Esophagus to Small Intestine
Lancet Gastroenterol Hepatol. 2022;7(7):617–26
Short-term anti-TNF therapy with surgical closure versus anti-TNF therapy in the treatment of perianal fistulas in Crohn’s disease (PISA-II): A patient preference randomized trial
Background: Guidelines on Crohn’s perianal fistulas recommend anti-tumor necrosis factor (TNF) treatment and suggest considering surgical closure for patients with surgically amenable disease. However, long-term outcomes following these 2 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 multicenter, patient preference study done in 9 hospitals in the Netherlands and 1 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 counseling, patients with no treatment preference were randomly assigned (1:1) using random block randomization (block sizes of 6 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 magnetic resonance imaging 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 (ITT) 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 ITT basis and additionally an as-treated analysis for radiological healing and clinical closure.
Findings: Between September 14, 2013, and December 7, 2019, 94 patients were enrolled onto the trial, of whom 32 (34%) were randomly assigned and 62 (66%) chose a specific treatment. 38 patients (40%) were assigned to the surgical closure group and 56 patients (60%) to the anti-TNF group. At 18 months, radiological healing was significantly more common in the surgical closure group (12 patients [32%]) than in the anti-TNF group (5 patients [9%]; p = 0.005). By contrast, clinical closure was not significantly different between the 2 treatment groups (26 patients [68%] in the surgical closure group vs. 29 patients [52%] 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 (5 patients [13%] in the surgical closure group, median 1 reintervention [interquartile range {IQR}, 1–3] vs. 24 patients [43%] in the anti-TNF group, median 2 reinterventions [IQR, 1–2]; p = 0.005). Among patients who reached clinical closure during follow-up, 4 of 29 (14%) in the surgical closure group and 5 of 31 (16%) 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 patients (11%) 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-tumor necrosis factor (TNF) treatment combined with surgical closure induces long-term magnetic resonance imaging 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 counseled for this therapeutic approach.