Hitchon Carol A, Alex Philip, Erdile Lawrence B, Frank Mark B, Dozmorov Igor, Tang Yuhong, Wong Keng, Centola Michael, El-Gabalawy Hani S
Arthritis Centre, University of Manitoba, 800 Sherbrook Street, Winnipeg, Manitoba R3A 1M4, Canada.
J Rheumatol. 2004 Dec;31(12):2336-46.
Early inflammatory arthritis is clinically heterogenous and biologically-based indicators are needed to distinguish severe from self-limited disease. Anti-cyclical citrullinated peptides (CCP) have been identified as potential prognostic markers in early arthritis cohorts. Since cytokine networks are known to play a critical role in the pathogenesis of rheumatoid arthritis (RA) and other forms of inflammatory arthritis, a panel of pro- and antiinflammatory cytokines was measured to identify biologically-based subsets of early arthritis, relating cytokine profiles to clinical measures and to the presence of RA-associated autoantibodies.
Plasma concentrations of cytokines [interleukin 1beta (IL-1beta), IL-2, IL-4, IL-5, IL-6, IL-7, CXCL8 (IL-8), IL-10, IL-12p70, IL-13, IL-17, granulocyte-colony stimulating factor (G-CSF), granulocyte macrophage-colony stimulating factor (GM-CSF), interferon-g (IFN-g), CCL2 (monocyte chemoattractant protein-1, MCP-1), CCL4 (MIP-1beta), and tumor necrosis factor-a (TNF-a)] were measured in patients with early, untreated inflammatory arthritis [symptom duration < or = 12 months; > or = 1 swollen joint; RA, n = 41; undifferentiated arthritis (UA), n = 23]. Cytokine expression patterns were determined using cluster analysis.
Both pro- and antiinflammatory cytokines were elevated in patients over controls (n = 21). RA clustered into subgroups based solely on cytokine profiles. The "mild" RA subgroup (n = 23) had higher CCL4 (MIP-1beta), CXCL8 (IL-8), IL-2, IL-12, IL-17, IL-5, and IL-10 levels, lower IL-6, IFN-g, GM-CSF, and IL-4 levels, less CCP positivity (52% vs 82%; p < 0.05), and lower CCP titers [71 (78) vs 153 (94); p < 0.01], but similar erythrocyte sedimentation rate, C-reactive protein, and joint counts compared to the "severe" RA groups. CCL4 (MIP-1beta), IL-13, IL-12, TNF-a, and IL-4 best distinguished the groups. Combining UA with RA samples preserved cytokine subgroups and strengthened the autoantibody associations. Fewer UA patients in the "mild" cluster (n = 16) were RF-positive (24% vs 100%; p < 0.002) or CCP-positive (24% vs 66%; p < 0.08) compared to the "severe" group.
Early untreated inflammatory arthritis can be categorized into distinct subgroups based on cytokine profiles. These subgroups are associated with CCP and RF autoantibodies. Integration of cytokine profiles with autoantibody status may assist prognostication and treatment decisions in these patients.
早期炎性关节炎在临床上具有异质性，需要基于生物学的指标来区分严重疾病和自限性疾病。抗环瓜氨酸化肽（CCP）已被确定为早期关节炎队列中的潜在预后标志物。由于已知细胞因子网络在类风湿关节炎（RA）和其他形式的炎性关节炎的发病机制中起关键作用，因此检测了一组促炎和抗炎细胞因子，以确定早期关节炎基于生物学的亚组，将细胞因子谱与临床指标以及RA相关自身抗体的存在相关联。
检测早期未治疗的炎性关节炎患者（症状持续时间≤12个月；≥1个肿胀关节；RA，n = 41；未分化关节炎（UA），n = 23）血浆中细胞因子[白细胞介素1β（IL-1β）、IL-2、IL-4、IL-5、IL-6、IL-7、CXCL8（IL-8）、IL-10、IL-12p70、IL-13、IL-17、粒细胞集落刺激因子（G-CSF）、粒细胞巨噬细胞集落刺激因子（GM-CSF）、干扰素-γ（IFN-γ）、CCL2（单核细胞趋化蛋白-1，MCP-1）、CCL4（MIP-1β）和肿瘤坏死因子-α（TNF-α）]的浓度。使用聚类分析确定细胞因子表达模式。
与对照组（n = 21）相比，患者体内促炎和抗炎细胞因子均升高。RA仅根据细胞因子谱聚类为亚组。“轻度”RA亚组（n = 23）的CCL4（MIP-1β）、CXCL8（IL-8）、IL-2、IL-12、IL-17、IL-5和IL-10水平较高，IL-6、IFN-γ、GM-CSF和IL-4水平较低，CCP阳性率较低（52%对82%；p < 0.05），CCP滴度较低[71（78）对153（94）；p < 0.01]，但与“重度”RA组相比，红细胞沉降率、C反应蛋白和关节计数相似。CCL4（MIP-1β）、IL-13、IL-12、TNF-α和IL-4最能区分这些组。将UA与RA样本合并保留了细胞因子亚组并加强了自身抗体关联。与“重度”组相比，“轻度”聚类中的UA患者（n = 16）RF阳性（24%对100%；p < 0.002）或CCP阳性（24%对66%；p < 0.08）的比例更低。
早期未治疗的炎性关节炎可根据细胞因子谱分为不同的亚组。这些亚组与CCP和RF自身抗体相关。将细胞因子谱与自身抗体状态相结合可能有助于这些患者的预后评估和治疗决策。
