[EULAR文摘] 滑膜HIF-1a与类风湿关节炎的关节破坏

滑膜HIF-1a与类风湿关节炎的关节破坏

Wei XN, et al. EULAR 2015. Present ID:
OP0070.

背景:低氧诱导因子(HIF)-1α是缺氧条件下细胞反应的一个关键转录调节子。在类风湿关节炎(RA)受累关节中存在低氧微环境,我们曾报道在RA滑膜中HIF-1α表达水平增高并促进微血管形成和炎症。近有体外研究显示HIF-1α可能促进破骨细胞介导的骨吸收。然而,尚不明确HIF-1α在RA关节破坏中的确切作用。

目的:探讨RA患者滑膜表达HIF-1α与关节破坏和进展的相关性。

方法:我们定期随访病情活动的RA患者,
并在基线和随访1年时对双手和双腕进行X线摄片。关节侵蚀病变的定义遵循EULAR2013。放射学进展的定义为Sharp总评分从基线至随访1年时增加>0.5。我们通过活检从RA、骨关节炎(OA)和骨科关节病(Orth.A)患者获得关节滑膜。一系列组织切片通过H&E染色以及免疫组化检测CD3、C20、CD38、CD68、CD15、C34以及HIF-1α。采用半定量方式对组织切片进行Krenn滑膜炎评分,并定量测定阳性细胞的密度。

结果: 1)25例RA患者完成1年随访, 84%为女性,
年龄(中位数和IQR, 下同)为50(40~57)年,
病程为24(10-48)个月,SDAI为35.0(25.3-46.3)。

2)HIF-1α在RA滑膜衬里层和衬里下层有表达, 伴有核浓染以及胞浆染色,
RA滑膜HIF-1α阳性细胞(57%(31%-77%))比例显著高于OA (n=13, 25% (9%-41%),
P=0.022)以及骨科关节病(n=8, 21%(12%-38%), P=0.021, 图 1)。HIF-1α阳性细胞比例分别与以下指数均显著相关(r=0.420-0.586,
所有P值均<0.05)：滑膜基质活化的亚评分、CD34阳性微血管计数、CD68阳性巨噬细胞计算以及CD15阳性中性粒计数。

3)11例(44%)RA患者在基线时有骨侵蚀。有骨侵蚀者HIF-1α阳性细胞比例显著高于无骨侵蚀者(78%(49%-82%)
vs 47%(23%-62%), P = 0.014]。ROC 曲线分析表明, HIF-1α对于诊断骨侵蚀的界值为 69%,
敏感性为73%, 特异性为 100%(AUC=0.792, 95%CI: 0.574-1.010,
P=0.014)。以69%为界值将患者分为HIF-1α高表达组(n=8)和低表达组(n=17)。高表达组的Sharp总评分和骨侵蚀评分显著高于低表达组(33(14-69)
vs 10(4-24)、 18(11-25) vs 3(2-12), p值均<0.05)。

4)
有8例(32%)RA患者随访满1年时出现影像学进展。有放射学进展患者HIF-1α阳性细胞比例高于放射学无进展者(80%(58%-85%)
vs 49% (18%-63%), P=0.018]。ROC曲线分析表明, HIF-1α预测放射学进展的界值为66%,
敏感性为75%, 特异性为82% (AUC = 0.798, 95%CI: 0.576-1.019, P =
0.018)。单变量逻辑回归分析显示, 高水平HIF-1α是随访1年时影像学进展的显著预测因子(P=0.011, 比值比=14.00,
95%CI: 1.841-106.465)。

结论:HIF-1α可能在RA关节破坏机制中起到重要作用。

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图1.
用免疫组化检测滑膜的HIF-1a的表达. 

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原文链接或参考以下信息。

Ann Rheum Dis 2015;74:94-95 doi:10.1136/annrheumdis-2015-eular.4760

• Oral Presentations

OP0070 Synovial Hypoxia-Inducible
Factor 1 Alpha Involved in Joint Destruction in Rheumatoid
Arthritis

1. X.-N. Wei,
2. J.-D. Ma,
3. D.-H. Zheng,
4. Y.-Q. Mo,
5. L.-F. Chen,
6. L. Dai

-Author Affiliations

1. Department of Rheumatology, Sun Yat-Sen Memorial Hospital, Sun
   Yat-Sen University, Guangzhou, China

1. Department of Rheumatology, Sun Yat-Sen Memorial Hospital, Sun
   Yat-Sen University, Guangzhou, China

Abstract

Background Hypoxia-inducible factor
(HIF)-1α is a critical transcription regulator in cellular response
to hypoxic condition. Hypoxic microenvironment exists in rheumatoid
arthritis (RA) joints and we have reported that elevated HIF-1α
promoted angiogenesis and inflammation in RA. Recent studies showed
HIF-1α might promote osteoclast-mediated bone resorption in vitro.
However, little was known about its role in RA joint
destruction.

Objectives To explore the correlation of
synovial HIF-1α with joint destruction and its progression in
RA.

Methods Patients with active RA were
followed up and X-ray assessment of hand/wrist was repeated at
baseline and one year. Erosive disease was defined according to
2013 EULAR definition and radiographic progression was defined as
the increase of total Sharp score more than 0.5 from baseline to
one year. Synovial tissue was obtained from RA patients as well as
OA and orthopedic arthropathies (Orth.A) patients. Serial tissue
sections were stained with H&E, immunohistochemically for CD3,
CD20, CD38, CD68, CD15, CD34 and HIF-1α. Krenn's synovitis score
was semi-quantitatively assessed and the density of
positive-staining cells was quantitatively determined.

Results (1) Twenty five RA patients
fulfilled 1 year follow-up, 84% were female, age (median and IQR,
similarly hereinafter) was 50 (40–57) years, disease duration was
24 (10–48) months and disease activity SDAI was 35.0
(25.3–46.3).

(2) HIF-1α expressed in lining and sublining area with intense
nuclear and endochylema staining in RA synovium and the percentage
of HIF-1α+ cells [57% (31%–77%)] was significantly higher than that
in OA [n=13,
25% (9%–41%), P=0.022]or
Orth.A [n=8,
21% (12%–38%), P=0.021, Fig.1]. The percentage of HIF-1α+ cells
significantly correlated with subscore of synovial stroma
activation, CD34+ microvessel count, CD68+ macrophage count and
CD15+ neutrophil count (r=0.420–0.586,
all P<0.05).

(3) Eleven (44%) RA patients had erosive disease at baseline. The
percentage of HIF-1α+ cells was significantly higher in erosive
patients than non-erosive patients [78% (49%–82%) vs 47%
(23%–62%), P=0.014].
ROC curve analysis showed that the tradeoff value of synovial
HIF-1α for diagnosing erosive disease was 69% with sensitivity 73%
and specificity 100% (AUC=0.792,
95%CI: 0.574–1.010, P=0.014).
Patients were then divided into high (n=8) and low synovial HIF-1α
(n=17) groups. Total Sharp score and erosion subscore were higher
in patients with high synovial HIF-1α than that in patients with
low synovial HIF-1α [33 (14–69) vs 10 (4–24), 18 (11–25) vs 3
(2–12), respectively, all P<0.05]

(4) Eight (32%) RA patients showed radiographic progression at one
year. The percentage of HIF-1α+ cells was significantly higher in
progressive patients than non-progressive patients [80% (58%–85%)
vs 49% (18%–63%), P=0.018].
ROC curve analysis showed that the tradeoff value of synovial
HIF-1α for predicting 1-year radiographic progression was 66% with
sensitivity 75% and specificity 82% (AUC=0.798,
95%CI :0.576–1.019, P=0.018).
Univariate logistic regression showed that high level of synovial
HIF-1α was a significant predictor of 1-year radiographic
progression (P=0.011, OR=14.00,
95%CI: 1.841
to 106.465).

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Conclusions HIF-1α might play important
roles in the pathogenesis of joint destruction in RA.

Acknowledgements This work was supported by
National Natural Science Foundation of China (81471597).