A 13-year-old, previously healthy boy, was seen by his pediatrician after developing perirectal swelling. The swelling ruptured after 7 days with bloody-mucoid discharge with rapid improvement in his pain. Four months later, he was seen in a gastroenterology clinic with complaints of abdominal pain and a 2-week history of diarrhea. Physical examination findings were significant for an anal fissure with an overlying skin tag at the 6 o'clock position, mild perianal erythema without swelling, and no visible fistulous tract opening. Laboratory tests were significant for an elevated fecal calprotectin, C-reactive protein, and sedimentation rate, which combined with his history and physical examination, were concerning for inflammatory bowel disease (IBD).
Upper gastrointestinal endoscopy and ileocolonoscopy were performed and showed histologic evidence of patchy esophagitis, gastritis and duodenitis, ileitis with a granuloma, and moderately active pan-colitis. A magnetic resonance enterography was completed and showed a segment of distal ileum approximately 20 cm in length up to the ileocecal valve with multiple areas of bowel wall thickening and enhancement alternating with short segments of saccular dilation without evidence of stricture, fistula, or bowel obstruction. The patient was started on prednisone, 6-mercaptopurine (6-MP), and mesalamine as induction therapy for his newly diagnosed Crohn's disease (CD) with quick resolution of his symptoms.
At his 2-month follow-up visit, he was tolerating a prednisone wean and was maintaining clinical remission on 6-MP and mesalamine. At his 4-month follow-up visit, he began developing increased abdominal pain; his prednisone was increased, which resolved his symptoms. At 5 months postdiagnosis, after the completion of a prolonged prednisone taper, he developed worsening abdominal pain, diarrhea, and decreased appetite, which resulted in reintroduction of prednisone in this steroid-dependent patient; again, the result was quick resolution of symptoms.
At his 6-month follow-up visit, still taking 10 mg of prednisone, the patient developed a recurrence of perianal swelling that was painful to the touch without expression of fluid. He was started on a course of metronidazole for the concern for perianal CD. Three days after starting antibiotics, the perianal swelling had drastically increased and became exquisitely tender, prompting admission to the hospital. A pelvic magnetic resonance imaging (MRI) scan showed two distinct, complex perianal abscesses measuring 3 cm × 1.3 cm in the anterior inferior left gluteal fold with a sinus tract connecting to the skin and the other measuring 8 mm × 7 mm within the right gluteal fold with a noncommunicating sinus tract. The patient was started on intravenous metronidazole and ciprofloxacin before surgical intervention.
In the operating room, the patient was found to have a complex Crohn's-related perianal fistula/abscess on the left spontaneously draining via three external openings all in communication with each other and the abscess cavity. The internal opening, located at the dentate line, was also in communication with an external opening and anal fissure. Two noncutting setons were sutured in place to allow for adequate drainage of the fistulous tracts. The patient tolerated the procedure well and the decision was made to initiate infliximab therapy as maintenance medication for his complex perianal CD. The patient was discharged home after 5 days of hospitalization and after receiving his first induction dose of infliximab.
IBD is a chronic inflammatory gastrointestinal disorder that includes a spectrum of diseases including CD and ulcerative colitis (UC). Common presentations of IBD can include diarrhea, hematochezia, abdominal pain, weight loss, and decreased appetite. Differentiating among the varying diagnoses can be difficult and requires laboratory, endoscopic, histologic, and radiographic examinations along with specific history and physical examination findings. CD, unlike UC, can affect any part of the gastrointestinal tract, from the mouth to the anus, and is characterized by transmural inflammation, which predisposes to the development of penetrating and fistulizing disease.
Perianal CD in children can include skin tags, rectal fissures, abscesses, fistulas, or rectal stenosis and carries an estimated prevalence between 13.6% to 62% in those with CD.1 A recent cohort study of perianal CD showed a significant association with younger age at diagnosis, complicated disease behavior, and location of disease.2 Treatment strategies and prognosis of perianal CD depend on the type of lesion and location of disease. Skin tags and fissures may heal without much intervention, but fistulae and abscesses may require aggressive medical and/or surgical intervention.
Classifying Perianal Crohn's Disease
The pathogenesis of perianal CD is proposed to occur due to rectal inflammation leading to ulcerations that are constantly exposed to fecal material and penetrate under the pressure caused by defecation, which can lead to the development of fistulae and abscesses.1 Different scoring systems have been described to classify perianal lesions based on the component of the lesion—its anatomic location with regard to anorectal sphincters. The more clinically relevant Bell Classification differentiates lesions into simple versus complex.1 Simple fistulae are regarded as emanating from an inter-/trans-sphincteric location, have a single-short tract, and have an internal and external opening close to the anal verge without the presence of an abscess.3 In contrast, a complex fistula can involve the sphincter, contain multiple fistulae with or without abscess, and arise above the sphincter internally and further from the anal verge externally.3 Classification systems, such as the Bell's Classification, help clinicians identify the most appropriate means of treatment for these patients.
Radiographic imaging is paramount in the identification and classification of perianal CD. Computed tomography (CT), endoscopic ultrasound (EUS), and MRI are the most frequently used imaging techniques, with the latter showing the highest level of sensitivity and specificity while minimizing radiation exposure. In addition to imaging studies, a properly conducted examination under anesthesia (EUA) performed by an experienced surgeon has the specificity of detecting up to 90% of perianal lesions.1 In a study of 32 patients with perianal CD, the diagnostic accuracy of EUS, EUA, and MRI alone was 91%, 91%, and 87%, respectively, and the combination of EUA and MRI/EUS increased the accuracy close to 100%.4
Managing Perianal Crohn's Disease
Treatment of perianal CD is geared toward drainage of fluid collections/abscesses, fistulae closure without recurrence, and subsequent mucosal healing. Additionally, therapy is aimed at improved quality of life and decreased need for surgical intervention. Current treatment modalities include surgical intervention, antibiotics, immunomodulators, and biologics.
Although pediatric data are limited, anecdotally antibiotics targeted at enteric flora remain first-line therapy for simple perianal CD.4 Few studies have been powered enough to show significance when receiving antibiotics (ie, metronidazole or ciprofloxacin) alone and subsequently show a high rate of relapse when discontinued. Current research has shown the concomitant use of an immunomodulator or biologic with antibiotics improves success rates of perianal lesions when compared to placebo.1,4
Immunomodulators (6-MP or azathioprine) have shown a clinical improvement in fistulous tract closure compared to placebo in children with perianal CD. The onset of action of these medications is delayed and it has been recommended that they be used to maintain closure as opposed to inducing closure.5 No controlled pediatric trials have been conducted with methotrexate alone, although when given in combination with biologics, a few studies have shown at least partial closure in up to 25% of patients.6 A recent study of over 1,000 patients with CD (children included) found that early introduction of immunomodulators was associated with reduced need for perianal surgery.7
The American Gastroenterology Association has set forth clinical practice guidelines that place anti-tumor necrosis factor biologic agents as the treatment of choice in complex perianal CD.5 The ACCENT II (ACrohn's disease Clinical trial Evaluating infliximab in a New long-term Treatment regimen in patients with fistulizing Crohn's disease) study evaluated the use of infliximab in 195 patients with fistulizing CD and showed early and sustained fistulous tract closure (at least partial) in 46% compared to 19% receiving placebo.4,8 The REACH (a Randomized, multi-center, open-label study to Evaluate the safety and efficacy of Anti-TNF-alpha Chimeric monoclonal antibody in pediatric subjects with moderate to severe Crohn's disease) trial was analyzed post hoc, and showed response rates of 72% at 52 weeks in those children receiving infliximab with perianal CD.9 Recent studies have shown that a combination of infliximab therapy and surgical drainage with seton placement has an enhanced and sustained effect compared to either alone.10 A recent systematic review on the treatment of perianal CD has also concluded that the combination of surgical and medical treatment (immunomodulators or biologics) has additional benefit when compared to either option alone.11 It is the current North American Society for Pediatric Gastroenterology, Hepatology and Nutrition (NASPGHAN) recommendation to treat complex perianal CD with a combination of surgical interventions and biologic medications.1
Although most studies involving biologic use in perianal CD have been conducted with infliximab, a few adult studies have shown success with adalimumab with no controlled pediatric trials completed. An open-labeled arm of the CHARM (Crohn's trial of the fully Humanized antibody Adalimumab for Remission Maintenance) study found that nearly 90% of fistulas remained closed at 2 years.4,12 The use of adalimumab after infliximab failure, in perianal CD, has shown varying results with some showing no effect versus placebo and others reporting up to 87% remission at 48 weeks.13,14
Few controlled trials have been conducted regarding the use of tacrolimus, cyclosporine, or thalidomide to make firm recommendations for their use in perianal CD. The side-effect profile of these medications limits their use. According to the European Society of Pediatric Gastroenterology, Hepatology and Nutrition, enteral therapy has been recommended as first-line therapy for pediatric CD, although data are limited in its use for perianal CD. Few pediatric and adult studies have been conducted looking solely at enteral therapy for inducing and maintaining closure of fistulous tracts/abscesses.
Surgical Management of Perianal Crohn's Disease
Surgical intervention has remained an important option in the treatment of perianal CD. In the presence of active intestinal inflammation, it has been recommended that surgical intervention be used as a means to relieve acute symptoms to allow for better wound healing.1,4 It is recommended that perianal abscesses be completely evacuated and probed to evaluate for a suspected internal fistulous tract. If identified, an internal and external opening of the tract should be maintained with the placement of a seton to allow for complete drainage.4 Recurrence of perianal abscesses and the formation of complex fistulae tend to occur when a single opening (either internal or external) is demonstrated. Although setons can delay the closure of fistulous tracts, the concomitant use of infliximab has been shown to prevent further abscess formation and allow for mucosal healing. A recent study conducted in Brazil showed that nearly 50% of patients with perianal lesions were in complete remission after the combination of seton placement and biologic therapy (either infliximab or adalimumab).15 Current NASPGHAN guidelines recommend that maintenance medical therapy continue after the setons have been removed.1
Children with severe and complicated perianal CD may benefit from a diversion surgery (colostomy vs ileostomy) to allow the perianal disease time to heal.4 The fundamental concept behind diversion is to decrease fecal matter from penetrating distally and “feeding” the fistulous tracts. The goal of diversion would be re-epithelialization of the fistulous tract with medically manageable disease. Ultimately, the aim would be ostomy closure and reconnection, although many of these children will have recurrence of their perianal CD and require re-diversion. In some instances, the ostomy can become permanent.1,4
Perianal CD is a severe manifestation of CD and can include anal skin tags, rectal fissures, perianal abscesses, or fistulae as well as rectal stricturing. Pediatric data are limited in the most appropriate treatment modalities but there has been some success in using a combination of antibiotics, immunomodulators, biologics, and/or surgical interventions. Future aims should be geared to more individualized treatment with regard to intestinal disease, perianal manifestation, prognosis for healing, and quality of life.
- de Zoeten EF, Pasternak BA, Mattei P, Kramer RE, Kader HA. Diagnosis and treatment of perianal Crohn disease: NASPGHAN clinical report and consensus statement. J Pediatr Gastroenterol Nutr. 2013;57(3):401–412. doi:10.1097/MPG.0b013e3182a025ee [CrossRef]
- Eglinton TW, Roberts R, Pearson J, et al. Clinical and genetic risk factors for perianal Crohn's disease in a population-based cohort. Am J Gastroenterol. 2012;107(4):589–596. doi:10.1038/ajg.2011.437 [CrossRef]
- Bell SJ, Williams AB, Wiesel P, Wilkinson K, Cohen RC, Kamm MA. The clinical course of fistulating Crohn's disease. Aliment Pharmacol Ther. 2003;17(9):1145–1151. doi:10.1046/j.1365-2036.2003.01561.x [CrossRef]
- Gecse KB, Bemelman W, Kamm MA, et al. A global consensus on the classification, diagnosis and multidisciplinary treatment of perianal fistulising Crohn's disease. Gut. 2014;63(9):1381–1392. doi:10.1136/gutjnl-2013-306709 [CrossRef]
- Sandborn WJ, Fazio VW, Feagan BG, Hanauer SBAmerican Gastroenterological Association Clinical Practice Committee. AGA technical review on perianal Crohn's disease. Gastroenterology. 2003;125(5):1508–1530. doi:10.1016/j.gastro.2003.08.025 [CrossRef]
- Schröder O, Blumenstein I, Schulte-Bockholt A, Stein J. Combining infliximab and methotrexate in fistulizing Crohn's disease resistant or intolerant to azathioprine. Aliment Pharmacol Ther. 2004;19(3):295–301. doi:10.1111/j.1365-2036.2004.01850.x [CrossRef]
- Kariyawasam VC, Selinger CP, Katelaris PH, et al. Early use of thiopurines or methotrexate reduces major abdominal and perianal surgery in Crohn's disease. Inflamm Bowel Dis. 2014;20(8):1382–1390. doi:10.1097/MIB.0000000000000119 [CrossRef]
- Sands BE, Blank MA, Diamond RH, Barrett JP, Van Deventer SJ. Maintenance infliximab does not result in increased abscess development in fistulizing Crohn's disease: results from the ACCENT II study. Aliment Pharmacol Ther. 2006;23(8):1127–1136. doi:10.1111/j.1365-2036.2006.02878.x [CrossRef]
- Crandall W, Hyams J, Kugathasan S, et al. Infliximab therapy in children with concurrent perianal Crohn disease: observations from REACH. J Pediatr Gastroenterol Nutr. 2009;49(2):183–190. doi:10.1097/MPG.0b013e3181a70f21 [CrossRef]
- Roumeguère P, Bouchard D, Pigot F, et al. Combined approach with infliximab, surgery, and methotrexate in severe fistulizing anoperineal Crohn's disease: results from a prospective study. Inflamm Bowel Dis. 2011;17(1):69–76. doi:10.1002/ibd.21405 [CrossRef]
- Yassin NA, Askari A, Warusavitarne J, et al. Systematic review: the combined surgical and medical treatment of fistulising perianal Crohn's disease. Aliment Pharmacol Ther. 2014;40(7):741–749. doi:10.1111/apt.12906 [CrossRef]
- Colombel JF, Schwartz DA, Sandborn WJ, et al. Adalimumab for the treatment of fistulas in patients with Crohn's disease. Gut. 2009;58(7):940–948. doi:10.1136/gut.2008.159251 [CrossRef]
- Sandborn WJ, Rutgeerts P, Enns R, et al. Adalimumab induction therapy for Crohn disease previously treated with infliximab: a randomized trial. Ann Intern Med. 2007;146(12):829–838. doi:10.7326/0003-4819-146-12-200706190-00159 [CrossRef]
- Echarri A, Castro J, Barreiro M, Carpio D, Pereira S, Lorenzo A. Evaluation of adalimumab therapy in multidisciplinary strategy for perianal Crohn's disease patients with infliximab failure. J Crohns Colitis. 2010;4(6):654–660. doi:10.1016/j.crohns.2010.07.012 [CrossRef]
- Kotze PG, Albuquerque IC, da Luz Moreira A, Tonini WB, Olandoski M, Coy CS. Perianal complete remission with combined therapy (seton placement and anti-TNF agents) in Crohn's disease: a Brazilian multicenter observational study. Arq Gastroenterol. 2014;51(4):284–289. doi:10.1590/S0004-28032014000400004 [CrossRef]