抗TNF治療改變JIA患者PBMC基因表達譜，可預測療效

抗TNF治療改變JIA患者PBMC基因表達譜，可預測療效

Moorthy LN, et al. ACR 2007. Presentation No:1713.

        

背景：咱們假設兒童期發生的特發性關節炎(JIA)和SLE的基因表達譜是獨特的，抗細胞因子或細胞毒藥物將改變之，並可能有預測療效的價值。

目的：利用核酸微陣列技術，分析Etanercept治療JIA以及環孢黴素/Rituximab(COME)聯合治療SLE，對患者外周血單個核細胞(PBMC)基因表達譜的影響。

方法：共 有4例活動性JIA[3例多關節型(PoJIA)，1例系統型(SoJIA)]以及1例活動性SLE，生物製劑治療前和治療後(90±30天)採集患者的 外周血。另設2例年齡匹配患者做爲對照(1例SoJIA，1例鏈球菌感染後反應性關節炎)，疾病無活動，也不接受任何治療。除了分析治療先後配對數據，還 比較治療有效患者(3例PoJIA中的2例)與無效者(1例PoJIA，1例SoJIA)以及1例SLE。

結果：PoJIA、 SoJIA、SLE以及對照組患者均有獨特的基因表達印章。共發現157個差別表達基因。Etanercept治療後，80個基因下調，77個基因上調 (p=0.01-0.0001)。3例PoJIA治療後，參與炎症通路的以及已知受TNF調控的基因出現下調，這與體內TNF受到功能性抑制相一致。治療 後上調基因有：UBE2V1，參與NFkB途徑；CD74，MHC-II偶聯的不變鏈；HSP90AB1，PKR的一種調控子，是I型干擾素途徑中的成 員；TLN1，維繫正常整合素的功能。SLE中過表達的某些基因也見於PoJIA治療無效者(CALR、IFNG、STAT1)以及 SoJIA(SLC16A三、MMP九、VSIG四、DEFA1和四、ARG一、CYP45三、CEACAM8和六、ANXA三、OLFM4)。

結論：初步分析提示Etanercept能夠改變JIA患者PBMC的基因表達譜，基因表達特徵能夠區分出治療有效與無效者。JIA患者中若有一種狼瘡樣的表達印章可能預示抗TNF治療療效不佳。

 

原文文摘以下。

 

Effect on Anti-TNF Agents on Gene Expression in Children with Juvenile Arthritis

Present ID: 1713.

We hypothesize that gene expression patterns for childhood juvenile idiopathic arthritis (JIA) and systemic lupus erythematosus (SLE) are unique, will be altered by anti-cytokine/cytotoxic agents, and may predict response to therapy.
Purpose: To examine the effect of etanercept in JIA and of cyclophosphamide/rituximab combination (COMB) in SLE on PBMC gene expression using microarray-based methods.
Methods: Paired blood samples were collected from 4 children with active JIA [3 polyarticular (PoJIA), 1 systemic onset (SoJIA)] and one with active SLE prior to and 90±30 days after initiation of therapy with etanercept for the JIA patients and COMB therapy for the SLE patient. Paired blood samples from 2 age-matched controls (1 SoJIA, 1 post-streptococcal reactive arthritis) with inactive disease on no therapy were also collected. PBMCs were separated, total RNA isolated and microarray experiments were conducted using Affymetrix chips (HGU133 plus 2). Pre and post treatment data were compared. The t-test (cut-off alpha 0.01), fold change tests and change expression analysis using Affymetrix MAS software were performed to compare the 2 groups. Change analysis compares the pre and post treatment samples from the same patient and is done on the level of probes (as opposed to probe-sets). In addition, data from responders (2 of 3 PoJIA) and non-responders (1 PoJIA, the SoJIA) and the SLE patient were compared.
Results: PoJIA, SoJIA, SLE and control subjects had distinct gene expression signatures. Probes not scored as present in at least 3 of 4 JIA samples at either time point were removed; 157 differentially expressed genes remained. After etanercept, 80 genes were downregulated and 77 upregulated (p=0.01-0.0001). Genes involved in inflammatory pathways and known to be regulated by TNF (CEBPD, SOCS3, and PBEF1) were decreased after treatment in 3 PoJIA patients, consistent with functional inhibition of TNF in vivo. UBE2V1, involved in the NFkB pathway; CD74, the MHC class II-associated invariant chain; HSP90AB1, a regulator of PKR, a component of the type I interferon pathway; and TLN1, a contributor to normal integrin function, were increased after treatment. Some genes over expressed in the SLE patient were also detected in the non-responder with PoJIA (CALR, IFNG, STAT1) and the non-responder with SoJIA (SLC16A3, MMP9, VSIG4, DEFA1 and 4, ARG1, CYP453, CEACAM8 and 6, ANXA3, OLFM4). Many of these are components or targets of pro-inflammatory cytokine pathways.
Conclusion: Our preliminary analysis suggests that gene expression is modified by etanercept in JIA patients and separates responders from non-responders. A lupus-like signature in JIA patients may predict lack of response to anti-TNF therapy.

L.N. Moorthy, Arthritis Foundation Investigator Award 2007-2009; G. Schemmann, NIH support on colon cancer-related work (unrelated), 2; UMDNJ, Princeton University in Mechanical Engineering Dept, 3; M.K. Crow, NIH, Alliance for Lupus Research, 2; Hospital For Special Surgery, 3; E. Zachariah, None; M. Peterson, Co-investigator on about 3 NIH grants, 2; Hospital For Special Surgery, 3; Dr. Moorthy's Pfizer clinical scholars grant on QOL and SLE; Consultant on 2 NIH grants; Consultant Burke Hospital, 5; Consultant on this project (no- fees), 9; T. Lehman, Hospital For Special Surgery, 3; Genentech, Abbott, Wyeth, 8; D. Notterman, NIH (NCI) support, 2.