Patients with PFCD represent a more aggressive and disabling disease course . To reduce the need for multiple operations and associated comorbidities, a combination of surgery with anti-TNF agents targeted at optimization of perianal and luminal diseases simultaneously has been suggested as the preferred treatment modality [3,5,16,17]. An important factor that should be taken into consideration when adopting combination therapy is time interval between surgical and medical treatments. In current study, we directly compared early combination approach with conventional combination approach. At a median follow-up of 3 years, the fistula closure rate in both groups are beyond 60% (61.6% in early combination vs. 65.9% in conventional combination). Our finding is similar to a retrospective study also using early combination therapy, with 2-4 weeks between fistula surgery and infliximab induction therapy. Fifty-nine percent of patients with PFCD completely healed after a combination of operative treatment and infliximab . Some recent studies highlight the benefit of early introduction of the biological agent after surgical drainage of sepsis [9,20-24]. The essential reason to support the concept of early combination therapy is the rapid therapeutic response of infliximab for both luminal and fistulous disease, thus timely infliximab delivery could promote fistula healing [18,27]. In an observational study of 129 patients, clinical response and remission for the fistulous disease occurred at a median of 9 days (ranging from 5 to 47 days) and 10 days (ranging from 6 to 54 days) respectively . In ACCENT I trial, 58% of patients responded to a single infusion of infliximab within 2 weeks . There is no difference in fistula closure between two combination approaches. It needs to be emphasized that significantly more patients in conventional combination group had fistulotomy than in early combination group (18.2% vs. 2.7%) at first attempt. Definitive surgery (such as fistulotomy, RAF, or LIFT) is justified by its effectiveness of fistula closure and decreasing repeat surgery for PFCD, compared with seton drainage along [18,21,23]. However, it could only be attempted in highly selected simple fistula without proctitis and abscess. For complex PFCD, placement of a non-cutting seton is still the treatment of choice. Almost all patients (95% of patients) in early combination group received seton placement as the initial surgery, still achieved a 62% fistula closure rate. The promising result may attribute to the multimodality approach we applied in daily practice, which included preoperative MRI-guided drainage of all sepsis and early initiation of anti‐TNF, followed by early removal of setons. This may indicate that timing instead of type of interventions plays an important role in managing PFCD patients.
Heterogeneity in outcome definition hampers effective data analysis and comparison between different studies about PFCD treatments. In solutions try to address this issue, we used the need for fistula‐related re-intervention as the primary endpoint. Since repeat surgery may act as a surrogate marker for fistula relapse and avoiding this event is the essential goal for PFCD management [30-32]. In the current study, 30% of patients required at least one repeat surgery through the follow-up period. There was a trend toward a higher re-intervention rate in early combination group (34%) as compared with conventional combination group (25%). This may be due to the higher proportion of anorectal stricture and abscess in early combination group, which increased the complexity of management. However, no significant difference in total and cumulative re-intervention was found between the two groups. Our finding is similar as recently reported by a multicenter study from Europe, 32% of PFCD patients who received multimodal treatment required repeating perianal fistula‐related surgery .
Identifying the predictors affecting long-term outcomes of early combination therapy remains the goal of directing future personalized therapy. However, the relevant study focus on this field is scarce [21,24,33]. Previous studies have identified multimodality treatment, seton removal, therapy with biological agents, and complete fistula response was associated with reduced surgical intervention [32,34]. In our study, the presence of abscess increased risk of surgical re-intervention and adversely impacted long-term fistula closure in early combination group. Concerns have been raised that use of infliximab might increase perianal abscess formation or fistula recurrence because of the rapid closure of the external fistula opening and persistent inflammation of the residual tract [35,36]. Literature remains controversial regarding the impact of infliximab on perianal infectious complications. Two population-based studies have observed the rising trend of abscess drainage since the introduction of infliximab [37,38]. On the contrary, data from the ACCENT II study fail to demonstrate the association between abscesses development and infliximab therapy . Our findings indicate that for patients associated with abscesses at the time of surgery, starting infliximab too early may increase the risk of surgical re-intervention and compromise long-term fistula closure. In a small case series of early combination therapy, 12 of 22 complex perianal fistula had abscess that required drainage. Long-term clinical fistula healing was only achieved in 18% of patients . One could speculate that concomitant abscess cavity may require a longer time of drainage to allow the inflammatory process to settle down before infliximab therapy is scheduled.
Maintenance infliximab therapy more than 3 times is another risk factor for surgical re-intervention in early combination group. Unlike previous studies, which showed that maintenance therapy with infliximab could reduce the risk of surgery and improve fistula closure in patients with PFCD [4,24]. This difference, however, may due to patients who need infliximab maintenance therapy more than 3 times in our study usually have more refractory fistulas, which required intermittent surgical intervention for local optimization. It also could be due to the potential increased risk of abscess formation with infliximab maintenance therapy, which also involves repeat surgical drainage. In our study, only 13% of patients in early combination group had ongoing infliximab therapy at the last follow-up, while almost half of the patients had switched to immunomodulators. The low infliximab maintenance rate was mainly due to the expense of infliximab was not covered by insurance in China during study period, and the cost is approximately $2000 per infusion. Several cohort studies have demonstrated promising fistula healing in patients who only received induction or short-term maintenance infliximab therapy, followed by immunomodulators maintenance therapy [9,18,23]. We hypothesize that early use of biologics for a limited duration to achieve a quick response, followed by cheaper immunosuppressant agents, could be considered as a cost-effective alternative for patients with PFCD.
Our study has several limitations: (1) A higher proportion of our cases received early combination approach leading to a significantly smaller conventional combination group and made it difficult to obtain a statistical difference between some results. (2) Due to the retrospective feature, objective fistula severity measurements such as MRI score or PDAI score were not routinely collected during our study. Although rectal MRI was performed in all included patients before treatment, a great percent of patients didn't receive MRI re-examination during follow-up. (3) All cases were collected from a single tertiary academic center, leading to the inclusion of a high number of patients with complex fistulas, and whether these data apply to patients with simple PFCD is uncertain. (4) The time interval of combination therapy was wide between different patients, especially in the conventional combination group; however, this may reflect the complexity of decision-making in PFCD management.
The strengths of this study include (1) The relatively large sample size in a single institution with two experienced surgeons performing all of the surgeries. (2) We measured perianal surgical re-intervention and long-term clinical fistula closure as endpoint definitions, which are clinically relevant parameters in reflecting real-world practice. (3) We only included patients who have finished infliximab induction therapy and have been followed up over one year, which is robust enough to provide reliable long-term outcomes.
In conclusion, early initiation of infliximab therapy after surgery results in promising long-term fistula closure in a significant proportion of PFCD patients with an acceptable surgical re-intervention rate. For patients with concomitant perianal abscesses or requiring infliximab maintenance therapy, a longer interval is warranted to establish durable drainage before beginning infliximab therapy. In patients with PFCD who receive early combination therapy, maintenance with immunomodulators such as azathioprine could be a reasonable alternative. The optimal timing to initiate treatment is still needed to be determined in future studies.