Disease-modifying antirheumatic drugs (DMARDs) are widely used for treating rheumatoid arthritis (RA). However, there are no established biomarkers to predict a patient’s response to these therapies. Prostanoids, encompassing prostaglandins, prostacyclins, and thromboxanes, are potent lipid mediators implicated in RA progression. Nevertheless, the influence of DMARDs on prostanoid biosynthesis in RA patients remains poorly understood. This study aims to assess the impact of various DMARDs on urinary prostanoids levels and to explore whether urinary prostanoid profiles correlate with disease activity or response to therapy. This study included 152 Swedish female patients with early RA, all rheumatoid factor (RF) positive, enrolled in the NORD-STAR trial (registration number: NCT01491815). Participants were randomized into four therapeutic regimes: methotrexate (MTX) combined with (i) prednisolone (arm ACT), (ii) TNF-α blocker certolizumab pegol (arm CZP), (iii) CTLA-4Ig abatacept (arm ABA), or (iv) IL-6R blocker tocilizumab (arm TCZ). Urine samples, collected before start of treatment and at 24 weeks post-treatment, were analyzed for tetranor-prostaglandin E metabolite (tPGEM), tetranor-prostaglandin D metabolite (tPGDM), 2,3-dinor thromboxane B2 (TXBM), 2,3-dinor-6-keto prostaglandin F1a (PGIM), leukotriene E4 (LTE4) and 12-hydroxyeicosatetraenoic acid (12-HETE) using liquid chromatography–mass spectrometry (LC–MS). Generalized estimating equation (GEE) models were used to analyze the change in urinary eicosanoids and their correlations to clinical outcomes. Patients receiving MTX combined with CZP or TCZ exhibited significant elevations in urinary tPGEM and TXBM levels after 24 weeks of treatment. Other eicosanoids did not show significant alterations in response to any treatment. Baseline urinary eicosanoid levels did not correlate with baseline clinical disease activity index (CDAI) levels, nor with changes in CDAI from baseline to week 24. Their levels were also similar between patients who achieved CDAI remission and those with active disease at week 24. Treatment with anti-TNF or anti-IL6R agents in early RA patients leads to an increased systemic production of proinflammatory and prothrombotic prostanoids. However, urinary eicosanoid levels do not appear to be predictive of the response to DMARDs therapy.

中文翻译：

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抗 TNF 和抗 IL6 受体疾病缓解抗风湿药物会升高尿前列腺素水平，但不能预测早期类风湿关节炎的治疗反应

缓解病情抗风湿药 (DMARD) 广泛用于治疗类风湿性关节炎 (RA)。然而，没有既定的生物标志物来预测患者对这些疗法的反应。前列腺素，包括前列腺素、前列环素和血栓素，是与 RA 进展有关的有效脂质介质。然而，DMARDs 对 RA 患者前列腺素生物合成的影响仍然知之甚少。本研究旨在评估各种 DMARD 对尿前列腺素水平的影响，并探讨尿前列腺素水平是否与疾病活动或治疗反应相关。该研究纳入了 152 名瑞典早期 RA 女性患者，所有类风湿因子 (RF) 均呈阳性，她们参加了 NORD-STAR 试验（注册号：NCT01491815）。参与者被随机分为四种治疗方案：甲氨蝶呤 (MTX) 联合 (i) 泼尼松龙（ACT 组）、(ii) TNF-α 阻滞剂聚乙二醇赛妥珠单抗（CZP 组）、(iii) CTLA-4Ig 阿巴西普（ABA 组）或(iv) IL-6R 阻滞剂托珠单抗（TCZ 臂）。在治疗开始前和治疗后 24 周收集尿液样本，分析四去甲前列腺素 E 代谢物 (tPGEM)、四去甲前列腺素 D 代谢物 (tPGDM)、2,3-二去甲血栓素 B2 (TXBM)，2，使用液相色谱-质谱 (LC-MS) 分析 3-二去-6-酮前列腺素 F1a (PGIM)、白三烯 E4 (LTE4) 和 12-羟基二十碳四烯酸 (12-HETE)。使用广义估计方程（GEE）模型来分析尿类二十烷酸的变化及其与临床结果的相关性。接受 MTX 联合 CZP 或 TCZ 治疗的患者在治疗 24 周后表现出尿 tPGEM 和 TXBM 水平显着升高。其他类二十烷酸在任何治疗后均未表现出显着变化。基线尿类二十烷酸水平与基线临床疾病活动指数 (CDAI) 水平无关，也与 CDAI 从基线到第 24 周的变化无关。在第 24 周实现 CDAI 缓解的患者和患有活动性疾病的患者之间，其水平也相似。在早期 RA 患者中使用抗 TNF 或抗 IL6R 药物会导致促炎和促血栓前列腺素的全身产生增加。然而，尿类二十烷酸水平似乎并不能预测 DMARD 治疗的反应。