Anal fistula is a pathological connection between the anal canal and perianal skin, which most commonly develops from an infected anal crypt. While the majority of anal fistulas are idiopathic, they are also associated with Crohn’s disease (CD) and other inflammatory conditions. The prevalence of anal fistula is estimated to be 1-2 per 10000 patients, but population-based studies on anal fistula epidemiology are limited and outdated.

To assess the prevalence of anal fistula and relevant comorbidities, with and without CD in the United Kingdom and Europe.

A retrospective population-representative observational cohort study was performed in The Health Improvement Network (THIN), a United Kingdom primary care database. Mid-year point prevalence of anal fistula was calculated on the first of July for each year between 2014 and 2017. Estimates were calculated for anal fistula overall and by CD status and standardized to the United Kingdom and European population. Prevalence of relevant comorbidities including lymphogranuloma venereum, hidradenitis suppurativa, anal presentation of sexually transmitted diseases, diabetes mellitus, and radiation in the pelvic area was reported.

The United Kingdom-standardized overall point prevalence of anal fistula was 1.80 (95%CI: 1.65-1.94) per 10000 patients in 2017, while the Europe standardized estimate was 1.83 (95%CI: 1.68-1.98) per 10000 patients. Both these standardized point prevalence estimates ranged from 1.89 to 2.36 between 2014-2016. The United Kingdom-standardized point prevalence of anal fistula without CD was 1.35 (95%CI: 1.23-1.48) per 10000 patients, while the Europe-standardized estimate was 1.39 (95%CI: 1.26-1.52) per 10000 patients. In contrast, the standardized point prevalence estimate of anal fistula with CD was lower for both United Kingdom and Europe (0.44; 95%CI United Kingdom: 0.37-0.52, 95%CI Europe: 0.37-0.51) per 10000 patients in 2017. In 2017, 19% of anal fistula patients without CD and 13% of anal fistula patients with CD had at least one relevant comorbidity. These results show that anal fistulas are infrequent in the general population. 24.5% of prevalent anal fistulas are associated with CD, but other potentially etiological comorbidities are rare.

This real-world evidence study estimated the United Kingdom-standardized prevalence of anal fistula was 1.80 per 10000 patients in 2017. Approximately 25% of cases may be associated with CD, while other comorbidities are rare.

An anal (or perianal) fistula is defined as an external abnormal anatomical connection between the anorectal canal and the perianal skin[1]. Symptoms of anal fistulas include perianal cellulitis, anorectal pain, pruritus ani, smelly or bloody drainage of pus, and in some cases difficulty controlling bowel movements[2,3].

Most anal fistulas are idiopathic (approximately 90% of cases), and arise from an infected anal crypt[1]. Men are more commonly affected than women[4], and the mean age of first presentation is reported to be 40 years[5]. Management of anal fistula usually requires surgery including fistulotomy[6], as very few heal without interven-tion. In Crohn’s disease (CD) patients, first-line treatment with anti-tumor necrosis factor α antibody is recommended[3].

The prevalence of anal fistula is reported to be approximately 1-2 per 10000 patients in European population studies[7]. The mean incidence of anal fistula is estimated to be 8.6 per 100000 people, 1.04 per 10000 people, and 2.32 per 10000 people in Finland, Spain and Italy, respectively[4,7]. However, being more than 10 years old, these reports may be outdated. A recent systematic review estimates the prevalence of anal fistula in Europe as 1.69 per 10000 patients[8].

Anal fistulas are also associated with CD, lymphogranuloma venereum, hidradeni-tis suppurativa, surgery, radiotherapy[9], and sexually transmitted diseases[10], as these can result in deep rectal/anal mucosal damage, which facilitates the development of fistula. Epidemiological reports on these and other etiologically relevant comorbid conditions in anal fistula are sparse. In CD, the cumulative incidence of anal fistula ranges between 17% and 50%, with about 35% of patients having at least one anal fistula during the course of the disease[11-14]. Anal fistulas reported to be associated with tuberculosis are 0.2%, and 3.3% are associated with trauma[4]. After surgery, between 1.2% of patients and 0.3% of patients develop anal fistula[15-18]. Approximately 7% of patients with lymphogranuloma venereum[19] and 80%-91% of patients with anorectal tuberculosis present with anal fistula[20].

Patients with chronic diseases like diabetes mellitus are also discussed to be at increased risk of anal fistula, due to their susceptibility to skin lesions and systemic infections[21], and increased risk for perianal abscesses[22].

There is no recent data on the prevalence of anal fistula in the European or United Kingdom. The frequency of underlying risk conditions in anal fistula is also poorly understood, and no comprehensive estimate of their prevalence within the population of anal fistula patients exists. Although there is an established association between CD and anal fistula, there remains a lack of current prevalence estimates as well as esti-mates of relevant risk comorbidities.

This observational study aimed to generate population-based real-world evidence on the epidemiology of anal fistula within a United Kingdom primary healthcare database. The study hopes to improve our understanding of the prevalence of anal fistula, with and without CD, as well as the prevalence of relevant comorbidities among anal fistula patients.

This observational real-world evidence study is the first to report comprehensive prevalence estimates of anal fistula in patients with and without CD, and the frequency of concomitant comorbidities in a United Kingdom population-based study. We report the United Kingdom-standardized overall prevalence of anal fistula to be 1.80 cases per 10000 patients.

Most anal fistula patients identified in this study were idiopathic. This finding is consistent with previous studies[4,31,32] and a recently conducted systematic literature review on anal fistula prevalence[8]. As the fistula duration is longer for patients with CD than for patients without[33-36], we adjusted the look-back period for prevalence estimates accordingly, which allowed for accurate prevalence estimate.

Reported population-based incidence estimates for anal fistula in CD patients range between 1.2%[37] to 7.5%[38]. Based on these values, a systematic review calculated anal fistula prevalence among CD patients to be 3.4%-6.0% in the Europe[8]. Our study’s prevalence estimates of anal fistula patients with CD (0.44/10000 patients, United Kingdom standardized) are not directly comparable to these results, as the denominators represent different patient populations (we used the number of total patients instead of number of CD patients). However, while literature typically suggests 90% of anal fistula to be idiopathic[2,3], the proportion of anal fistula patients with a diagnosis of CD in the THIN database was 25%. This may be explained by the different methods applied, as well as characteristics of the databases: We included a look-back period for CD at any time in the patient’s history as well as a four-year prospective period from the index anal fistula diagnosis to account for the possibility that anal fistula are the first manifestation of CD. This is likely to have increased the proportion of CD patients within anal fistula patients compared to studies that did not allow for a prospective follow-up time.

In line with previous studies[4], we found men to be more frequently affected by anal fistula than women, in both patients with and without CD. This is attributable to the substantially higher prevalence of anal abscesses in men[39].

In THIN, both Direct (capturing anal fistula diagnoses) and Indirect (capturing procedures explicitly related to anal fistula) anal fistula Read codes are used – Direct codes being more frequent than Indirect ones. This was expected, because procedures associated with anal fistula therapy are commonly conducted in a secondary care setting. Although diagnoses are reported back from secondary care to the general practitioner (GP) in the United Kingdom, this data transfer is often facilitated by letters; therefore, it is possible that not all procedures may have been transcribed into the fields of the data source. A small subset of anal fistula cases may also be treated without invasive methods[40].

In addition to the well-established connection between CD and anal fistula, anal fistula has been associated with anal/rectal infectious diseases[4,19,20], anal carcinoma[41], and systemic diseases[42,43]. We report diabetes mellitus to be the most common comorbidity of interest within anal fistula patients with and without CD, and elderly patients to be most frequently affected by comorbidities. This is not surprising, as diabetes is common in the general population, with a reported United Kingdom prevalence of 4.3% in 2005[44]. Diabetic patients are more susceptible to skin lesions and systemic infections[21], and are reported to be at increased risk for anal abscess-es[22]. It is also possible that diabetic patients are more likely to be diagnosed instead of remaining undetected, as they are more frequently clinically assessed. They may thus be at increased risk for anal fistula. Diverticulitis is regarded as a risk factor for anal fistula, if a low sigmoid diverticular infection or abscess damages all mucosal layers.

However, typically, diverticulosis is associated with fistulas between the colon and bladder or the colon and vagina in women[45,46]; not anal fistula. Other comorbid conditions included in our study are very rare. However, it is to be noted that sexually transmitted diseases are under-recorded in THIN, as patients in the United Kingdom are frequently treated at specialized sexual health clinics, and data are not always conveyed to the GP, or transcribed into the fields of the data source if they are conveyed. We may also have missed cases with radiation to the pelvic area as a comorbidity, as procedure codes from secondary care may not all be transcribed into THIN.

A decline in the number of practices using Vision software has led to a decline in active patients in THIN. This may contribute to the observed decline in anal fistula prevalence 2014-2017. It is unclear to what extent differential changes in patient demographics and healthcare structure affect the estimates. New and personalized treatment options for CD and anal abscesses may also affect the trend of anal fistula prevalence. These hypotheses should be explored in further studies.

The main strength of this real-world evidence study is the population-based nature of the data source, which allows results to be generalized to the United Kingdom and Europe populations. Most cases of anal fistula are thought likely to be captured in the THIN database, as fistulas do not heal on their own and need medical intervention, and the gateway to the medical system in the United Kingdom is through primary care. Similarly, it is unlikely that many patients only receive their care in hospital and appear inactive in THIN. Furthermore, we have accounted for the different courses of disease between patients with and without CD, to report the most accurate overall anal fistula prevalence estimates. Standardization of the prevalence estimates to the Europe is considered to be valid, as biological variation across Europe compared to the United Kingdom is minimal.

This study was funded by Takeda Pharmaceuticals International Inc. Rachel Tham, Catrina Richards, Javeed Kahn and Louise Raiteri from IQVIA provided program-ming support. Mounika Parimi from IQVIA provided medical writing support.