van der Heijden Eefje Hanna Martine, Blokland Sofie Liny Marie, Hillen Maarten Reinier, Lopes Ana Paula Pinheiro, van Vliet-Moret Fréderique Marie, Rosenberg Antoine Johan Wilhelm Peter, Janssen Nard Gabriëlle, Welsing Paco Mattheus Jacobus, Iannizzotto Valentina, Tao Weiyang, Pandit Aridaman, Barone Francesca, Kruize Aike Albert, Radstake Timothy Ruben Dirk Jan, van Roon Joel Adrianus Gijsbert
Department of Rheumatology and Clinical Immunology, University Medical Center Utrecht, Utrecht University, Utrecht, Netherlands; Center of Translational Immunology, Department of Immunology, University Medical Center Utrecht, Utrecht University, Utrecht, Netherlands.
Center of Translational Immunology, Department of Immunology, University Medical Center Utrecht, Utrecht University, Utrecht, Netherlands.
Lancet Rheumatol. 2020 May;2(5):e260-e269. doi: 10.1016/S2665-9913(20)30057-6. Epub 2020 Mar 26.
Primary Sjögren's syndrome is a systemic autoimmune disease characterised by secretory gland dysfunction, for which no effective therapy is available. Based on the complementary properties of leflunomide and hydroxychloroquine in inhibiting activation of key immune cells in primary Sjögren's syndrome, we aimed to evaluate the clinical efficacy and safety of leflunomide-hydroxychloroquine combination therapy in patients with primary Sjögren's syndrome.
We did a placebo-controlled, double-blinded, phase 2A randomised clinical trial in patients with primary Sjögren's syndrome at the University Medical Center Utrecht (Utrecht, Netherlands). Eligible patients were aged 18-75 years, had a European League Against Rheumatism (EULAR) Sjögren's syndrome disease activity index (ESSDAI) score of 5 or higher, and a lymphocytic focus score of 1 or higher in labial salivary gland biopsy specimens. Patients were randomly assigned (2:1) with block randomisation (block size of six) to receive leflunomide 20 mg and hydroxychloroquine 400 mg daily or placebo for 24 weeks. The primary endpoint was the between-group difference in change in ESSDAI scores from 0 to 24 weeks, adjusted for baseline ESSDAI score. Patients were analysed according to the intention-to-treat principle. This study is registered with EudraCT, 2014-003140-12.
Between March 7, 2016, and Nov 30, 2017, 37 patients were screened, of whom 29 patients (28 women and one man) were enrolled. 21 patients were assigned to receive leflunomide-hydroxychloroquine and eight patients were assigned to receive placebo. One patient in the placebo group required high-dose prednisone to treat polymyalgia rheumatica at week 13 and was excluded from the primary analysis. From 0 to 24 weeks, the mean difference in ESSDAI score, adjusted for baseline values, in the leflunomide-hydroxychloroquine group compared with the placebo group was -4·35 points (95% CI -7·45 to -1·25, p=0·0078). No serious adverse events occurred in the leflunomide-hydroxychloroquine group and two serious adverse events occurred in the placebo group (hospital admission for pancreatitis and hospital admission for nephrolithiasis). The most common adverse events in the leflunomide-hydroxychloroquine group were gastrointestinal discomfort (11 patients [52%] vs two [25%] in the placebo group), modest transient increases in alanine aminotransferase (ten [48%] vs one [13%]), and short episodes of general malaise and shivering (nine [43%] vs one [13%]).
Leflunomide-hydroxychloroquine was safe and resulted in a clinical response in patients with primary Sjögren's syndrome. These results warrant further evaluation of leflunomide-hydroxychloroquine combination therapy in larger clinical trials.
ZonMw.
原发性干燥综合征是一种以分泌腺功能障碍为特征的系统性自身免疫性疾病，目前尚无有效的治疗方法。基于来氟米特和羟氯喹在抑制原发性干燥综合征关键免疫细胞激活方面的互补特性，我们旨在评估来氟米特 - 羟氯喹联合治疗原发性干燥综合征患者的临床疗效和安全性。
我们在荷兰乌得勒支大学医学中心对原发性干燥综合征患者进行了一项安慰剂对照、双盲、2A期随机临床试验。符合条件的患者年龄在18 - 75岁之间，欧洲抗风湿病联盟（EULAR）干燥综合征疾病活动指数（ESSDAI）评分≥5分，唇唾液腺活检标本中淋巴细胞灶评分≥1分。患者采用区组随机化（区组大小为6）按2:1随机分配，接受每日20 mg来氟米特和400 mg羟氯喹或安慰剂治疗24周。主要终点是调整基线ESSDAI评分后，0至24周ESSDAI评分的组间差异。患者按意向性分析原则进行分析。本研究已在欧洲临床试验数据库（EudraCT）注册，注册号为2014 - 003140 - 12。
2016年3月7日至2017年11月30日期间，共筛选了37例患者，其中29例（28例女性和1例男性）入组。21例患者被分配接受来氟米特 - 羟氯喹治疗，8例患者被分配接受安慰剂治疗。安慰剂组有1例患者在第13周需要高剂量泼尼松治疗多肌痛性风湿，被排除在主要分析之外。0至24周，调整基线值后，来氟米特 - 羟氯喹组与安慰剂组的ESSDAI评分平均差异为 - 4.35分（95%CI - 7.45至 - 1.25，p = 0.0078）。来氟米特 - 羟氯喹组未发生严重不良事件，安慰剂组发生了2例严重不良事件（胰腺炎住院和肾结石住院）。来氟米特 - 羟氯喹组最常见的不良事件是胃肠道不适（11例[52%]对比安慰剂组2例[25%]）、丙氨酸转氨酶适度短暂升高（10例[48%]对比1例[13%]）以及短暂的全身不适和寒战发作（9例[43%]对比1例[13%]）。
来氟米特 - 羟氯喹对原发性干燥综合征患者安全且有临床疗效。这些结果值得在更大规模的临床试验中对来氟米特 - 羟氯喹联合治疗进行进一步评估。
荷兰卫生与福利研究所（ZonMw）
