From the Department of Pediatric Rheumatology and Immunology, University Children's Hospital Münster, Münster, Germany; Department of Pediatrics/Pediatric Rheumatology, Erasmus MC Sophia Children's Hospital Rotterdam, Rotterdam, the Netherlands; Center for Autoimmune Genomics and Etiology, Cincinnati Children's Hospital Medical Center; Department of Pediatrics, University of Cincinnati, College of Medicine, Cincinnati, Ohio, USA; Emma Children's Hospital, Academic Medical Centre and Amsterdam Rheumatology and Immunology Centre, Reade location, Jan van Breemen Institute; Department of Pediatrics/Pediatric Rheumatology, Onze Lieve Vrouwe Gasthuis, Amsterdam; Department of Pediatrics/Pediatric Rheumatology, St. Maartenskliniek and Radboud University Medical Centre, Nijmegen; Leiden University Medical Centre, Leiden, the Netherlands; School of Biological Sciences, Royal Holloway, University of London; Infection, Immunity, Inflammation Programme, University College London (UCL) Great Ormond Street (GOS) Institute of Child Health; UK National Institute for Health Research (NIHR) GOS Hospital Biomedical Research Centre (BRC); Arthritis Research UK Centre for Adolescent Rheumatology at UCL, London, UK; Centre of Pediatric Rheumatology, Department of General Pediatrics, Asklepios Clinic Sankt Augustin, Sankt Augustin; German Pediatric Pain Centre, Children's and Adolescents' Hospital, Datteln; Klinik für Kinderheilkunde III, Zentrum für Kinder- und Jugendmedizin, Universitätsklinikum Essen, Essen, Germany.
F. Gohar, MD, Department of Pediatric Rheumatology and Immunology, University Children's Hospital Münster; J. Anink, MD, PhD, Department of Pediatrics/Pediatric Rheumatology, Erasmus MC Sophia Children's Hospital Rotterdam; H. Moncrieffe, PhD, Center for Autoimmune Genomics and Etiology, Cincinnati Children's Hospital Medical Center, and Department of Pediatrics, University of Cincinnati; L.W. Van Suijlekom-Smit, MD, PhD, Department of Pediatrics/Pediatric Rheumatology, Erasmus MC Sophia Children's Hospital Rotterdam; F.H. Prince, MD, PhD, Department of Pediatrics/Pediatric Rheumatology, Erasmus MC Sophia Children's Hospital Rotterdam; M.A. van Rossum, MD, PhD, Emma Children's Hospital, Academic Medical Centre and Amsterdam Rheumatology and Immunology Centre, Reade location, Jan van Breemen Institute; K.M. Dolman, MD, PhD, Department of Pediatrics/Pediatric Rheumatology, Onze Lieve Vrouwe Gasthuis; E.P. Hoppenreijs, MD, Department of Pediatrics/Pediatric Rheumatology, St. Maartenskliniek and Radboud University Medical Centre; R. ten Cate, MD, PhD, Leiden University Medical Centre; S. Ursu, PhD, School of Biological Sciences, Royal Holloway, University of London; L.R. Wedderburn, MD, PhD, Infection, Immunity, Inflammation Programme, UCL GOS Institute of Child Health, UCL; G. Horneff, MD, Centre of Pediatric Rheumatology, Department of General Pediatrics, Asklepios Clinic Sankt Augustin; M. Frosch, MD, German Pediatric Pain Centre, Children's and Adolescents' Hospital; D. Foell, MD, Department of Paediatric Rheumatology and Immunology, University Children's Hospital Münster; D. Holzinger, MD, Department of Paediatric Rheumatology and Immunology, University Children's Hospital Münster, and Klinik für Kinderheilkunde III, Zentrum für Kinder- und Jugendmedizin, Universitätsklinikum Essen.
J Rheumatol. 2018 Apr;45(4):547-554. doi: 10.3899/jrheum.170438. Epub 2018 Jan 15.
Around one-third of patients with juvenile idiopathic arthritis (JIA) fail to respond to first-line methotrexate (MTX) or anti-tumor necrosis factor (TNF) therapy, with even fewer achieving ≥ American College of Rheumatology Pediatric 70% criteria for response (ACRpedi70), though individual responses cannot yet be accurately predicted. Because change in serum S100-protein myeloid-related protein complex 8/14 (MRP8/14) is associated with therapeutic response, we tested granulocyte-specific S100-protein S100A12 as a potential biomarker for treatment response.
S100A12 serum concentration was determined by ELISA in patients treated with MTX (n = 75) and anti-TNF (n = 88) at baseline and followup. Treatment response (≥ ACRpedi50 score), achievement of inactive disease, and improvement in Juvenile Arthritis Disease Activity Score (JADAS)-10 score were recorded.
Baseline S100A12 concentration was measured in patients treated with anti-TNF [etanercept n = 81, adalimumab n = 7; median 200, interquartile range (IQR) 133-440 ng/ml] and MTX (median 220, IQR 100-440 ng/ml). Of the patients in the anti-TNF therapy group, 74 (84%) were also receiving MTX. Responders to MTX (n = 57/75) and anti-TNF (n = 66/88) therapy had higher baseline S100A12 concentration compared to nonresponders: median 240 (IQR 125-615) ng/ml versus 150 (IQR 87-233) ng/ml, p = 0.021 for MTX, and median 308 (IQR 150-624) ng/ml versus 151 (IQR 83-201) ng/ml, p = 0.002, for anti-TNF therapy. Followup S100A12 could be measured in 44/75 MTX-treated patients (34/44 responders) and 39/88 anti-TNF-treated patients (26/39 responders). Responders had significantly reduced S100A12 concentration (MTX: p = 0.031, anti-TNF: p < 0.001) at followup versus baseline. Baseline serum S100A12 in both univariate and multivariate regression models for anti-TNF therapy and univariate analysis alone for MTX therapy was significantly associated with change in JADAS-10.
Responders to MTX or anti-TNF treatment can be identified by higher pretreatment S100A12 serum concentration levels.
约三分之一的幼年特发性关节炎 (JIA) 患者对一线甲氨蝶呤 (MTX) 或抗肿瘤坏死因子 (TNF) 治疗无反应，甚至更少的患者达到美国风湿病学会儿科 70%反应标准 (ACRpedi70)，尽管目前尚无法准确预测个体反应。由于血清 S100-蛋白髓样相关蛋白复合物 8/14 (MRP8/14) 的变化与治疗反应相关，我们检测了粒细胞特异性 S100 蛋白 S100A12 作为治疗反应的潜在生物标志物。
在接受 MTX（n=75）和抗 TNF（n=88）治疗的患者中，通过 ELISA 在基线和随访时测定 S100A12 血清浓度。记录治疗反应（≥ACRpedi50 评分）、达到无疾病活动状态和改善幼年关节炎疾病活动评分 (JADAS)-10 评分。
在接受抗 TNF 治疗的患者中测量了 S100A12 的基线浓度 [依那西普 n=81，阿达木单抗 n=7；中位数 200，四分位距 (IQR) 133-440ng/ml] 和 MTX（中位数 220，IQR 100-440ng/ml）。在抗 TNF 治疗组中，74 名患者（84%）还接受了 MTX 治疗。MTX（n=57/75）和抗 TNF（n=66/88）治疗的反应者与无反应者相比，S100A12 基线浓度更高：中位数 240（IQR 125-615）ng/ml 与 150（IQR 87-233）ng/ml，p=0.021；中位数 308（IQR 150-624）ng/ml 与 151（IQR 83-201）ng/ml，p=0.002。在 44/75 名接受 MTX 治疗的患者（44/44 名反应者）和 39/88 名接受抗 TNF 治疗的患者（26/39 名反应者）中可测量随访时的 S100A12。与基线相比，反应者的 S100A12 浓度显著降低（MTX：p=0.031，抗 TNF：p<0.001）。在抗 TNF 治疗的单变量和多变量回归模型以及 MTX 治疗的单变量分析中，基线血清 S100A12 与 JADAS-10 的变化显著相关。
通过更高的预处理 S100A12 血清浓度水平可以识别出对 MTX 或抗 TNF 治疗有反应的患者。
