血清白细胞介素-6和白细胞介素-1β水平在预测依那西普治疗类风湿关节炎患者临床应答中的作用
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摘要
目的通过检测基线期血清8个与炎症调节相关蛋白的表达水平,评估其在预测依那西普(ETN)治疗类风湿关节炎(RA)患者临床应答中的作用。方法研究连续纳入58例接受ETN治疗24周的活动性RA患者。采用酶联免疫吸附实验检测患者基线期血清标志物的表达水平。结果 ETN治疗24周后,38例RA患者达到临床应答,划归为应答组,20例RA患者未达到临床应答,划归为无应答组。应答组患者基线期血清白细胞介素-1β(IL-1β)(P=0.011)和白细胞介素-6 (IL-6)(P=0.004)水平相对于无应答组显著升高。受试者工作特征曲线表明,IL-1β(AUC:0.703,95%CI:0.558～0.847)和IL-6 (AUC:0.732,95%CI:0.601～0.862)表达水平具有较好的区分临床应答和无应答患者的能力。进一步单元、多元回归分析显示,IL-6高表达可以独立预测ETN治疗RA患者更好的临床应答(P=0.031)。结论基线期血清IL-1β和IL-6表达水平可能会作为ETN治疗RA患者临床应答的生物标记物。
Objective To investigate the predictive value of eight pro-inflammatory protein levels in serum for clinical response to etanercept(ETN) treatment in patients with rheumatoid arthritis(RA). Methods This study enrolled 58 consecutive patients with active RA. All patients received ETN for 24 weeks "on demand" based on clinical need and patient request. Serum samples were obtained from each patient at baseline and biomarker levels were quantified with enzyme-linked immunosorbent assay. Results After 24 weeks,38 RA patients who achieved a clinical response were categorized as the responder group,while 20 RA patients who failed to achieve clinical response were included in the non-responder group. Baseline serum interleukin-1β(IL-1β) and interleukin-6(IL-6) levels were increased in the responder group compared to those in the non-responder group(P = 0.011 and P = 0.004,respectively). Receiver operating characteristic curves showed that both baseline serum IL-1β(AUC:0.703,95% CI:0.558-0.847) and IL-6(AUC:0.732,95% CI:0.601-0.862) expression had a good predictive value in distinguishing responders from non-responders. In addition,univariate and multivariate logistic regression analysis showed that high expression of IL-6 was an independent predictor of clinical response to ETN treatment(P = 0.031).Conclusion Baseline IL-1β and IL-6 expression might be useful as biomarkers for predicting clinical response to ETN treatment in RA patients.
Objective To investigate the predictive value of eight pro-inflammatory protein levels in serum for clinical response to etanercept(ETN) treatment in patients with rheumatoid arthritis(RA). Methods This study enrolled 58 consecutive patients with active RA. All patients received ETN for 24 weeks "on demand" based on clinical need and patient request. Serum samples were obtained from each patient at baseline and biomarker levels were quantified with enzyme-linked immunosorbent assay. Results After 24 weeks,38 RA patients who achieved a clinical response were categorized as the responder group,while 20 RA patients who failed to achieve clinical response were included in the non-responder group. Baseline serum interleukin-1β(IL-1β) and interleukin-6(IL-6) levels were increased in the responder group compared to those in the non-responder group(P = 0.011 and P = 0.004,respectively). Receiver operating characteristic curves showed that both baseline serum IL-1β(AUC:0.703,95% CI:0.558-0.847) and IL-6(AUC:0.732,95% CI:0.601-0.862) expression had a good predictive value in distinguishing responders from non-responders. In addition,univariate and multivariate logistic regression analysis showed that high expression of IL-6 was an independent predictor of clinical response to ETN treatment(P = 0.031).Conclusion Baseline IL-1β and IL-6 expression might be useful as biomarkers for predicting clinical response to ETN treatment in RA patients.
引文
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[11]WIJBRANDTS CA,DIJKGRAAF MG,KRAAN MC,et al.The clinical response to infliximab in rheumatoid arthritis is in part dependent on pretreatment tumour necrosis factor alpha expression in the synovium[J].Ann Rheum Dis,2008,67(8):1139-1144.DOI:10.1136/ard.2007.080440.
[12]FLEISCHER S,RIES S,SHEN P,et al.Anti-interleukin-6 signalling therapy rebalances the disrupted cytokine production of B cells from patients with active rheumatoid arthritis[J].Eur J Immunol,2018,48(1):194-203.DOI:10.1002/eji.201747191.
[13]SANTOS SAVIO A,MACHADO DIAZ AC,CHICO CAPOTE A,et al.Differential expression of pro-inflammatory cytokines IL-15Ralpha,IL-15,IL-6 and TNF alpha in synovial fluid from rheumatoid arthritis patients[J].BMC Musculoskelet Disord,2015,16:51.DOI:10.1186/s12891-015-0516-3.
[14]MOOTS RJ,SEBBA A,RIGBY W,et al.Effect of tocilizumab on neutrophils in adult patients with rheumatoid arthritis:pooled analysis of data from phase 3 and 4 clinical trials[J].Rheumatology(Oxford),2017,56(4):541-549.DOI:10.1093/rheumatology/kew370.
[15]SAEKI Y,KUDO-TANAKA E,OHSHIMA S,et al.Baseline anti-citrullinated peptide antibody(ACPA)titers and serum interleukin-6(IL-6)levels possibly predict progression of bone destruction in early stages of rheumatoid arthritis(ERA)[J].Rheumatol Int,2013,33(2):451-456.DOI:10.1007/s00296-012-2397-1.
[2]SMOLEN JS,ALETAHA D,MCINNES IB.Rheumatoid arthritis[J].Lancet,2016,388(10055):2023-2038.DOI:10.1016/S0140-6736(16)30173-8.
[3]REIN P,MUELLER RB.Treatment with biologicals in rheumatoid arthritis:an overview[J].Rheumatol Ther,2017,4(2):247-261.DOI:10.1007/s40744-017-0073-3.
[4]ALETAHA D,NEOGI T,SILMAN AJ,et al.2010 Rheumatoid arthritis classification criteria:an American college of rheumatology/European league against rheumatism collaborative initiative[J].Arthritis Rheum,2010,62(9):2569-2581.DOI:10.1002/art.27584.
[5]ALETAHA D,NELL VP,STAMM T,et al.Acute phase reactants add little to composite disease activity indices for rheumatoid arthritis:validation of a clinical activity score[J].Arthritis Res Ther,2005,7(4):R796-806.DOI:10.1186/ar1740.
[6]FELSON DT,ANDERSON JJ,BOERS M,et al.American college of rheumatology.Preliminary definition of improvement in rheumatoid arthritis[J].Arthritis Rheum,1995,38(6):727-735.
[7]WU Q,WANG Y,WANG Q,et al.The bispecific antibody aimed at the vicious circle of IL-1beta and IL-17A,is beneficial for the collagen-induced rheumatoid arthritis of mice through NF-kappaB signaling pathway[J].Immunol Lett,2016,179:68-79.DOI:10.1016/j.imlet.2016.09.001.
[8]SHODA H,NAGAFUCHI Y,TSUCHIDA Y,et al.Increased serum concentrations of IL-1 beta,IL-21 and Th17 cells in overweight patients with rheumatoid arthritis[J].Arthritis Res Ther,2017,19(1):111.DOI:10.1186/s13075-017-1308-y.
[9]WANG XT,LI P,XU TS,et al.Effect of iguratimod and methotrexate on RANKL and OPG expression in serum and IL-1beta-induced fibroblast-like synoviocytes from patients with rheumatoid arthritis[J].Cell Mol Biol(Noisy-le-grand),2016,62(12):44-50.DOI:10.14715/cmb/2016.62.12.8.
[10]HUEBER W,TOMOOKA BH,BATLIWALLA F,et al.Blood autoantibody and cytokine profiles predict response to anti-tumor necrosis factor therapy in rheumatoid arthritis[J].Arthritis Res Ther,2009,11(3):R76.DOI:10.1186/ar2706.
[11]WIJBRANDTS CA,DIJKGRAAF MG,KRAAN MC,et al.The clinical response to infliximab in rheumatoid arthritis is in part dependent on pretreatment tumour necrosis factor alpha expression in the synovium[J].Ann Rheum Dis,2008,67(8):1139-1144.DOI:10.1136/ard.2007.080440.
[12]FLEISCHER S,RIES S,SHEN P,et al.Anti-interleukin-6 signalling therapy rebalances the disrupted cytokine production of B cells from patients with active rheumatoid arthritis[J].Eur J Immunol,2018,48(1):194-203.DOI:10.1002/eji.201747191.
[13]SANTOS SAVIO A,MACHADO DIAZ AC,CHICO CAPOTE A,et al.Differential expression of pro-inflammatory cytokines IL-15Ralpha,IL-15,IL-6 and TNF alpha in synovial fluid from rheumatoid arthritis patients[J].BMC Musculoskelet Disord,2015,16:51.DOI:10.1186/s12891-015-0516-3.
[14]MOOTS RJ,SEBBA A,RIGBY W,et al.Effect of tocilizumab on neutrophils in adult patients with rheumatoid arthritis:pooled analysis of data from phase 3 and 4 clinical trials[J].Rheumatology(Oxford),2017,56(4):541-549.DOI:10.1093/rheumatology/kew370.
[15]SAEKI Y,KUDO-TANAKA E,OHSHIMA S,et al.Baseline anti-citrullinated peptide antibody(ACPA)titers and serum interleukin-6(IL-6)levels possibly predict progression of bone destruction in early stages of rheumatoid arthritis(ERA)[J].Rheumatol Int,2013,33(2):451-456.DOI:10.1007/s00296-012-2397-1.
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