Anal fissures, perianal fistula or abscesses are the first symptoms of Crohn’s disease (CD’) in 3,8% of patients and they precede the diagnosis of luminal CD [1]. At the time of CD’s diagnosis, 11,5% of patients had perianal disease [1]. Therefore, anal fissures, perianal fistula and abscesses should raise the suspicion for Crohn’s disease, particularly if they show some clinical characteristics.

Anal fissures associated with CD’s tend to be multiple, placed eccentrically, larger, deeper, with larger skin tags and/or a cyanotic hue in the surrounding anal skin. Also, they tend to be less painful than a typical fissure-in-ano [2].  Moreover, they tend to relapse.

Fistulas associated with Crohn’s disease are usually complex, relapsing, associated with recurrent abscesses and pain. Complex fistulas are defined by the American Gastroenterological Association (AGA) as fistula tracts that are located high intersphincteric, high transsphincteric, extrasphincteric or suprasphincteric; may have multiple external openings; associated with rectovaginal fistula, anorectal stricture; associated with proctitis on endoscopic exam [2].

These particular features should trigger a diagnostic workup for CD’s: blood analysis, fecal calprotectin, serologic and fecal tests to exclude infection, ileocolonoscopy with biopsies, MRI or CT enterography and videocapsule endoscopy.

It can be extremely difficult to distinguish perianal Crohn’s disease, particularly fistulizing disease, from some complex cryptoglandular fistulas, sexually transmitted diseases, HIV infection, suppurative hidradenitis, tuberculosis, actinomycosis, and carcinoma.

A small minority of patients (3,4%) were reported to have isolated perianal CD [3].Besides excluding the above-mentioned entities, for considering the diagnosis of isolated Crohn’s disease, all the gastrointestinal tract should be assessed. Data showed that the widespread use of videocapsule endoscopy added value to diagnostics methods, such as MRI or CT enterography, and plays an important role in this particular setting [4].

It is common knowledge between IBD-treating physician’s that fistulizing perianal disease is a severe phenotype and it is associated with higher rates of hospitalizations, surgical interventions, and immunosuppressive use [1]. Furthermore, fecal incontinence is reported in two thirds of patients with fistulizing CD [5]. Despite the advances of medical therapy, two thirds of patients require anal surgeries and 7% require major abdominal surgery [1][6].

The impact of fistulizing CD on patient’s quality of life has been repeatedly reported, but there is still a lack of strategies to deal with this issue, particularly psychologic support [7][8].From the patient’s perspective, perianal location affects intimate, close, and social relationships, and causes losses in life- and work-related opportunities. Treatments are considered to be difficult to tolerate [8]. Questionnaires have revealed that 73% of patients self-reported periods of depression and 13% reported suicidal ideation whilst living with perianal CD’s. It was also found that there is a relation between depressive symptoms and the duration of disease, prior surgery, past or present stoma, and anal stenosis [9]. Body image and  sexual function were also affected [10]. Having this in mind, the team treating these patients must embrace a strategy that fulfills all patient’s needs, including regular screening of psychological well-being and prompt intervention.

The treatment of perianal CD demands a multidisciplinary team, a targeted and individualized strategy, and the patient’s commitment to the therapeutic plan.

The multidisciplinary team is recommended to have a gastroenterologist with skills in IBD’s treatment, a colorectal surgeon, an IBD trained nurse, a stoma therapist, and a psychologist.

The strategy involves a multistep process with three main goals. The first goal is to eliminate the sepsis via drainage of septic collection and placement of a seton and antibiotics. The second goal is to control the disease, either luminal or perianal, with a biological based therapy, associated or not with an immunosuppressant. The third goal is, if possible, to close  the fistula by continuing medical therapy or by combining medical and surgical procedures (closure of internal opening, with or without injection of mesenchymal stem cells, advancement flaps and other appropriate surgical technics) [11] [12].

Nevertheless, for patients with refractory disease, the only possibility might be to achieve symptomatic improvement, in order to reach less pain, no sepsis and less drainage [12]. In some patients, the severity of the disease may demand the diversion of the fecal stream, for instance in uncontrolled sepsis or irreversible damage of the anal sphincter.

Although not yet validated, a new classification for fistulizing perianal disease that seems to be a promising tool to stratify patients according to the disease’s severity, as well as the disease goal, has been proposed. Theoretically, this classification could allow the synchronization of both patient’s and clinician’s goals in the decision-making process, as well as the combination of medical and surgical approaches to the defined goals.  It also reflects the dynamic nature of the disease: patients could cycle through different classes over the time [13].

The combination of medical therapy, primarily anti-TNF based, with seton placement and minimal invasive surgical procedures are the cornerstone for the majority of patients with perianal CD’s. Nevertheless, the evidence of medical and surgical combination was supported by small retrospective studies [14][15].

During this process, the team has to deal with the patient’s expectations and fears and offer personalized care to help the patient overcome the most difficult treatment steps.

The use of antibiotics is a matter of global concern due to its misuse and to the emergence and spread of drug-resistant pathogens. However, antibiotics, specifically ciprofloxacin and metronidazole, associated with surgical drainage, seem to play an important role in perianal CD for treatment of sepsis and fistula healing. The evidence supporting its use comes mainly from small, open label studies, without randomization or observational studies [16]. It was also shown that when antibiotics where stopped there was recurrence of the disease [17]. There is evidence supporting the use of antibiotics associated with anti-TNF, infliximab (IFX) or adalimumab. Data on adalimumab and ciprofloxacin showed that the combination was more effective than adalimumab alone to achieve fistula closure. However, it also showed that after discontinued the beneficial effect of the combination was not maintained [18]. A small randomized trial on infliximab and ciprofloxacin’s combination showed benefit in fistula closure over the use of infliximab alone [19].

In conclusion, it seems that in induction therapy and with the aim of treating sepsis and fistula closure antibiotics do play a role.  However, its use must be weighted and not for an undefined period of time.

Biological therapy represents an immense progress in CD’s treatment either luminal or perianal. Nevertheless, concerning specifically perianal location, the evidence supporting its use is qualitatively different.

Infliximab, a chimeric  TNF monoclonal antibody, was the first approved biological for treatment of CD and remains the only biological with a randomized double blind controlled trial that had as the primary endpoint fistula closure [20]. Previously, Present et al, showed that 68% of IFX treated patients (5 or 10mg/kg) had a reduction of at least 50% of draining fistulas compared with 26% of placebo treated patients. Complete healing, defined has the absence of drainage in two consecutive visits, was observed in 55% of IFX treated patients versus 13% of placebo treated patients [21]. The ACCENT II showed that IFX treated patients in a fixed dosing scheme (5 mg/kg every 8 weeks) had a significantly longer time to loss of response to maintenance therapy than the placebo group (40 weeks versus 14 weeks).  At week 54, 19% of patients in the placebo maintenance group had a complete absence of draining fistulas, as compared with 36% of patients in the infliximab maintenance group. The population included abdominal and perianal fistulas [20].

Adalimumab, a fully humanized TNF monoclonal antibody, was approved for the treatment of CD. Although there were no trials dedicated to fistulizing disease, either perianal or abdominal, a post hoc analysis  showed efficacy of adalimumab versus placebo in fistula closure [22]. At 26 and 56 weeks, adalimumab 40 mg every 2 weeks versus placebo showed respectively  30% versus 13% and 33% versus 13%  of fistula closure [22]. The response to therapy was maintained in 90% of patients after one year of follow up [23].

A metanalysis of patients treated with adalimumab that included 379 patients, from seven studies, showed 36% of patients with a  complete fistula closure and 31% a partial response. [24]

There is evidence on the use of adalimumab in previously treated patients. An open label, single arm multicenter study, phase IIIB, that included 673 patients, either primary non responders or patients with loss of response to IFX, were treated with adalimumab.  88 of them presented perianal fistulas. Complete fistula closure occurred in 39% (34/88) of patients. Analysis by subgroup showed that 30.8% (4 of 13) of primary non responders to IFX and 40.0% (30 of 75) of initial responders achieved complete fistula healing during adalimumab therapy. Of the 34 patients with complete fistula healing, 29.4% (10 of 34) completed week 12 and 64.7% (22 of 34) completed week 24 or week 36 [25].

Ustekinumab, a fully human immunoglobulin Ig1K monoclonal antibody directed against the common p40 sub unit of IL 12 and IL 23, has proven to be effective for the treatment of CD. There is no direct evidence of ustekinumab on fistulizing disease. While a sub group analysis of phase 2b of CERTIFI and phase 3 studies (UNITI 1 and 2) showed that patients treated with ustekinumab IV and ustekinumab sc had higher rates of fistula healing and response (47%)  than placebo treated patients (30%), the difference was not statistically significant. At week 44, in IM-UNITI study,   fistula response occurred in 80% of ustekinumab treated patients and 46% of placebo treated patients (pns) [26].

Two systematic reviews and metanalysis assessed the efficacy of ustekinumab on perianal fistulizing CD [27][28].

A systematic review of 25 studies that included  5 abstracts  and 20 full manuscripts, the majority of them multicenter and retrospective, found that 44% (92/209) of patients with active perianal fistulas had a clinical response within 6 months of follow- up, and 53.9% (85/152) of patients with 12 months of follow- up achieved clinical response [27].

Another metanalysis showed that patients with one dose of ustekinumab experienced 41% of fistula response and 17% of fistula closure. The proportion of patients with fistula response increased to 56% after one year of treatment [28].

Vedolizumab, a fully humanized monoclonal antibody to α₄β₇ integrin, was approved for CD treatment. Data on its effect in perianal fistulizing disease is scarce. A subgroup analysis from GEMINI II found that there was an increase of fistula closure in vedolizumab treated patients. At week 52, more patients that were on vedolizumab (300 mg every 8 weeks) achieved fistula closure compared with those on placebo (30,8% versus 11,1%). All patients on the analysis did the induction with vedolizumab [29]. The ENTERPRISE study prospectively compared two dosing regimens (with and without an additional dose at week 10) of vedolizumab in patients with complex perianal fistulas. At week 30, most of patients on vedolizumab (53,6 %) responded to treatment (≥ 50% decrease in draining fistula) and 42,9% had fistula closure [30]. A metanalysis showed that 34,9% vedolizumab treated patients achieved a partial healing of the fistula and 27,6 % a complete healing. However, the treated population included 87% of patients previously treated with anti-TNF [31].

Other biologicals, like gulsekumab or rizankizumab, still do not have studies supporting their use in the context of perianal fistulizing CD.

Upadacitinib, a JAK 1 selective inhibitor, was recently approved for treatment of moderate to severe CD. A subgroup analysis of phase III studies, showed that, from 126 patients with fistulizing perianal CD, 47,7% of upadacitinib treated patients versus 9,1 % of placedo achieved complete fistula closure and 50% of upadacitinib treated patients achieved 50% of reduction of draining fistulas versus 13,6% of placebo treated patients. However, at week 52 the difference between the groups was not statistically significant [32].

In conclusion, IFX has higher levels of evidence for its use on perianal fistulizing CD, followed by adalimumab. Most of IFX treated patients showed on clinical evaluation (either with ultrasound or pelvic MRI) decreased or absence of  inflammation around the fistula tracts,  an improvement of the symptoms and less fistula drainage [33][34]. However, most patients fistula tracts persisted open [33][34].

After medical therapy has started, particularly anti-TNF, therapy should still be optimized. There is evidence favoring the fact that trough levels matter in peri anal CD’s and they should be higher than for luminal disease [35][36]. The first study of IFX in fistulizing disease done by Present et al did not show differences between IFX 5 or 10 mg /kg [21]. However, more recent data suggests that IFX higher trough levels are associated with an increase rate of fistula healing and IFX antibodies are related with loss of response or relapse of the disease [35][36][37] .

There is some divergence related to the optimal trough level and it varies according to treatment time point [36][37] . During induction, serum IFX levels of 15 µg/ml at week 6 and 6,1 µg/ml at week 14 were associated with complete fistula healing at week 14  [35].  During maintenance IFX serum levels 10,1 µg/ml were associated a higher rate of response [36].

Similar to infliximab, higher adalimumab serum levels were associated with higher rates of fistula closure. Adalimumab trough level >9 µg/ml was associated with higher rates of fistula closure [37–40].

Ustekinumab and vedolizumab trough levels do not have enough support for the monitorization/optimization of therapy based on trough levels neither on luminal disease nor on perianal disease.

Combination therapy of IFX and azathioprine or methotrexate may play a role by decreasing the immunogenicity of IFX, but evidence for fistulizing perianal CD’s is lacking.

Seton placement is an important step of surgical therapy. However, when possible, the goal of therapy is fistula healing.  In CD’s 80% of fistulas are associated with perianal abscesses and the most common surgical intervention is incision and drainage [41]. Despite that, due to recurrence of abscesses and the possibility of new fistulous tracts, additional surgical treatment with non-cutting setons is commonly used.

Seton placement allows the drainage of septic collections before the beginning of biological therapy, when perianal disease occurs at disease presentation or during biological therapy when perianal disease presents as a de novo manifestation of the disease. The correct seton placement preserves the anal sphincter function protecting it from sepsis spreading and fibrosis.

Surgical and medical approach – seton placement and biological therapy – are the standard of care in perianal CD[42,43]. However, if the seton is not removed the fistula does not heal. There must be a strategy for each patient that considers several factors: firstly, if the goal of the therapy is fistula healing or symptomatic relief; secondly, if there is active proctitis even with optimized medical treatment; thirdly, if there are persistent septic collections; fourthly, if there is irreversible damage to the anal sphincter.  The majority of patients are candidates to seton removal. However, there are the following exceptions: the existence of recurrent septic collections, the presence of some grade of functional damage to anal sphincter, and patients with ongoing anal active disease or active proctitis.

The time for seton removal is not consensual, but most agree that it could be considered after a successful induction with medical therapy when there is no proctitis nor septic collections [43].

After seton removal, several surgical options could be considered: fistula curettage and internal orifice closure adding or not to mesenchymal stem cells injection, endorectal advancement flaps, ligation of intersphincteric fistula tract, fistula laser closure, or video assisted fistula treatment.

Unfortunately, in some patients, disease progress and destruction may require a fecal diversion and a proctectomy.

Perianal CD phenotype is associated with worse outcomes and it affects negatively patients QoL in different domains.  It extends far beyond restrictions of daily activities and capacity of working.   Adding to a particularly disabling disease, the treatment, either medical or surgical, can also have negative impact on the patient’s life: multiple anal surgeries, increased number of hospitalizations, and adverse effects of medical therapy, like infections. Data has shown that patients want to be included in the decision process [44]. In a patient-centered strategy, the multidisciplinary team and the patient should have a synergistic involvement in order to achieve the desirable goals.