Navigating the complexities of perianal Crohn’s disease: Diagnostic strategies, treatment approaches, and future perspectives

Abstract

This article discusses the literature review article by Pacheco et al published in July 2024; the authors provided good reviews of perianal Crohn’s disease (CD), and challenges faced by clinicians in the management. CD, characterized by its chronic and relapsing nature, is an idiopathic condition that can involve any segment of the gastrointestinal tract. Perianal disease impacts up to 40% of patients with CD, with perianal fistulas constituting up to 80% of perianal lesions. Perianal CD can be highly incapacitating and profoundly diminish the overall well-being of patients. The management focuses on controlling the perianal sepsis and treating luminal CD. Biologics are crucial to the treatment approach, and results have been encouraging. The surgery focuses on controlling the sepsis, with more definitive treatments being fistula surgery, fecal diversion, and proctectomy as the last resort. This manuscript briefly describes the burden of CD, the challenges posed by perianal CD, and the role of different treatment modalities from colorectal surgeon’s perspective.

Key Words: Crohn’s disease; Perianal; Fistula; Fistulotomy; Biologics; Stem cell therapy

Core Tip: Perianal disease affects a significant number of Crohn’s patients. Perianal fistulizing Crohn’s disease can be very debilitating and adversely affect the quality of life. These patients are primarily managed through a multidisciplinary approach. This editorial provides a detailed analysis of current management strategies for perianal diseases in Crohn’s patients and an analysis of the literature by Pacheco et al.

TO THE EDITOR

Crohn’s disease (CD) is an idiopathic, chronic, and relapsing inflammatory disorder of the gastrointestinal tract (GIT). It can involve any segment of the GIT, from the oral cavity to the anus[1,2]. More than one million individuals in the United States are affected by CD, and its incidence is rising for reasons that are not fully understood. The disease is more common in those over 45 years old and does not differ based on sex[2]. The transmural inflammatory nature of CD results in fibrostenotic, and penetrating phenotypes[2].

Perianal disease impacts up to 40% of patients with CD[3-6]. There are two kinds of perianal manifestations of CD: Fistulizing and non-fistulizing. Perianal fistulizing CD (PFCD) includes abscesses and fistulas, while non-fistulizing CD may manifest as hemorrhoids, skin tags, fissures or ulcers, anorectal strictures, and malignancies[3-6]. Perianal fistulas account for 50%-87% of perianal lesions in CD[7]. Perianal fistula is the primary presentation in roughly 10% of patients, but the majority will subsequently develop intestinal symptoms[8-10]. The disease remains confined to the perianal area in only about 5% of the patients[11,12]. Perianal involvement is most frequently observed in CD patients with involvement of the colon and rectum[3]. In Heller et al’s study, perianal disease was found in 92% of patients with colon and rectal involvement, compared to 41% in those with colonic disease, 15% in those with ileocolic disease, and 12% in patients with ileal disease[3].

The review article by Pacheco et al[13] offers a good introduction. However, we have expanded on it by discussing the prevalence of perianal CD detailing the types of perianal manifestations, emphasizing the significance of different segments of the GIT affected, and exploring their correlation with perianal CD. We have added sections covering the pathogenesis and clinical presentation of perianal CD, focusing on the common types of abscesses.

PATHOGENESIS

Typical development of perianal fistulas in CD begins with an anal ulcer or fissure that deepens into a pocket. The mechanical pressure during defecation pushes stool into this pocket and further into the subcutaneous tissue. This leads to the formation of a fistula with multiple external openings through which stool is extruded[14]. The other mechanism is the infection of cryptoglandular glands, leading to abscesses and fistulas[15].

ANATOMY AND CLINICAL PRESENTATION

Parks classified perianal fistulas according to their position relative to the sphincter muscles, categorizing them as superficial, intersphincteric, suprasphincteric, transsphincteric, and extrasphincteric[16]. The American Gastroenterological Association categorizes fistulas as simple or complex. Simple fistulas are low, featuring a single external opening and lacking complications such as anorectal strictures, abscesses, or rectovaginal fistulas. Complex fistulas, on the other hand, are higher, often with multiple external openings and commonly associated with abscesses, anorectal strictures, and rectovaginal fistulas[4]. Most of the patients with CD have complex fistulas[11]. Around 60% of patients with PFCD develop an abscess[17]. The most common form of these abscesses is an ischiorectal abscess, which accounts for 40% of Crohn’s-related perianal abscesses[18].

DIAGNOSIS

The article by Pacheco et al[13] commented on diagnostic modalities, but we have further explored the role and accuracy of various diagnostic methods. A thorough diagnostic evaluation is essential to identify the type and site of fistulas, as well as to assess whether visible rectal inflammation is present. Both elements are crucial in determining the management plan. This can be achieved by in office digital rectal exam with anoscope, and supplemented with an examination under anesthesia (EUA), endorectal ultrasound (ERUS), and magnetic resonance imaging (MRI)[4]. In-office examinations, while helpful, can be limited due to patient discomfort. Based on our experience, EUA is better tolerated by patients and offers superior clinical information. It allows for better identification of the fistula’s location, determination of whether it is simple or complex, and provides improved visualization of the rectal mucosa. In their study, Schwartz et al[19] found that ERUS and EUA had diagnostic rates of 91% each, while MRI had a diagnostic rate of 87% in determining fistula anatomy. When integrating two methods, the diagnostic accuracy improves to nearly 100%, offering a promising avenue for improved patient outcomes[19]. However, Sahni et al[20] found that MRI offered greater accuracy compared to EUA and ERUS. The likelihood ratio for MRI in diagnosing complex disease is 22.7, significantly higher than the 2.1 ratio for EUA and the 6.2 ratio for ERUS[20].

MANAGEMENT

Perianal CD poses significant challenges due to higher failure rates and recurrent diseases. In a prospective cohort study, Makowiec et al[21] observed that the probability of fistula recurrence was 48% at one year and increased to 59% at two years. The study by Malian et al[22] identified colonic and stricturing disease as key risk factors for recurrent fistulas. When CD affects the colon and rectum, fistula healing is compromised due to chronic inflammation at the internal fistula site. The presence of a stricture suggests a more severe disease, with anorectal strictures making fistula healing even more challenging due to the presence of fibrotic changes, physical obstructive changes, and inflammation. Biologics provide an excellent response for mucosal inflammation; however, they are not as successful in treating fibrostenotic disease, which promotes fistula formation even after luminal inflammation improves[22]. The primary goals of management are to control perianal sepsis, heal and cure fistulas, and treat luminal disease. The most effective patient care involves a team approach, integrating the expertise of gastroenterologists, surgeons, pathologist, and radiologists, as this allows for a comprehensive and coordinated treatment plan that addresses all aspects of the disease.

MEDICAL MANAGEMENT

Antibiotics

Pacheco et al’s review underscored the effectiveness of ciprofloxacin and metronidazole in the management of PFCD[13]. Antibiotics are primarily used to control the perianal infection. They are effective when used in combination with thiopurines and biologics. Their long-term use is not recommended due to poor tolerance and adverse effects, and therefore, their use should be limited in acute infectious settings and as a bridge to more definitive medical treatment[23-25].

Thiopurines

Azathioprine and 6-mercaptopurine provide a modest advantage in inducing remission or clinical improvement in active CD. While these antimetabolites may aid in reducing steroid usage, it’s important to note that adverse events were more frequently reported in those receiving antimetabolites compared to placebo. Though azathioprine is not as efficacious as infliximab in attaining remission without steroids, it has been shown to be more successful when combined with infliximab, exceeding the effectiveness of infliximab alone[26]. Additionally, thiopurines have a delayed response time of 3 or more months, and therefore, they are initiated in combination with other agents and used for maintenance rather than induction[27].

Calcineurin inhibitors

The use of tacrolimus and cyclosporine is primarily reserved for severe CD patients who cannot tolerate or do not respond to biologics, and where diverting ostomy or rectal resection are being contemplated[4]. Tacrolimus improved fistula drainage but not the closure[28]. Cyclosporine also showed a strong initial response, but this effect diminished once the treatment was stopped[29]. Calcineurin inhibitors are associated with notable adverse reactions, such as paresthesia, tremors, and nephrotoxicity[29]. Salem et al’s review reported that topical tacrolimus showed clinical remission in 57% of patients with PFCD[30]. Tacrolimus was delivered locally in the form of ointment, enema, or suppositories, and it had negligible side effects. There is a need for carefully conducted randomized clinical trials to determine the optimal dosage and delivery method[30].

Biologics

Pacheco et al’s review article has included the role of various biologics, which we have highlighted in this editorial along-with some details[13]. The ACCENT II trial, a landmark study in the field, showed that infliximab was more effective than placebo in inducing and sustaining remission in PFCD. It also showed a notable improvement in fistula closure rates and prevention of recurrence[31]. Subsequent analysis of the ACCENT-II study showed that higher infliximab concentrations following induction correlate with a prompt and full fistula response[32].

Adalimumab has demonstrated its potential in closing CD-related fistulas in patients with no prior exposure to infliximab, as well as in those who did not respond to infliximab treatment[33-37]. The CHARM trial revealed a higher fistula closure with adalimumab compared to placebo, along with a higher persistence of closure at 56 weeks[33]. The role of certolizumab was investigated in the PRECISE 1 and PRECISE 2 trials, as well as in a post hoc analysis[38-40]. In the PRECISE 1 trial, certolizumab was associated with a moderate increase in response rates for patients with PFCD. However, it did not significantly improve disease remission[38]. The PRECISE 2 trial showed that patients who had a positive response to certolizumab induction had a better chance of achieving remission at 26 weeks if certolizumab was continued, compared to transitioning to placebo[39]. The subsequent analysis of the PRECISE 2 trial showed that fistula closure was sustained when certolizumab was continued, as opposed to placebo. The data imply that continuing treatment with certolizumab provides fistula closure and therapeutic benefits to CD patients with draining fistulas[40].

The GEMINI II trial assessed the effectiveness of vedolizumab and found that 28% of patients receiving vedolizumab reached fistula closure by week 14, in contrast to 11% of those who received a placebo. By week 52, the closure rates increased to 31% in patients who received vedolizumab, compared to 11% in those who received placebo[41,42]. Ustekinumab has demonstrated effectiveness in alleviating fistula symptoms in 61% of patients and achieving closure in 31%[43,44]. Pacheco et al’s review discussed the role of various biologics, including certolizumab, vedolizumab, and ustekinumab[13]. We have expanded on their roles, highlighting the benefits these biologics bring to the treatment of complicated perianal CD. These insights offer valuable information on the comparative effectiveness of different biologic agents.

Hyperbaric oxygen therapy

Pacheco et al[13] highlighted the role of hyperbaric oxygen therapy (HBOT) in PFCD. Singh et al[45] reported that adjunctive HBOT demonstrated improved healing in PFCD patients. In the HOT-TOPIC trial, Lansdorp et al[46] explored the effectiveness of HBOT in 20 CD patients with treatment-resistant perianal fistulas. The patients were given 40 sessions of HBOT over 8 weeks and were followed for 60 weeks. The results showed that in 20% of patients, the fistula became fibrotic, and their MRI indicated no active disease. 60% of patients exhibited non-active perianal disease, as determined by the perianal activity index. The study’s limitation was not having a comparison control group. Overall, when combined with medical and surgical treatments, HBOT can lead to positive outcomes in CD patients with perianal fistulas. Further randomized controlled trials are required to establish a conclusive recommendation.

SURGICAL MANAGEMENT

Effective surgical management of fistulas in CD requires careful attention to complicating factors. Approximately 80% of these fistulas are complex and are associated with increased recurrence and poor healing rates[10,47,48]. Key factors to consider include the fistula type-whether low or high, simple or complex-as well as the presence of proctitis, abscesses, rectovaginal fistulas, and/or anorectal strictures.

Fistulotomy

Fistulotomy may be appropriate for a simple, low-lying fistula with limited sphincter involvement, provided there is no active Crohn’s proctitis or other complicating factors. CD activity index of 150 or higher is a contraindication for fistulotomy[49].

Draining setons

Draining setons maintain the patency of the fistula tract, reduce surrounding inflammation, and prevent abscess formation[50,51]. Present et al[52] showed that more patients developed abscesses when treated with infliximab monotherapy, likely due to the sealing of the external fistula opening. Incorporating setons with anti-tumor necrosis factor therapy has been shown to improve fistula healing rates and extend periods of closure[53-55].

Endorectal advancement flap and ligation of intersphincteric fistula tract

Definitive surgical procedures should be attempted once luminal Crohn’s is quiescent. Endorectal advancement flap (ERAF) and ligation of intersphincteric fistula tract (LIFT) have been the cornerstone surgical options in these patients. ERAF can be used to repair perianal fistula in Crohn’s patients without active proctitis. The success rate for ERAF is reported at 60%-64%, with 9.4% of patients experiencing incontinence and 57% having a recurrence[56-58]. The LIFT procedure was found to be effective in 67% to 75% of patients with PFCD[59,60]. No case of incontinence was reported among the 15 patients studied[59]. Smoking has a negative effect on flap healing[61]. Additionally, active proctitis and anal stenosis are relative contraindications for ERAF[62].

Fibrin glue and fistula plugs

Fibrin glue is a biodegradable injection that stimulates fibroblasts to form fibrin clots[63]. Grimaud et al’s RCT involving 34 PFCD patients showed that treatment with fibrin glue led to remission in 38% of patients after eight weeks, compared to a 16% remission rate in those who were only observed following seton removal[63]. The advantage was more pronounced for patients with simple fistulas. Cirocchi et al’s meta-analysis showed no substantial advantage of fibrin glue over conventional surgery (fistulotomy, seton, and advancement flap) regarding recurrence and fecal incontinence rates[64]. Fistula plugs are bioprosthetic grafts that create a collagen framework over which endogenous cells grow. Fibrin glue and fistula plug therapy show variable results with a success rate of 0%-80%[63,65-68]. Senéjoux et al’s multicenter RCT, involving 106 PFCD patients, reported that the fistula closure rate was comparable between fistula plug treatment and cases where setons were removed without any additional treatment[69]. Overall, the effectiveness of fibrin glue and fistula plugs in treating PFCD is quite limited. While they have shown some success with simple perianal fistulas, they have a high failure rate in complex cases.

Mesenchymal stem cell therapy

Mesenchymal stem cell (MSC) therapy offers a potentially revolutionary new solution for nonhealing perianal fistulas. In Panés et al’s trial, which included 212 Crohn’s patients with complex fistulas, 56.3% achieved successful fistula closure, compared to 38.6% in the placebo cohort[70]. Additionally, remission was achieved in a significantly shorter time frame: 6.7 weeks compared to 14.6 weeks. A meta-analysis by Lightner et al[71], covering 11 studies, showed increased healing rates at 6-24 weeks and again at 24-52 weeks. Cao et al’s meta-analysis showed higher healing outcomes in patients with a CD activity index over 150 compared to patients with a CD activity index under 150[72]. These findings offer encouraging evidence that MSC therapy is effective and safe for treating PFCD. However, the ideal dosage and frequency of MSC treatments required to achieve the best results are still unknown. This highlights the potential for enhancing protocols in cell-based therapy. We anticipate that this innovative approach has the capacity to significantly enhance PFCD care, paving the way for safer and more effective treatments.

Fecal diversion and proctectomy

Approximately 10%-20% of patients with PFCD require fecal diversion to alleviate symptoms in cases that are resistant to other treatments. The chances of reversal are lower for these patients, who are also more likely to require proctectomy[73-75]. Most of the time, proctectomy is performed in two stages because of the higher likelihood of perineal wound complications associated with primary closure[76,77]. In the first stage, the rectum is divided at the pelvic floor, and a stoma is created. Once the perineal disease is improved, then a completion perineal anoproctectomy is performed, offering a potential for significant improvement with a decreased risk of wound complications[78]. Non-healing wounds may need closure with flaps/skin grafts[79]. Overall, the treatment algorithm presented in Pacheco et al’s review is well-written and detailed[13].

RECTOVAGINAL FISTULA

About 10% of CD patients are affected by rectovaginal fistulas. Inflammation of the rectum and anus can erode through the vaginal wall, resulting in the development of a rectovaginal fistula[80,81]. Treatment principles are similar to those for a perianal fistula: Controlling sepsis, using a seton for fistula maturation, managing CD medically, and then performing surgical treatment. Surgical options include an advancement flap from either the rectal or vaginal side, interposition with a Martius or gracilis flap, episioproctotomy, or an abdominal pull-through procedure[82].

NON-FISTULIZING COMPLICATIONS

Crohn’s patients can also experience non-fistulizing complications, including anal fissures, anal ulcers, skin tags, hemorrhoids, and malignancies. Non-surgical management, in conjunction with medical treatment for CD, is recommended. However, surgery might be an option for certain patients with quiescent disease[83].

ANAL CANCER

Both adenocarcinoma and squamous cell cancer can arise in long-standing perianal CD. These might develop in either the anal canal or the fistulous tracts[84,85]. These cancers are managed similarly to sporadic cancers. Pacheco et al’s review, which analyzed data from the French CESAME study involving 19486 inflammatory bowel disease patients[13], found that the risk of anorectal cancer in perianal Crohn’s patients was 9.36 times higher than in those with CD without anal and perianal involvement[86]. At present, no specific protocol exists for the screening of anal cancer in patients with perianal CD. We support the recommendation to include patients with PFCD in screening programs for anal cancer. A potential screening program for patients with PFCD could involve periodic clinical examinations, including biopsies of suspicious lesions or an anal Pap smear in the absence of such lesions, followed by high-resolution anoscopy if the Pap smear is positive for dysplasia.

CONCLUSION

Perianal CD remains a debilitating condition that poses significant challenges for clinicians. A coordinated approach involving inflammatory bowel disease surgeons, gastroenterologists, radiologists, and pathologists is essential for effective management. Medical management with new biologics has been a breakthrough, improving success rates in these patients. Draining setons are crucial for maturing the fistula tract and preventing abscess formation. Combining setons with biologics has enhanced patient response. Surgical interventions, like fistulotomy, advancement flaps, and LIFT, should be carefully timed and performed on select patients, as they carry high failure rates and increased risks of incontinence. HBOT has shown promising results, as has MSC therapy, which could revolutionize the treatment of complex fistulizing CD. Chronic inflammatory changes in fistulizing CD can lead to malignant transformation, so clinicians should be mindful of the possibility of cancer in these patients. Although there is currently no screening program for anal cancer in these patients, we recommend establishing a periodic screening program, given their high risk and poor prognosis once diagnosed.