The Optimal Management of Fistulizing Crohn’s Disease: Evidence beyond Randomized Clinical Trials

Fistulizing Crohn’s disease (FCD) remains the most challenging aspect of treating patients with CD. FCD can occur in up to 30% of patients with CD and may lead to significant disability and impaired quality of life. The optimal treatment strategies for FCD require a multidisciplinary approach, including a combined medical and surgical approach. The therapeutic options for FCD are limited due to sparse evidence from randomized clinical trials (RCTs). The current recommendations are mainly based on post hoc analysis from RCTs, real-world clinical studies and expert opinion. There is variation in everyday clinical practice amongst gastroenterologists and surgeons. The evidence for anti-tumor necrosis factor therapy is the strongest in the treatment of FCD. However, long-term fistula healing can be achieved in only 30–50% of patients. In recent years, emerging data in the advent of therapeutic modalities, including the use of new biologic agents, therapeutic drug monitoring, novel surgical methods and mesenchymal stem cell therapy, have been shown to improve outcomes in achieving fistula healing. This review summarizes the existing literature on current and emerging therapies to provide guidance beyond RCTs in managing FCD.

2.1. What Is the Evidence of Anti-TNF Therapy from RCTs and beyond RCT?

Anti-TNF has become the cornerstone of therapy for FCD. Several randomized, placebo-controlled trials have demonstrated the efficacy of anti-TNF therapy for the induction and maintenance of remission in FCD. Thus, current evidence suggests the use of anti-TNF therapy as a first-line treatment for FCD [14]. However, evidence indicates that certolizumab pegol may not be effective in the induction of fistula remission. The selected key studies in FCD are summarized in Table 1.

2.2. What Is the Optimal Timing for Anti-TNF Treatment in Fistulizing CD?

The practice guideline recommends that immunosuppressive therapy should be started after adequate seton placement [19]. Given the concern for worsening perianal infection, real-world data demonstrated a significant delay in the induction of biologic therapy, with a median period of over 6 months between the diagnosis of perianal fistula and the induction of anti-TNF therapy [55].

The current data suggests that an early combination of seton and anti-TNF is safe and reasonably effective in treating perianal FCD. In a retrospective study, 76 patients were started on infliximab either late or early (250 days vs. 12 days) after seton insertion for perianal CD. The results regarding complete remission and fistula or abscess recurrence were not different between the early and delayed groups [56]. Recently, a cohort of 117 patients confirmed that the early duction of infliximab after surgery could achieve a fistula healing rate and re-intervention rate comparable to a delayed induction [57]. Thus, the early initiation of anti-TNF is preferred over delayed therapy to prevent consequent complications from fistulas.

In patients who achieve a fistula response thanks to medical therapy, maintenance therapy is recommended to maintain the long-term clinical response. The discontinuation of anti-TNF treatment is not recommended due to a high risk of relapse. Approximately half of the patients relapsed after anti-TNF was stopped, and one-third of patients with relapse required surgery [58,59,60].

2.3. What Is the Evidence Regarding New Biologics in Fistulizing CD?

2.4. Do You Need to Use Combination Therapy for Optimizing Outcomes in Fistulizing CD?

Despite the widespread use of anti-TNF as the treatment of choice for CD, there is an unmet need in terms of treating FCD. Only one-third of patients treated with anti-TNF achieved short-term remission, and approximately 40% of patients who had an initial response maintained fistula healing remission in the long term [26,63]. Current studies have focused on treatment strategies to enhance the efficacy of anti-TNF therapy for fistula healing, including the use of combination therapy involving the use of anti-TNF with antibiotics, immunomodulators, therapeutic drug monitoring (TDM) and setons drainage [58].

2.5. Are Biologics, Immunosuppressives and Combination Therapy Safe to Use in Fistulizing CD?

Patients with FCD have a high risk of recurrent perianal abscess or sepsis. Biological therapy and immunosuppressants are used for controlling active fistulas and inducing healing. Eventually, corticosteroids may be needed in some patients with active concomitant luminal disease. However, there is an increased concern that the use of biologics, immunosuppressive or combination therapy may increase the risk of serious infection, sepsis, hospitalization and need for urgent surgery [1,75,76].

In a meta-analysis of 15 observational studies, the risk of serious infection increased with the combination of anti-TNF and an immunosuppressive agent (in six cohorts; RR, 1.19; 95% CI, 1.03–1.37), especially in the case of anti-TNF and corticosteroids (in four cohorts; RR, 1.64; 95% CI, 1.33–2.03) or the use of all three drugs (in two cohorts; RR, 1.35; 95% CI, 1.04–1.77) compared to anti-TNF monotherapy [77]. A network meta-analysis of patients with active CD also showed no significant difference regarding the rate of adverse events and infections or serious/severe infections among biological/small molecule therapies (IFX, ADA, VDZ, UST, tofacitinib and CT-P13) [78].

In practice, only systemic corticosteroids should be avoided in patients with FCD or perianal abscess, given the higher risk of severe infections. Biologics and thiopurines are a safe combination therapy when combined with careful monitoring for perianal infection.

2.6. Is Therapeutic Drug Monitoring (TDM) Helpful in Optimize Treatment for Fistulizing CD?

Multiple studies have shown a correlation between higher anti-TNF levels and higher rates of perianal fistula response or closure [79,80,81,82,83]. In a post hoc analysis of the ACCENT-II trial, 282 patients with FCD received IFX for induction and 139 patients received maintenance therapy. Higher post-induction IFX concentrations were independently associated with remission at week 14 (OR: 2.32; 95% CI: 1.55–3.49) and at week 54 (OR: 2.05; 95% CI: 1.10–3.82). An IFX threshold of 15 μg/mL at week 6 and 7.2 μg/mL at week 14 stratified patients who achieved early fistula remission [45].

In a large cohort of 117 patients with perianal FCD, Yarur et al. reported that patients who achieved fistula healing had significantly higher trough IFX levels when compared to those who did not achieve healing (15.8 μg/mL vs. 4.4 μg/mL, p < 0.0001). In addition, the cuff off IFX level ≥ 10.1 μg/mL and > 20.3 μg/mL had a likelihood of achieving fistula healing 3- and 8-fold, respectively, when compared to those with IFX levels below 2.8 μg/mL [46].

Similar findings were noted for adalimumab levels. Patients with fistula closure had significantly higher drug levels than those without fistula closure (adalimumab:14.8 vs. 5.7 μg/mL, and IFX: 8.2 vs. 3.2 μg/mL). This study identified a cut off level > 7.1 μg/mL with IFX and >9.8 μg/mL with adalimumab for fistula closure [84].

In a more recent study of 193 perianal FCD patients treated with maintenance IFX or ADA, patients with MRI remission had higher anti-TNF levels compared with those with active disease (IFX 7.4 vs. 3.9 μg/mL; and ADA 9.8 vs. 6.2 μg/mL) [47].

Current evidence suggests that higher anti-TNF drug levels correlate with clinical and radiologic fistula remission. However, this causality is not proven. The optimal cut-off trough level varied amongst the studies. The target drug levels in fistulizing disease may be higher than conventional drug levels in luminal CD. The benefit of proactive TDM optimization is not proven in patients with FCD.

2.7. Is a Seton Required in the Long-Term or Short-Term as a Combination Therapy?

A seton is recommended as an adjunct to medical therapy for providing adequate fistula tract drainage to prevent recurrent abscess formation. In a systemic review including 305 patients with seton drainage, the rates of complete fistula closure after seton drainage varied from 13.6–100% and the fistula recurrence rate was up to 83.3% [85]. Multiple studies have shown the combination of a seton with IFX has a better fistula healing closure rate and lower recurrent rates of perianal fistulas and abscesses [56,86,87,88]. Thus, guidelines recommend using setons in combination with anti-TNF for FCD [19,89].

The optimal timing for seton removal is debatable. Seton drainage appears to promote fistula healing in combination with anti-TNF. However, prolonged drainage may interfere with the closure of the fistula. In a large retrospective study of patients treated with maintenance infliximab therapy, the cumulative rates of fistula recurrence were 12% and 36% at 1 and 5 years, respectively. The duration of seton drainage less than 34 weeks was associated with a higher fistula closure rate (HR 2.31), suggesting that a longer duration of seton placement does not prevent abscess recurrence [24]. One study reported that 14 patients treated with IFX and seton drainage successfully completed seton removal after five doses of infusions without early recurrence [90].

Recently, a randomized control study (PISA study) by Wasmann et al., the first of its kind, reported on 44 CD patients with a single internal opening perianal fistula. Patients were randomized into three treatment groups: chronic seton drainage for 1-year, anti-TNF therapy for 1 year and surgical closure after 2 months under a short course of anti-TNF. The seton treatment was associated with the highest re-intervention rate [10/15 seton vs. 6/15 anti-TNF vs. 3/14 surgical closure patients, p = 0.02]. There were no substantial differences in perianal disease activity and quality of life among the groups. This study showed an inferior outcome with respect to chronic seton treatment concerning re-interventions, suggesting that chronic seton treatment should not be recommended as the only treatment for perianal CD [91].

According to the result from the published literature, short-term seton placement should be considered as a bridging therapy and in combination with anti-TNF to control sepsis and promote fistula healing. However, setons should be removed after the induction of anti-TNF therapy, and their use should not exceed one year [17,92].

Table 2

3.1. Internal Fistula of GI Tract

Internal FCD of the GI tract includes entero-enteric, entero-colonic, gastro-enteric and gastro-colonic fistulas. The largest study assessing biological therapy in these types of FCD was a retrospective cohort that included 156 patients treated with anti-TNF therapy, 44% of whom had enteroenteric fistulas. The fistula healing rates according to MRI were 15%, 32% and 44% at 1, 3 and 5 years, respectively. However, 43% of patients required major abdominal surgery during the 3.5-year follow-up, and 20% of patients developed an intestinal abscess [101]. In another cohort of 93 patients treated with anti-TNFs, with 77% of patients having enteroenteric/colonic fistulas, the fistula closure rate and the surgery rate were 27% and 47% at 5 years from the induction of anti-TNF therapy, respectively [102]. Only case series data are available for non-biologic therapy. In a systematic review of seven studies, with 14 patients treated with thiopurine, 65% of patients had fistula healing [4].

3.2. Enterovesical Fistula

In a large observational cohort study of 97 patients with enterovesical (EV) fistulas, 33 patients (35%) were treated with anti-TNF and 45% of them achieved remission without needing surgery over a follow-up period of 35 months. The use of anti-TNF therapy was associated with an increased remission rate without the need for surgery (HR 0.23, 95% CI 0.12–0.44). However, 80% of patients required surgery over a median follow-up of 8 years [103]. In a systematic review, the anti-TNF treatment of 14 patients with EV fistulas resulted in 57% of them having a complete response and 35% having a partial response [104]. In addition, antibiotics have an important role to play in the symptomatic control and treatment of urosepsis or associated abscesses. Thiopurine, used with or without long-term antibiotics in 99 entero-urinary fistulas, resulted in an overall response of 39.4% [4].

3.3. Rectovaginal Fistula

Rectovaginal (RV) fistulas may cause UTIs, abscess formation and fecal incontinence. The use of antibiotics can improve short-term symptoms, especially in patients with recurrent UTIs [108]. In terms of biological therapy, the efficacy of anti-TNFs on RV fistulas was demonstrated in a systemic review reporting on 78 patients with RV fistulas who were treated with anti-TNF alone or combined with antibiotics or immunosuppressants. The overall response rate was 63%, and 37% of patients had no response [104]. In 2018, a large national-wide retrospective cohort reported on 204 patients with RV fistulas who received anti-TNF (79% infliximab, 20% adalimumab and 1% certolizumab), where 37% had complete fistula closure and 22% had a partial response at 1-year follow-up [105]. One case report of combined dual biologic therapy with VDZ and UST showed a successful fistula closure in a patient with a refractory RV fistula [109]. Thiopurines and 6-MP were reported to have efficacy in a small group of patients, with an overall response rate of 50% in 12 reported cases [110,111]. Cyclosporin was shown to be effective in the induction phase for RV fistulas, with an 89% improvement in nine patients. However, the relapse rates were reported to be 38% of responders during the maintenance phase [112]. The efficacy of tacrolimus has also been demonstrated in two out of three patients with refractory RV fistulas who had failed other therapies, including infliximab [113].

3.4. Enterocutaneous Fistula

Enterocutaneous (EC) fistulae can occur primary or secondary to surgery and can be complicated by malnutrition, coexisting intraabdominal infection, abscesses or a high output of small bowel content, with the majority of affected patients requiring intestinal surgery [53]. Anti-TNFs seem to have limited efficacy only after sepsis has been resolved and when intestinal stenosis is excluded. In a retrospective cohort of 48 CD patients with EC fistulas, 33% of patients had complex fistulas with multiple tracts and 23% had high output. Regarding the fistulas treated with anti-TNF (infliximab; 78%), 33% of patients achieved completed fistula closure. However, half of the patients failed to avoid surgery after 2 years. Stenosis, complex fistulas and concomitant steroids were significant predictors for anti-TNF failure [106]. A similar rate of fistula closure was reported in a cohort of eight patients treated with IFX; in total, 38% of patients experienced the complete cessation of EC fistula drainage [107].

In conclusion, the data on medical treatment for non-perianal FCD are scarce. Despite limited studies, anti-TNF was noted to have the most evidence in for treating non-perianal FCD in selected patients [53]. However, there is a high risk of non-response, and the likelihood of the need for surgery is high. Therefore, surgery is still the mainstay of treatment in the long term. Medical therapy can reduce the pre-operative disease severity and postoperative disease recurrence [114]. Nonetheless, there is insufficient data to recommend the use of immunomodulators alone or non-anti-TNF agents in non-perianal FCD [4,17,19].

Table 3

4.1. Seton Drainage

To maintain the patency of fistula tracts, preventing the premature closure of the external orifice and thus limiting recurrent abscess formation, seton placement has been shown to be effective [121]. There are two techniques when it comes to seton placement, with the preferred technique being the loose, non-cutting seton technique, which avoids the risk of incontinence and perianal pain [122,123].

A meta-analysis has shown short-term successful fistula healing in the use of setons alone, ranging from 14–81%, with long-term fistula recurrence reported in 47% [124]. Long-term setons can be considered for symptom control in patients with recurrent perianal abscesses to avoid proctectomy [125]. Nevertheless, a recent RCT suggests that chronic setons alone should not be used for treating perianal fistulas. [91]. The guidelines recommend seton placement in combination with anti-TNF therapy for improving the healing of perianal FCD [17,19,53].

4.2. Fistulotomy and Ligation of the Intersphincteric Fistula Tract (LIFT)

For patients with low intersphincteric and low trans-sphincteric fistulas, a fistulotomy or lay-open are safe and effective methods of choice, with an 81–100% healing rate and low post surgical fistula recurrence. A fistulotomy is usually performed after the failure of medical treatment and no active proctitis [126,127]. However, this procedure is associated with fecal incontinence, reported in 60% of patients. If the fistula is located more anteriorly, fistulotomy should be avoided due to the risk of incontinence [128].

A study by Van Onkelen et al. demonstrated that trans-sphincteric fistulas can be treated by the ligation of the intersphincteric fistula tract, a procedure called “LIFT”, if they have matured into fibrotic tubes with granulation tissue, as that enables ligation and transection. Furthermore, “LIFT” preserves the sphincter and reduces the risk of incontinence, with comparable rates of healing to other methods [129,130].

4.3. Advancement Flap, Fistula Plug and Fibrin Glue

Management of high fistulas can be categorized into three different categories: the mucosal advancement flap and the filling of the perianal fistula tract with bioprosthetic plugs or glue. The mucosal advancement flap involves mobilizing rectal tissue to cover the internal opening of the fistula tract, without affecting the sphincter complex. A systematic review showed that the average success rate of the mucosal advancement flap after a mean follow-up of 29 months was 64% (range 33–92%), with reoperation needed in 50% of patients [131]. Furthermore, this procedure can be used for rectovaginal fistulas, although their recurrence rate is higher.

Bioprosthetic plugs made of collagen or porcine intestinal submucosa have been shown to be effective in closing fistulas [132,133,134]. A systematic review of 20 studies showed wide variations in fistula closure, ranging from 15 to 86%, with pooled closure rates of 55% in patients with CD [124,135]. Nevertheless, a randomized open-label trial showed that fibrin plugs were not more effective than seton removal alone in achieving fistula closure.

Fibrin glue, which is made up of fibrinogen and thrombin, when injected into a fistula tract, forms a clot in the lumen to help to seal the tract. A randomized open-label of 77 patients with perianal FCD reported a higher rate of fistula healing in patients who received fibrin glue compared to the observation group (36% vs. 16%, OR 3.2) [136]. However, the benefit was more significant only in patients with simple fistulas, and real-world observational studies reported a large variation in fistula healing rates, ranging from 40–67% [124,137,138,139,140]. Another recent RCT compared seton removal plus surgical closure (79% had fibrin glue) to seton removal alone in 64 patients with perianal FCD treated with adalimumab. The fistula closure rate was not significant between the groups (surgical closure plus seton 56% vs. seton alone 65%) [119]. Of note, fibrin glue is not effective in patients with complex fistulas [136], even when combined with other modalities such as antibiotics [141].

4.4. Fecal Diversion and Proctectomy

Fecal diversion and a diverting stoma can be considered for patients with severe sepsis or those who have not responded to drainage or seton placement. It can also be used as a temporary method to improve the overall condition of patients and their quality of life up to the point that they receive medical therapy or proctectomy [142,143]. In a meta-analysis, 64% of patients had an early clinical response after fecal diversion for refractory perianal CD. Restoration of bowel continuity was successful in only 17%, and 26.5% of those who had restoration required re-diversion because of severe relapse. Overall, 42% of patients required a proctectomy after the failure of temporary fecal diversion [142].

Proctectomy with a permanent stoma is used in those patients that have failed prior therapies and hence is only used as a final alternative for severe refractory perianal FCD. Studies have shown that it is required in 10–20% of patients with refractory disease [144,145]. Complications, such as poor wound healing and perineal sinus formation, may occur in up to 25–50% of patients [146,147]. To prevent this, the transposition of the gracilis is an option. This could also be used before a proctectomy for patients with other types of Crohn’s-related or complicated fistulas for whom other treatments have failed [148].

4.5. Mesenchymal Stem Cell Therapy

In the last decade, stem cell-based therapy has emerged as an attractive new therapeutic option for patients with FCD. Adipose-derived stem cells of mesenchymal origin are activated in an inflammatory environment (e.g., fistula). An early RCT demonstrated their success in healing the fistulas, with 71% of patients receiving stem cell therapy, but the long-term follow-up showed a recurrence rate of 17.6% [149,150].

Most recently, the ADMIRE-CD Phase 3 RCT demonstrated the efficacy of stem cell therapy, namely darvadstrocel administration, used once, locally in patients who did not respond to conventional and/or biological treatments. Clinical and MRI remission was achieved and was significantly greater in patients treated with darvadstrocel 51.5% (53/103) compared to the placebo group 35.6% (36/101) at 24 weeks follow-up [116]. At 2 years follow-up, 56% of patients had sustained remission [117].

A recent real-world retrospective cohort study (INSPECT study) reported that 54% (23/43) of patients in the ADMIRE-CD trial remained in remission at 3 years follow-up, with a favorable safety profile, i.e., treatment-related tumorigenicity [118]. Alofisel^®/darvadstrocel is approved for use for this purpose in the European Union [151].

The efficacy of autologous adipose tissue-derived stem cell (ASC) transplantation was compared to anti-TNF after seton placement in the retrospective study of 69 patients with perianal FCD. The closure rate was faster, and the time to closure was significantly shorter in patients who underwent auto-ASC transplantation when compared to anti-TNF treatment (14 vs. 37 months) [152].

A recent meta-analysis of 29 studies demonstrated that stem cells had a higher rate of fistula healing compared to placebos (61.75% vs. 40.46%, OR; 2.21, 95% CI 1.19–4.11, p < 0.05), suggesting that stem cell therapy is a promising method in the treatment of FCD, especially the use of adipose-derived mesenchymal stem cells [153].

In addition, multiple advanced surgical methods, such as endoscopic fistulotomy, intra-lesional anti-TNF injection, fistula-tract laser closure (FiLaCTM), video-assisted anal fistula treatment (VAAFT) and hyperbaric oxygen therapy, may be effective alternative treatments for complex refractory fistulas. However, there have only been a small number of patients included in the reported studies on these techniques. Larger studies and longer follow-up results are warranted before suggesting the use of these methods [154,155].

In conclusion, the optimal surgical approach for fistulizing CD in clinical practice can differ among individuals, with there being no consensus regarding the best surgical approach. Therefore, the type of surgical procedure should be tailored to the anatomical location of the fistulas and the surgeon’s expertise. Seton placement should be combined with anti-TNF therapy to induce fistula healing. Fistulotomy or LIFT may be considered in patients with symptomatic low-simple fistulas without active proctitis or abscess. For complex fistulas (those that are high up, involving muscle, associated with strictures or abscesses and multiple opening fistulas), LIFT, an advancement flap, fibrin glue or fistula plugs (limited efficacy) can be considered. Recently, mesenchymal stem cell therapy has been approved, with promising efficacy in patients with medical refractory fistulizing CD. Lastly, proctectomy or diversion may be required in patients with severe uncontrolled perianal fistulas [144].