Reduction of synovial sublining layer inflammation and proinflammatory cytokine expression in psoriatic arthritis treated with methotrexate
Reduction of synovial sublining layer inflammation and proinflammatory cytokine expression in psoriatic arthritis treated with methotrexate
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DOI：
10.1002/art.20518
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发表时间：
2004-10-01
影响因子：
--
通讯作者：
FitzGerald, O
中科院分区：
文献类型：
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作者：
Kane, D;Gogarty, M;FitzGerald, O
objective.甲氨蝶呤是治疗银屑病关节炎（PsA）最常用的疾病缓解抗风湿药物之一。尽管PsA和类风湿性关节炎（RA）的炎症之间存在差异，但甲氨蝶呤对滑膜的影响仅在RA中描述。在这项研究中，我们试图确定甲氨蝶呤对炎症浸润和细胞因子和金属蛋白酶基因表达的PsA患者的滑膜的影响。10例PsA患者（中位持续时间18个月）在甲氨蝶呤诱导临床改善之前和之后对发炎的膝关节进行关节镜检查和滑膜活检。免疫组织学分析使用抗体CD3，CD4，CD8，CD68，因子VIII，血管细胞粘附分子，E-选择素，和细胞间粘附分子（ICAM）。通过竞争性逆转录聚合酶链反应（RTPCR）定量测定基质金属蛋白酶3（MMP-3）和金属蛋白酶组织抑制剂1（TIMP-1）信使RNA（mRNA）。通过实时PCR定量白细胞介素-1 α（IL-1 alpha）、IL-1 β、IL-2、IL-4、IL-5、IL-8、IL-10、IL-12 p35、IL-12 p40、IL-15、干扰素-γ（IFN-γ）和肿瘤坏死因子α（TNF-α）mRNA表达。患者接受的中位甲氨蝶呤剂量为13.75 mg/周（范围7.5 - 15），中位时间为11.5个月（范围7 - 14个月）。里奇关节指数、肿胀关节计数和疾病活动评分均显著降低。所有免疫组织学染色均减少，但仅CD 3、CD 4、CD 8、CD 68、E-选择素和ICAM具有统计学显著性。尽管所有患者的临床改善，但在所有滑膜活检组织中均存在残留的T细胞浸润。滑膜衬里层厚度显著减少，但血管丰富程度没有显著降低。MMP-3的表达也显著降低，但TIMP-1的表达没有显著降低。治疗前，PsA滑膜的特征是促炎细胞因子IL-15、IFN γ、IL-1 β和TNF α以及促炎细胞因子IL-10的主要表达。甲氨蝶呤可降低滑膜IL-1 α、IL-1 β、IL-8、IL-10、IL-15、IFN-γ和TNF α mRNA的表达，但仅对IL-8有显著影响。甲氨蝶呤通过减少但不消除滑膜中的炎性浸润、粘附分子表达、MMP-3和促炎细胞因子基因表达（特别是IL-8）而在PsA中产生临床反应。甲氨蝶呤并没有减少血供过多，这是PsA滑膜的一个突出的鉴别特征。
Objective. Methotrexate is one of the most commonly used disease-modifying antirheumatic drugs in the management of psoriatic arthritis (PsA). Despite the differences between the inflammation in PsA and rheumatoid arthritis (RA), the effects of methotrexate on the synovium have been described solely in RA. In this study, we sought to determine the effects of methotrexate on the inflammatory infiltrate and on cytokine and metalloproteinase gene expression in the synovium of PsA patients.Methods. Ten patients with PsA (median duration 18 months) underwent arthroscopy and synovial biopsy of an inflamed knee before and after clinical improvement induced by methotrexate. Immunohistologic analysis was performed using antibodies to CD3, CD4, CD8, CD68, factor VIII, vascular cell adhesion molecule, E-selectin, and intercellular adhesion molecule (ICAM). Matrix metalloproteinase 3 (MMP-3) and tissue inhibitor of metalloproteinases 1 (TIMP-1) messenger RNA (mRNA) were quantified by competitive reverse transcription-polymerase chain reaction (RTPCR). Interleukin-1alpha (IL-1alpha), IL-1beta, IL-2, IL-4, IL-5, IL-8, IL-10, IL-12p35, IL-12p40, IL-15, interferon-gamma (IFNgamma), and tumor necrosis factor alpha (TNFalpha) mRNA expression was quantified by real-time PCR.Results. Patients received a median methotrexate dosage of 13.75 mg/week (range 7.5-15) for a median of 11.5 months (range 7-14 months). The Ritchie Articular Index, swollen joint count, and Disease Activity Score were significantly reduced. There was a decrease in all immunohistologic staining, although this was statistically significant only for CD3, CD4, CD8, CD68, E-selectin, and ICAM. Despite clinical improvement in all patients, there was a residual T cell infiltrate in all synovial biopsy tissues. The synovial lining layer thickness, but not hypervascularity, was significantly reduced. There was also a significant reduction in MMP-3, but not TIMP-1, expression. Before treatment, PsA synovium was characterized by a predominant expression of the proinflammatory cytokines IL-15, IFNgamma, IL-1beta, and TNFalpha and the antiinflammatory cytokine IL-10. Methotrexate reduced synovial IL-1alpha, IL-1beta, IL-8, IL-10, IL-15, IFNgamma, and TNFalpha mRNA expression, but the effect was significant only for IL-8.Conclusion. Methotrexate produced a clinical response in PsA by reducing, but not abolishing, the inflammatory infiltrate, adhesion molecule expression, and MMP-3 and proinflammatory cytokine gene expression, particularly IL-8, in the synovium. Methotrexate did not reduce hypervascularity, which is a prominent differentiating feature of PsA synovium.