Audo Rachel, Sanchez Pauline, Rivière Benjamin, Mielle Julie, Tan Jian, Lukas Cédric, Macia Laurence, Morel Jacques, Immediato Daien Claire
Department of Rheumatology, Montpellier University Hospital (CHRU), University Of Montpellier, Montpellier, France.
University of Montpellier, PhyMedExp, Inserm U1046, CNRS UMR 9214, Montpellier, FRANCE.
Rheumatology (Oxford). 2022 Aug 10. doi: 10.1093/rheumatology/keac454.
to assess how rheumatoid arthritis (RA) and Disease Modifying Anti Rheumatic Drugs (DMARDs) affect gut permeability.
to explore colonic mucosa integrity, tight junction proteins ZO-1, occludin and claudin 2 were quantified by immunohistochemistry on colonic biopsies in 20 RA patients and 20 age- and sex-matched controls. Staining intensity was assessed by two blinded independent readers. To explore intestinal permeability, serum concentrations of LPS-binding protein (LBP), sCD14 and zonulin-related proteins (ZRP) were evaluated by ELISA in another cohort of 59 RA: 21 patients naive of DMARDs (17 before and after introduction of a conventional synthetic (cs) DMARDs), 38 patients with severe RA (before and after introduction of a biological (b) DMARDs), and 33 healthy controls.
Z0-1 protein was less expressed in colon of RA patients than controls (mean score ± SEM of 1.6 ± 0.56 vs 2.0 ± 0.43; p= 0.01), while no significant difference was detected for occludin and claudin-2. RA patients had higher serum LBP and sCD14 concentrations than controls. LBP and sCD14 levels were significantly correlated with DAS28 (r = 0.61, p= 0.005 and r = 0.57, p= 0.01, respectively) while ZRP did not. bDMARD responders had significantly reduced LBP and sCD14 concentrations unlike bDMARDs non-responders and patients treated with csDMARDs.
RA patients have altered colonic tight junction proteins and increased serum biomarkers of intestinal permeability. There was a correlation between serological markers of intestinal permeability and disease activity as well as bDMARD response. These results suggest a link between impaired gut integrity and systemic inflammation in RA.
评估类风湿关节炎（RA）和改善病情抗风湿药物（DMARDs）如何影响肠道通透性。
为探究结肠黏膜完整性，对20例RA患者及20例年龄和性别匹配的对照者的结肠活检组织进行免疫组化，定量检测紧密连接蛋白ZO-1、闭合蛋白和Claudin 2。由两名独立的盲法阅片者评估染色强度。为探究肠道通透性，在另一组59例RA患者中通过酶联免疫吸附测定（ELISA）评估血清脂多糖结合蛋白（LBP）、可溶性CD14（sCD14）和zonulin相关蛋白（ZRP）的浓度：21例初治DMARDs的患者（17例在引入传统合成（cs）DMARDs之前和之后）、38例重症RA患者（在引入生物（b）DMARDs之前和之后）以及33例健康对照者。
RA患者结肠中ZO-1蛋白的表达低于对照者（平均评分±标准误为1.6±0.56对2.0±0.43；p = 0.01），而闭合蛋白和Claudin-2未检测到显著差异。RA患者的血清LBP和sCD14浓度高于对照者。LBP和sCD14水平与疾病活动度评分28（DAS28）显著相关（r分别为0.61，p = 0.005和r = 0.57，p = 0.01），而ZRP则无相关性。与bDMARDs无反应者和接受csDMARDs治疗的患者不同，bDMARDs反应者的LBP和sCD14浓度显著降低。
RA患者的结肠紧密连接蛋白发生改变，肠道通透性的血清生物标志物增加。肠道通透性的血清学标志物与疾病活动度以及bDMARDs反应之间存在相关性。这些结果提示RA患者肠道完整性受损与全身炎症之间存在联系。
