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2012 ACR进展——建立和验证多个以DAS28为基础的类风湿关节炎复发标准

发布时间:2012-12-28 12:47:56

背景/目的:为了能稳定评估药物减量、撤药和剂量优化策略对临床的影响,类风湿关节炎(RA)临床研究中越来越需要一个确切有效能评价疾病复发的指标。已有多个以DAS28为基础的复发标准,但都未经验证。

方法:我们选择3个纵向观测数据库,包括因RA恶化撤药或改变治疗的患者来测试以往发表的以DAS28为基础的复发标准,是否符合标准构建效度的5个假设。已发表的DAS28复发标准为:1 ] DAS28增加值 > 1.2,或DAS28 > 5.1时增加> 0.6;2 ] DAS28增加值 > 1.2,或DAS28≥3.2时增加> 0.6;3 ]DAS增加> 0.6或DAS28 > 3.2;4 ] DAS28 增加> 1.2;5 ] DAS28 > 3.2;6 ] DAS 28 > 2.6。用于评估有效性的5个假设为:A+B)与RA恶化评估中病人/医生的总体评价相比,敏感性和特异性> 70% ; C)DMARD/类固醇激素开始或增加的比例> 0.2,D) C反应蛋白均值变化> 10 mg /l,和E)符合复发标准的与不符合的患者相比,SF36心理健康(MH)指标变化没有统计学上差异。检测灵敏度/特异性,卡方和双样本student’s T检验。

结果:3个研究中分别有51、147和744例RA患者纳入本研究。两项研究中患者接受英夫利昔治疗,其中较大的一项研究(NOR-DMARD)还包括新合成或生物DMARD治疗的患者。基线特征见表1。标准2(DAS28增加值 > 1.2,DAS28≥3.2时DAS28增加> 0.6)符合大多数预定的假设(5项中的4项,表2)。敏感性和特异性分别介于63 - 78%和84 - 92%。建构效度结果表明23%以上的个治疗变化、较高的CRP(11.4mg/l)和 SF – 36 MH只减少 5。标准3,5和6敏感高较高,而标准1,2和4则特异性较高。

结论:DAS28增加值 > 1.2,或DAS28≥3.2时增加> 0.6似乎是最严格的标准并得到预定指标。不同的DAS28为基础的复发标准,敏感性和特异不同,可能是因为各自为特定研究所选择的参数不同。 该标准对疾病恶化程度的影响有待进一步的评价,同样还需要更多的数据来改进它。

原文:

Construct and Criterion Validity of Several Proposed DAS28 Based Rheumatoid Arthritis Flare Criteria: A Cohort Validation Study

Abstract#: 2609
Presenter: Aatke van der Maas: Sint Maartenskliniek
Date: Wednesday, November 14

Background/Purpose: To enable consistent assessment of impact of tapering, withdrawal and dose optimization strategies, there is an increasing need for validated measures of flare in rheumatoid arthritis (RA) clinical studies. Several DAS28 based flare criteria have been described, but none validated

Methods: We used 3 longitudinal observational databases that included treatment withdrawal or change in relation to RA worsening to test 6 previously published DAS28 based flare criteria on fulfilment of 5 hypotheses concerning criterion and construct validity. Published DAS28 based flare criteria were: 1] an increase in DAS28>1.2, or >0.6 if current DAS28>5.1, 2] an increase in DAS28>1.2, or >0.6 if DAS28≥3.2, 3] an increase>0.6 or DAS28>3.2, 4] an increase in DAS28>1.2, 5] DAS28 >3.2, 6] DAS28 >2.6. The 5 hypotheses used to assess validity were: A+B) Sensitivity and specificity >70% compared to patient|s/physician|s judgment of RA worsening assessed with a transition question, and C) difference in proportion with DMARD/corticosteroid initiation/increase >0.2, D) difference in mean CRP change >10mg/L, and E) no statistical difference in SF36 Mental Health (MH) subscale change in patients fulfilling versus not fulfilling the flare criteria. Sensitivity/specificity, Chi square and two sample student|s T test were done

Results: Analyses included 51, 147 and 744 RA patients in the 3 studies. Two studies included patients treated with infliximab and the larger study (NOR-DMARD) included patients initiating a new synthetic or biologic DMARD. Baseline characteristics are described in Table 1. Criterion 2 (an increase in DAS28>1.2, or >0.6 if DAS28≥3.2) fulfilled most predefined hypotheses (4 out of 5, Table 2). Sensitivity and specificity for criterion 2 varied between 63 - 78% and 84 - 92%, respectively. Construct validity was demonstrated with 23% more treatment change, a higher mean CRP (11.4 mg/L) and a difference in SF-36 MH of only -5. Criteria 3, 5 and 6 tended to be more sensitive, criteria 1, 2 and 4 more specific .

Conclusion: An increase in DAS28>1.2, or >0.6 if DAS28≥3.2 appears most discriminating and valid by our predefined criteria. The differences in sensitivity and specificity between the various DAS28-based flare criteria may be of importance for selection of flare criteria for specific studies. Further assessment, with evaluation of impact relative to levels of worsening, in additional databases may refine criteria

Table 1 Baseline characteristics - mean (SD) unless otherwise noted    

Database123
Number of patients51147744
Age, years59 (11.2)58 (12)56 (13.5)
Female, No (%)29 (57)101 (69)539 (72)
Disease duration in years14 (7.5)11 (7)6.4 (9.5)
RF positive, No (%)42 (82)117 (81)496 (68)
Anti-CCP positive, No (%)37 (73)95 (69)146 (70)
DAS28 at inclusion2.5 (0.7)3.5 (1.3)5.2 (1.1)
DAS28 at 3 months after inclusion  3.4 (1.2)*
No. of previous DMARDs, median [p25-p75]3 [2-3]3 [2-3]

0 [0-2]

Table 2 Fulfilment of DAS28 based flare criteria on 5 hypotheses regarding construct and criterion validity

 

 Criterion validity: databases 1 and 2Construct validity: database 3
Flare criteriaHypothesis 1Hypothesis 2Hypothesis 3Hypothesis 4Hypothesis 5
In patients classified as a having a flare:Sens/spec patient >70% compared to transition scaleSens/spec physician >70% compared to transition scaleHigher proportion of DMARD/corticosteroid change (>0.2)Higher CRP     No change in depression (≤5 points in MH scale)
(>10 mg/L)
 Sens*Spec*Sens*Spec*Proportion difference**CRP difference mg/L (SE)***MH difference (SE)
%%%%
1) ΔDAS28 > 1.2 or > 0.6 if DAS28>5.146/5695/9253/7895/920.2813.1 (2.2)-6.1 (1.4)
2) ΔDAS28> 1.2 or > 0.6 if DAS28>3.269/6392/8473/7892/860.2311.4 (1.7)-5.0 (1.2)
3)  ΔDAS28> 0.6 or a DAS28>3.298/9470/61100/8967/600.163.7 (1.2)-2.8 (1.0)
4)  ΔDAS28>1.246/5696/9351/7895/920.2713.0 (2.3)-6.6 (1.4)
5) reaching DAS28>3.291/8878/6791/8976/680.183.1 (1.2)-2.6 (1.0)
6)  reaching DAS28 > 2.698/9455/46100/8953/470.132.4 (1.0)-3.2 (1.1)
*Sens=sensitivity, Spec= specificity. Results from database1 / database2 are represented on sensitivity and specificity. ** All proportion differences are statistically significant, with p<0.0001.*** All differences in CRP are statistically significant, with at least p<0.05  

Aatke van der Maas1, Elisabeth Lie2, Robin Christensen3, Ernest Choy4, Yaël A. de Man5, Piet L.C.M. van Riel6, Thasia G. Woodworth7 and Alfons A. den Broeder1, 1Sint Maartenskliniek, Nijmegen, Netherlands, 2Diakonhjemmet Hospital, Oslo, Norway, 3Musculoskeletal Statistics Unit, The Parker Institute, Copenhagen University Hospital, Copenhagen, Denmark, 4Cardiff University School of Medicine, Cardiff, United Kingdom, 5Erasmus Medical Centre, Rotterdam, Netherlands, 6Radboud University Nijmegen Medical Centre, Nijmegen, Netherlands, 7Visiting Clinical Researcher, Geffen School of Medicine, UCLA, Los Angeles, CA

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