钙素和Rantes（p<0.0001）。当根据放射学表型分层分析时，仅10种生物标记物存在差异：与对照者相比，进展者组MMP-9、转化生长因子α、TNFα显著升高（p<0.0001）；非进展者组干扰素α2、单核细胞趋化蛋白3显著升高。在AS患者中，进展者组IL-17、干扰素γ和巨噬细胞抑制蛋白β显著升高。6种生物标记物仅在男性患者和进展者组升高，特别是巨噬细胞衍生趋化因子和CD40配体（p<0.0001）。
结论：对一组反映AS病理生理过程的生物标记物进行多重分析，发现数种生物标记物可能是AS结构损害的预测因素，这有待进一步前瞻性研究证实。
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