Fast Facts: Complex Perianal Fistulas in Crohn's Disease: A multidisciplinary approach to a clinical challenge

By J. Warusavitarne and P.G. Kotze

Over the course of their Crohn's disease, up to half of affected individuals will develop a perianal penetrating complication (either perianal fistula or abscess). Symptoms can be debilitating, and the impact on quality of life significant. This first edition of 'Fast Facts: Complex Perianal Fistulas in Crohn's Disease' explains how fistulas form, who is at risk and the principles of diagnosis and classification. Later chapters explore the medical and surgical options, including innovative therapies. The intention throughout is to emphasize the importance of ‘joined-up thinking’ when caring for patients. Perianal fistulas are often challenging to treat in patients with Crohn’s disease, and a multidisciplinary approach is needed to get the best outcomes. Table of Contents: • Epidemiology, etiology and pathology • Anatomy and classification • Diagnosis • Management principles • Medical treatment Local perianal surgical (sphincter-preserving) interventions • Innovative therapies • Managing complications

• Language: English
• Publisher: S. Karger
• Release date: May 26, 2021
• ISBN: 9783318068160

Book preview

Introduction

Over the course of their Crohn’s disease, up to half of affected individuals will develop a perianal penetrating complication (either perianal fistula or abscess). Symptoms can be debilitating, and the impact on quality of life significant.

In Fast Facts: Complex Perianal Fistulas in Crohn’s Disease, we explain how fistulas form, who is at risk and the principles of diagnosis and classification. Later chapters explore the medical and surgical options, including innovative therapies. Our intention throughout is to emphasize the importance of ‘joined-up thinking’ when caring for patients.

Perianal fistulas are often challenging to treat in patients with Crohn’s disease, and a multidisciplinary approach is needed to get the best outcomes. We trust that this book will be of interest and value to a range of health professionals involved in the care of affected patients and perhaps also to some patients. We hope that readers will appreciate our efforts to make our book informative and easy to read.

Finally, we thank our co-authors, Christopher Ma and Fabio Vieira Teixeira, for their invaluable contributions to this first edition.

While most individuals with Crohn’s disease (CD) present for medical attention because of luminal inflammatory features, perianal fistulas are among the most feared disease-related complications and can be extremely challenging to treat.

Epidemiology

Over the course of their disease, 15–50% of individuals with CD will develop a perianal penetrating complication (either perianal fistula or abscess). While 10–20% of patients present with perianal fistulizing CD (PFCD) as an initial manifestation of CD, the cumulative incidence of perianal complications increases over time. In a population-based cohort study from Olmsted County (Minnesota, USA) the cumulative incidence of perianal or rectovaginal fistulas was 18% after 10 years, 23% after 20 years and 24% after 30–40 years from CD diagnosis.¹

Although originally thought to be less common in children, similar incidence rates have been reported in pediatric populations: among 6679 prospectively enrolled children with CD in the multicenter ImproveCareNow Network, 21% developed perianal complications.²

Over time, despite advances in treatment, the cumulative probability of developing PFCD has remained stable and the rate of recurrent perianal fistulas has not significantly decreased. A population-based study in the Inflammatory Bowel Disease South Limburg (IBDSL) cohort evaluated the cumulative probability of perianal or rectovaginal fistulas by year of diagnosis (1991–1998, 1999–2005 and 2006–2011): whereas the cumulative 5-year probability of PFCD was 14.1% in individuals diagnosed in the 1991–1998 era, this was not significantly lower in patients diagnosed during 2006–2011 (10.3%, p = 0.70).³ Similarly, cumulative 5-year perianal fistula recurrence rates were stable (19.5% versus 25.5% versus 33.1%, p = 0.28).

Risk factors

Active rectal inflammation is the predominant risk factor associated with the development of PFCD. Correspondingly, patients with colonic disease are significantly more likely to develop PFCD than patients with isolated ileal or ileocolonic inflammation (41%, 12% and 15%, respectively), and approximately 9 in 10 patients will have rectal anatomic involvement.⁴

Anorectal stricture. PFCD is associated with the presence of an anorectal stricture, which is hypothesized to increase the intraluminal rectal pressure. In an observational cohort study, 61% of patients with CD and concurrent anorectal stricture had perianal fistulas compared with 34% of patients with CD but without an anorectal stricture (p = 0.001).⁵

Other clinical features associated with the development of PFCD include younger age at diagnosis and the presence of other intestinal stricturing or penetrating complications.⁶

Genetic factors have also been associated with PFCD. Single nucleotide polymorphisms in the nucleotide oligomerization domain 2 gene (NOD2) have been associated with perianal fistulas.⁷ An analysis of data from the Canterbury Inflammatory Bowel Disease (IBD) database, including information from 190 patients with perianal CD, identified a stronger association between perianal CD and the neutrophil cytosolic factor 4 gene (NCF4) compared with CD without perianal complications and healthy controls: odds ratios (ORs) 1.47 (95% confidence interval [CI] 1.08, 1.99) and 1.47 (95% CI 1.10, 1.95), respectively.⁶ Genetic variants in the IBD5 risk haplotype (5q31 cytokine cluster) have been associated with CD, though the relationship with perianal CD has been inconsistently demonstrated. In contrast, the gene for pseudouridine synthase 10 (PUS10) confers a protective effect against development of perianal disease.⁸

Pathophysiology

In PFCD, fistulas are caused by an abscess or luminal inflammation penetrating from the gut to the perianal skin (Figure 1.1). This contrasts with the pathophysiology of anorectal fistulas that originate from an infected anal crypt gland in patients without CD. The pathophysiology of PFCD is complex and is thought to be driven by two major processes: epithelial-to-mesenchymal transition (EMT) and the activity of matrix remodeling enzymes.⁹

Figure 1.1 A perianal fistula arising from an anorectal ulcer.

Epithelial-to-mesenchymal transition. By definition, fistulas represent a connection between two epithelial surfaces. To initiate fistula development, differentiated intestinal epithelial cells must transform to mesenchymal-type cells so that they can penetrate adjacent tissues. This transition, termed EMT, is fundamentally similar to the processes involved in both normal embryogenesis and organ development, as well as pathological stricturing fibrosis and invasive tumor metastasis.

Several lines of evidence suggest that EMT is an important contributor to PFCD pathogenesis. First, perianal fistulas in individuals with CD are lined with myofibroblast-like transitional cells that express both epithelial markers, such as cytokeratin 8 and 20, and mesenchymal markers, such as smooth muscle actin and vimentin.¹⁰

Second, fistula tracts in patients with CD express high levels of transforming growth factor β (TGF-β), tumor necrosis factor (TNF) and interleukin (IL)-13, but low levels of E-cadherin, an important epithelial cell adhesion molecule. Luminal inflammation at the site of a perianal fistula in patients with CD is rich with type 17 and type 1 T helper cells, in addition to macrophages, neutrophils