Background

Guidelines on Crohn's perianal fistulas recommend anti-tumour necrosis factor (TNF) treatment and suggest considering surgical closure for patients with surgically amenable disease. However, long-term outcomes following these two strategies have not been directly compared. The aim of this study was to assess radiological healing in patients who received short-term anti-TNF treatment and surgical closure compared with those who received anti-TNF treatment alone.

Methods

The PISA-II trial was a multicentre, patient preference study done in nine hospitals in the Netherlands and one hospital in Italy. Adult patients with Crohn's disease and an active high perianal fistula with a single internal opening were eligible for inclusion. After counselling, patients with no treatment preference were randomly assigned (1:1) using random block randomisation (block sizes of six without statification), to 4-month anti-TNF therapy and surgical closure or anti-TNF therapy for 1 year, after seton insertion. Patients with a treatment preference received their preferred therapy. The primary outcome was radiological healing assessed by MRI at 18 months, defined as a complete fibrotic tract or a MAGNIFI-CD (Magnetic Resonance Index for Fistula Imaging in Crohn's Disease) score of 0, assessed according to the intention-to-treat principle. Secondary outcomes included clinical closure, number of patients undergoing surgical reintervention and number of reinterventions, recurrences, and impact on quality of life measured by the Perianal Disease Activity Index (PDAI). Analyses were performed on an intention-to-treat basis and additionally an as-treated analysis for radiological healing and clinical closure. This study was registered at the Dutch Trial Registry, NL7625, and with EudraCT, 2018-002064-15, and is closed to accrual due to completion.

Findings

Between Sept 14, 2013, and Dec 7, 2019, 94 patients were enrolled onto the trial, of whom 32 (34%) were randomly assigned and 62 (66%) chose a specific treatment. 38 (40%) patients were assigned to the surgical closure group and 56 (60%) patients to the anti-TNF group. At 18 months, radiological healing was significantly more common in the surgical closure group (12 [32%] patients) than in the anti-TNF group (five [9%] patients; p=0·005). By contrast, clinical closure was not significantly different between the two treatment groups (26 [68%] patients in the surgical closure group vs 29 [52%] patients in the anti-TNF group; p=0·076). Significantly fewer patients required a reintervention in the surgical closure group than in the anti-TNF therapy group (five [13%] patients in the surgical closure group, median one reintervention [IQR one to three] vs 24 [43%] patients in the anti-TNF group, median two reinterventions [one to two]; p=0·005). Among patients who reached clinical closure during follow-up, four (14%) of 29 in the surgical closure group and five (16%) of 31 in the anti-TNF therapy group had a recurrence, which occurred only in patients without radiological healing. PDAI was significantly lower in the surgical closure group than in the anti-TNF group after 18 months (p=0·031). Adverse events and serious adverse events were similar in both treatment groups and mostly entailed reinterventions. Ten (11%) patients had side-effects associated with anti-TNF treatment. Two serious adverse events unrelated to study treatment occurred (appendicitis and myocardial infarction). One patient died from a tongue base carcinoma, unrelated to study treatment.

Interpretation

Short-term anti-TNF treatment combined with surgical closure induces long-term MRI healing more frequently than anti-TNF therapy in patients with Crohn's perianal fistulas. These data suggest that patients with Crohn's perianal fistula amenable for surgical closure should be counselled for this therapeutic approach.

Funding

Netherlands Organisation for Health Research and Development and Broad Medical Research Program.

中文翻译：

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短期抗 TNF 治疗联合手术闭合与抗 TNF 治疗治疗克罗恩病肛周瘘 (PISA-II)：患者偏好随机试验

背景

克罗恩肛周瘘指南推荐抗肿瘤坏死因子 (TNF) 治疗，并建议考虑对可手术治疗的疾病患者进行手术闭合。然而，尚未直接比较这两种策略的长期结果。本研究的目的是评估接受短期抗 TNF 治疗和手术闭合的患者与单独接受抗 TNF 治疗的患者的放射愈合情况。

方法

PISA-II 试验是一项多中心、患者偏好研究，在荷兰的九家医院和意大利的一家医院进行。患有克罗恩病和具有单个内部开口的活动性高位肛周瘘管的成年患者符合入选条件。咨询后，无治疗偏好的患者被随机分配（1:1），使用随机区组随机化（区组大小为 6 个无统计），接受 4 个月的抗 TNF 治疗和手术闭合或 1 年的抗 TNF 治疗。挂线插入。有治疗偏好的患者接受了他们首选的治疗。主要结果是 18 个月时通过 MRI 评估的放射学愈合情况，定义为完整的纤维化道或 MAGNIFI-CD（克罗恩病瘘管成像的磁共振指数）评分为 0，根据意向治疗原则进行评估。次要结局包括临床关闭、接受手术再干预的患者人数和再干预次数、复发以及对肛周疾病活动指数 (PDAI) 测量的生活质量的影响。分析是在意向治疗的基础上进行的，另外还对放射愈合和临床闭合进行了治疗分析。该研究已在荷兰试验登记处注册，NL7625，并在 EudraCT，2018-002064-15 注册，并因完成而关闭。分析是在意向治疗的基础上进行的，另外还对放射愈合和临床闭合进行了治疗分析。该研究已在荷兰试验登记处注册，NL7625，并在 EudraCT，2018-002064-15 注册，并因完成而关闭。分析是在意向治疗的基础上进行的，另外还对放射愈合和临床闭合进行了治疗分析。该研究已在荷兰试验登记处注册，NL7625，并在 EudraCT，2018-002064-15 注册，并因完成而关闭。

发现

2013 年 9 月 14 日至 2019 年 12 月 7 日期间，94 名患者参加了试验，其中 32 名 (34%) 被随机分配，62 名 (66%) 选择了特定治疗。38 名（40%）患者被分配到手术闭合组，56 名（60%）患者被分配到抗 TNF 组。在 18 个月时，手术闭合组（12 [32%] 例患者）的放射愈合明显高于抗 TNF 组（5 [9%] 例患者；p=0·005）。相比之下，两个治疗组之间的临床闭合没有显着差异（手术闭合组的 26 [68%] 名患者与抗 TNF 组 29 名 [52%] 名患者；p=0·076)。与抗 TNF 治疗组相比，手术闭合组需要再次干预的患者显着减少（手术闭合组 5 例 [13%] 患者，中位数 1 例再次干预 [IQR 1 到 3]对比抗 TNF 组 24 名 [43%] 名患者，中位数为 2 次再干预 [1 到 2 次]；p=0·005)。在随访期间达到临床闭合的患者中，手术闭合组 29 例中有 4 例 (14%) 和抗 TNF 治疗组 31 例中有 5 例 (16%) 复发，仅发生在未放射愈合的患者中. 18 个月后，手术闭合组的 PDAI 显着低于抗 TNF 组（p=0·031）。两个治疗组的不良事件和严重不良事件相似，并且大多需要重新干预。10 名 (11%) 患者出现与抗 TNF 治疗相关的副作用。发生了两起与研究治疗无关的严重不良事件（阑尾炎和心肌梗塞）。一名患者死于舌根癌，与研究治疗无关。

解释

在克罗恩肛周瘘患者中，短期抗 TNF 治疗联合手术闭合比抗 TNF 治疗更频繁地诱导长期 MRI 愈合。这些数据表明，克罗恩氏肛周瘘患者应接受手术封堵治疗。

资金

荷兰卫生研究与发展组织和广泛的医学研究计划。