Fistulizing perianal lesions in a French population with Crohn's disease

Fistulizing perianal Crohn's disease (FPCD) – defined as the presence of perianal fistula (PF) and/or abscesses – is an aggressive and debilitating complication of Crohn's disease (CD) and affects >25% of patients with CD within two decades of diagnosis [[1]Gomollón F. Dignass A. Annese V. et al.3rd European evidence-based consensus on the diagnosis and management of Crohn's disease 2016: part 1: diagnosis and medical management.J Crohns Colitis. 2017; 11: 3-25Crossref PubMed Scopus (947) Google Scholar,[2]Schwartz D.A. Loftus Jr., E.V. Tremaine W.J. et al.The natural history of fistulizing Crohn's disease in Olmsted County, Minnesota.Gastroenterology. 2002; 122: 875-880Abstract Full Text Full Text PDF PubMed Scopus (641) Google Scholar. Symptoms of FPCD include rectal pain, persistent drainage from external fistula openings, and urinary tract infections [[1]Gomollón F. Dignass A. Annese V. et al.3rd European evidence-based consensus on the diagnosis and management of Crohn's disease 2016: part 1: diagnosis and medical management.J Crohns Colitis. 2017; 11: 3-25Crossref PubMed Scopus (947) Google Scholar]. Besides impaired quality of life, FPCD leads to frequent relapses, and surgical intervention is often required [[1]Gomollón F. Dignass A. Annese V. et al.3rd European evidence-based consensus on the diagnosis and management of Crohn's disease 2016: part 1: diagnosis and medical management.J Crohns Colitis. 2017; 11: 3-25Crossref PubMed Scopus (947) Google Scholar]. Much of the literature describing the incidence/prevalence of FPCD refers to data from 10–20 years post-diagnosis [[2]Schwartz D.A. Loftus Jr., E.V. Tremaine W.J. et al.The natural history of fistulizing Crohn's disease in Olmsted County, Minnesota.Gastroenterology. 2002; 122: 875-880Abstract Full Text Full Text PDF PubMed Scopus (641) Google Scholar,[3]Tang L.Y. Rawsthorne P. Bernstein C.N. Are perineal and luminal fistulas associated in Crohn's disease? A population-based study.Clin Gastroenterol Hepatol. 2006; 4: 1130-1134Abstract Full Text Full Text PDF PubMed Scopus (123) Google Scholar. The frequency of patients who present with fistulizing lesions at the time of their CD diagnosis, and what their initial diagnostic and therapeutic management consists of, is largely unknown. Here, we aimed to describe the frequency of FPCD at CD diagnosis, its diagnostic and therapeutic management, and any associated factors. We investigated these questions using the population-based EPIMAD registry, which records incidences of patients with inflammatory bowel disease in northern France. Registry data are recorded from patients’ charts by interviewing practitioners (IPs) at the offices of 262 gastroenterologists (GEs) using a standardized questionnaire. Besides standard baseline demographic information, data regarding the description and factors associated with the presence of FPCD, at diagnosis, were retrospectively collected by IPs from charts completed by a GE, radiologist and/or surgeon. This information described radiological assessment outcomes, details of medical and surgical treatment, and any other relevant information regarding patients’ FPCD. Patients were considered to have a clinical history of FPCD if they were diagnosed with perianal lesions (PL) 6 weeks prior to a diagnosis of CD. The study population includes patients with CD diagnosed from January 1, 2007 to December 31, 2012. Outcome measures included: diagnostic procedure(s) performed at FPCD diagnosis (e.g. clinical examination, clinical examination under anesthesia [EUA], perianal magnetic resonance imaging [MRI] and echo-endoscopy), and initial medical and/or surgical management within the first 3 months after diagnosis. Additionally, we examined the frequency of patients presenting with lesions associated with FPCD at diagnosis versus those presenting without, according to sociodemographic, clinical and phenotypic characteristics. All patients consented to have their medical information used for this study. All definite and probable CD cases diagnosed from 2007–2012 were extracted from the EPIMAD registry, totalling 2906 patients, of which 116 (4%) were identified as having FPCD at the time of CD diagnosis. Of these, 56% were male; the median age at diagnosis (for both sexes) was 25 (19–39) years. The most frequently reported perianal symptoms at diagnosis were discharge (fistula drainage following gentle finger compression of the surrounding tissue) (64.7%), pain (58.8%), induration (localized hardening of the soft tissue surrounding a fistula opening) (14.7%), incontinence (2.9%) and dyspareunia (1.5%). At diagnosis, patients with FPCD could present with more than one type of lesion: 81% (n = 94) had ≥1 PF and 58% (n = 67) had ≥1 abscess; 15% (n = 14) of PF were classified as simple, 63% (n = 59) as complex [[4]Sandborn W.J. Fazio V.W. Feagan B.G. et al.AGA technical review on perianal Crohn's disease.Gastroenterology. 2003; 125: 1508-1530Abstract Full Text Full Text PDF PubMed Scopus (438) Google Scholar], and 22% (n = 21) were unspecified; 10% had a rectovaginal fistula (3% [4/116 patients] were anovulval). Fifty-seven percent of patients had one fistula, 16% had two, 3% had ≥3 fistulas and 23% were non-specified. Regarding abscesses, 72% were classed as singular; 9% of patients had ≥2 abscesses (19% were non-specified). From the 116 patients presenting with FPCD at CD diagnosis, 81% (n = 93) underwent a clinical examination (all patients likely underwent this examination but it was not recorded in the patients’ charts), 50% (n = 58) underwent EUA, 34% (n = 39) underwent perianal MRI, and one was examined using echo-endoscopy (Fig. 1A). Patients could undergo >1 type of examination at the time of CD diagnosis: nearly half (49%) had one examination performed, 36% had two forms of examination, and 15% of patients had three types of examination performed (Fig. 1B). Considering all patients with FPCD who underwent at least two forms of examination at diagnosis, the most frequent combination (33% of patients) was a clinical examination combined with EUA (Fig. 1C). Concerning diagnosis of patients presenting with abscesses, 63% (n = 42) were examined via clinical examination. Of these, one patient had abscess size recorded as 5 mm; abscess size was non-specified for the remaining 41 patients. Forty-nine percent (n = 33) of patients underwent EUA, abscess size was not specified for 30 of these patients; three patients had abscess size recorded as 5 mm, 30 mm and 40 mm, respectively. Twenty-one percent (n = 14) of patients underwent perianal MRI, in whom abscess size was not specified. When examining the number of patients receiving a particular medical treatment within the first 3 months after presenting with FPCD, sample sizes varied from N = 116 on account of missing patient information. However, we found 63% (n = 59/93) of patients were prescribed antibiotics and 47% (n = 54/116) received corticosteroids (n = 35 oral systemic steroids, n = 19 budesonide); the median delay following diagnosis at which oral corticosteroids were prescribed was 8 days (interquartile range [IQR], 0–25 days). Forty-two percent (n = 49/116) of patients received 5-aminosalicylic acid (5-ASA) therapy (prescribed on the day of CD diagnosis) and 33% of patients (n = 31/106) received anti-tumor necrosis factor (TNF) therapy (26% infliximab; 4% adalimumab) (Fig. 1D), with 44 days (IQR, 13–76) as the median duration after which a biologic was prescribed. Azathioprine was prescribed for 27% (n = 29/108) of patients (Fig. 1D) after a median time of 38 days (IQR, 9–84). Combination therapy (azathioprine and infliximab) was prescribed for 12% (n = 13/105) of patients. Over half (57%, n = 64/113) of patients presenting with FPCD at diagnosis underwent surgery (Fig. 1D) (patients could have >1 type of surgery). A diverting ileostomy was performed for 2 patients; the remaining 62 patients underwent minor perianal surgeries (e.g. seton placement and abscess drainages). Patients who underwent surgery also received complementary therapies (Fig. 1E), with antibiotics most frequently used in combination with surgery (30%, n = 35/116). Univariate comparisons between patients with (n = 116) and without (n = 2790) FPCD at diagnosis revealed that FPCD was significantly associated with male gender, absence of abdominal pain and colonic CD location; multivariate analysis revealed these variables were also independently linked to FPCD (Table 1).Table 1Univariate and multivariate comparisons between patients with (n = 116) and without (n = 2790) FPCD at diagnosis.Patient characteristicsUnivariateMultivariateOR95% CIPOR95% CIPPatient symptoms, FPCD according to CD locationSex female (vs. male)0.60.4–0.90.0060.60.4–0.80.006Area of residence0.23– Nord – Pas-de-Calais1.0– Somme1.60.9–2.8 Seine-Maritime1.20.7–1.8Tobacco consumption0.22– Never1.0– Current0.70.4–1.1 Past0.80.3–1.8Age at CD diagnosis0.69– Adult1.0– Pediatric0.80.4–1.4 Senior0.90.4–2.0Family history of IBD (vs. no history of IBD)1.00.6–1.70.95–Patient symptomsIntestinal transit0.06– Normal1.0– Constipation0.90.4–1.8 Diarrhea0.60.4–0.9Constipation/diarrhea alternation0.40.1–1.0Blood in stools (vs. no blood in stools)1.10.7–1.60.62–Mucus (vs. no mucus)1.20.8–1.90.38–Abdominal pain (vs. no abdominal pain)0.50.3–0.70.00020.60.4–0.90.003Weight loss (vs. no weight loss)1.00.7–1.50.94–Fever (vs. no fever)1.00.5–1.70.98–FPCD according to CD locationMontreal classification⁎The Montreal classification for CD defines CD as: L1, ileal; L2, colonic; L3, ileocolonic. CD, Crohn's disease; CI, confidence interval; FPCD, fistulizing perianal Crohn's disease; IBD, inflammatory bowel disease; OR, odds ratio.0.010.02 L11.0–1.0– L2 (vs. L1)2.11.2–3.92.01.1–3.7 L3 (vs. L1)1.20.7–2.31.20.7–2.2Phenotype (Montreal classification)0.01– Non-stricturing non-penetrating (B1)1.0– Stricturing (B2)0.40.2–0.9 Penetrating (B3)4.02.4–6.5 The Montreal classification for CD defines CD as: L1, ileal; L2, colonic; L3, ileocolonic. CD, Crohn's disease; CI, confidence interval; FPCD, fistulizing perianal Crohn's disease; IBD, inflammatory bowel disease; OR, odds ratio. Open table in a new tab In this general population, the rate of patients with FPCD at CD diagnosis (4%) is similarly reported in a 2020 study [[5]Yzet C. Sabbagh C. Lorreau J. et al.Inflammatory bowel disease symptoms at the time of anal fistula lead to the diagnosis of Crohn's disease.Clin Res Hepatol Gastroenterol. 2020; 44: 968-972Crossref PubMed Scopus (1) Google Scholar] where a medical history of anal fistula lead to diagnosis of CD in ≈7% of patients. The delayed diagnosis of fistulizing disease can reasonably be assumed to have delayed the commencement of optimal medical treatment for anal fistula in at least some patients. As anal/perianal fistulas can precede other CD clinical manifestations [[1]Gomollón F. Dignass A. Annese V. et al.3rd European evidence-based consensus on the diagnosis and management of Crohn's disease 2016: part 1: diagnosis and medical management.J Crohns Colitis. 2017; 11: 3-25Crossref PubMed Scopus (947) Google Scholar,[6]Nordgren S. Fasth S. Hulten L. Anal fistulas in Crohn's disease: incidence and outcome of surgical treatment.Int J Colorectal Dis. 1992; 7: 214-218Crossref PubMed Scopus (91) Google Scholar, patients presenting with fistulizing lesions should be assessed for underlying luminal CD. However, the rate of FPCD that we found is lower versus reports in other large population studies, in which the prevalence of FPCD has been reported to be around 20% [[2]Schwartz D.A. Loftus Jr., E.V. Tremaine W.J. et al.The natural history of fistulizing Crohn's disease in Olmsted County, Minnesota.Gastroenterology. 2002; 122: 875-880Abstract Full Text Full Text PDF PubMed Scopus (641) Google Scholar,[3]Tang L.Y. Rawsthorne P. Bernstein C.N. Are perineal and luminal fistulas associated in Crohn's disease? A population-based study.Clin Gastroenterol Hepatol. 2006; 4: 1130-1134Abstract Full Text Full Text PDF PubMed Scopus (123) Google Scholar. This discrepancy could be explained by varying definitions of perianal disease (e.g. we excluded patients with non-fistulizing perianal lesions) and study methodologies (e.g. population-based or from referral centers, or if a certain timeframe is utilized [e.g. in the present study, identification is restricted to within 6 weeks of the CD diagnosis date]). We also emphasize that the rate of FPCD reported here only includes patients at the time of their CD diagnosis – that is, not several years later when the risk of developing FPCD would have increased [[2]Schwartz D.A. Loftus Jr., E.V. Tremaine W.J. et al.The natural history of fistulizing Crohn's disease in Olmsted County, Minnesota.Gastroenterology. 2002; 122: 875-880Abstract Full Text Full Text PDF PubMed Scopus (641) Google Scholar]. Regarding diagnostic approaches utilized at the time of FPCD diagnosis, these were typically in accordance with European guidelines [[1]Gomollón F. Dignass A. Annese V. et al.3rd European evidence-based consensus on the diagnosis and management of Crohn's disease 2016: part 1: diagnosis and medical management.J Crohns Colitis. 2017; 11: 3-25Crossref PubMed Scopus (947) Google Scholar]. For example, half of the patients identified underwent EUA (Fig. 1A) [[1]Gomollón F. Dignass A. Annese V. et al.3rd European evidence-based consensus on the diagnosis and management of Crohn's disease 2016: part 1: diagnosis and medical management.J Crohns Colitis. 2017; 11: 3-25Crossref PubMed Scopus (947) Google Scholar,[7]Gionchetti P. Dignass A. Danese S. et al.3rd European evidence-based consensus on the diagnosis and management of Crohn's disease 2016: part 2: surgical management and special situations.J Crohns Colitis. 2017; 11: 135-149Crossref PubMed Scopus (351) Google Scholar, and two diagnostic methodologies were used to confirm FPCD for over a third (36%) of patients (Fig. 1B). However, combining both EUA and perianal MRI at diagnosis was infrequent (Fig. 1C). As per current guidelines [[1]Gomollón F. Dignass A. Annese V. et al.3rd European evidence-based consensus on the diagnosis and management of Crohn's disease 2016: part 1: diagnosis and medical management.J Crohns Colitis. 2017; 11: 3-25Crossref PubMed Scopus (947) Google Scholar], we recommend using two different examinations among MRI, EUA and endoscopic anorectal ultrasound for diagnosing FPCD to identify high-risk patients, thereby leading to increased use of more efficacious first-line treatments. For initial treatment of FPCD, a multidisciplinary approach that combines surgical and medical therapy is advocated as the gold standard of care [[7]Gionchetti P. Dignass A. Danese S. et al.3rd European evidence-based consensus on the diagnosis and management of Crohn's disease 2016: part 2: surgical management and special situations.J Crohns Colitis. 2017; 11: 135-149Crossref PubMed Scopus (351) Google Scholar,[8]Panes J. Garcia-Olmo D. Van Assche G. et al.Expanded allogeneic adipose-derived mesenchymal stem cells (Cx601) for complex perianal fistulas in Crohn's disease: a phase 3 randomised, double-blind controlled trial.Lancet. 2016; 388: 1281-1290Abstract Full Text Full Text PDF PubMed Scopus (442) Google Scholar. In our study population, the majority of patients who underwent surgery also underwent complementary medical treatment, primarily with antibiotics, 5-ASA or oral corticosteroids (Fig. 1E). This emphasis on more conventional treatment, including a high percentage of patients prescribed 5-ASA (42%) and low utilization of anti-TNF therapies (30%), may be reflective of an intentional delay in utilization of anti-TNF therapy on account of patients’ requiring surgical interventions after a FPCD diagnosis. Use of anti-TNFs in CD patients ≤8 weeks prior to any intestinal or intra-abdominal surgery has been associated with increases in infections and surgical complications [[9]Syed A. Cross R.K. Flasar M.H. Anti-tumor necrosis factor therapy is associated with infections after abdominal surgery in Crohn's disease patients.Am J Gastroenterol. 2013; 108: 583-593Crossref PubMed Scopus (90) Google Scholar]. In addition, guidelines during the study period recommended antibiotics and thiopurines combined with surgical therapy as first-line therapy for patients with FPCD; anti-TNFs were recommended as a second-line treatment [[10]Van Assche G. Dignass A. Reinisch W. et al.The second European evidence-based consensus on the diagnosis and management of Crohn's disease: special situations.J Crohns Colitis. 2010; 4: 63-101Abstract Full Text Full Text PDF PubMed Scopus (634) Google Scholar], which may also have been a contributing factor to infrequent anti-TNF use. Current guidelines recommend anti-TNFs as first-line therapy, followed by adequate surgical drainage [[7]Gionchetti P. Dignass A. Danese S. et al.3rd European evidence-based consensus on the diagnosis and management of Crohn's disease 2016: part 2: surgical management and special situations.J Crohns Colitis. 2017; 11: 135-149Crossref PubMed Scopus (351) Google Scholar]. However, PFs can be refractory to anti-TNF treatment [[11]Sands B.E. Anderson F.H. Bernstein C.N. et al.Infliximab maintenance therapy for fistulizing Crohn's disease.N Engl J Med. 2004; 350: 876-885Crossref PubMed Scopus (1737) Google Scholar], with relapse of perianal disease possible after discontinuation [[7]Gionchetti P. Dignass A. Danese S. et al.3rd European evidence-based consensus on the diagnosis and management of Crohn's disease 2016: part 2: surgical management and special situations.J Crohns Colitis. 2017; 11: 135-149Crossref PubMed Scopus (351) Google Scholar]. Encouragingly, the therapeutic armamentarium for FPCD is expanding and now includes stem-cell therapy [[8]Panes J. Garcia-Olmo D. Van Assche G. et al.Expanded allogeneic adipose-derived mesenchymal stem cells (Cx601) for complex perianal fistulas in Crohn's disease: a phase 3 randomised, double-blind controlled trial.Lancet. 2016; 388: 1281-1290Abstract Full Text Full Text PDF PubMed Scopus (442) Google Scholar]. Our univariate analysis suggests that male patients with PL and without congruent intestinal pain should be suspect for underlying FPCD and, thus, be assessed accordingly (via endoscopy). There were some limitations of this study. The information collected did not include precise descriptions concerning the anatomical involvement of fistulizing lesions. Data concerning abscess size were also limited and details concerning the therapeutic approach taken according to abscess size were not specified, so the extent to which these characteristics influenced treatment could not be evaluated. Only a third of patients underwent an MRI, and this is likely to reflect the less widespread use of MRI in the diagnostic evaluation of perianal involvement in CD during the period of enrollment (January 2012–December 2017). To conclude, we found that in this general population, FPCD frequency evaluated at time of CD diagnosis was lower compared with previous studied populations (where incidence of FPCD was reported at 10–20 years post-diagnosis). Importantly, we found several disease and patient characteristics (such as male gender, colonic CD location and absence of abdominal pain) were significantly linked to FPCD presentation at the time of CD diagnosis. We recommend future studies include a description of the FPCD recurrence process (and associated burden) and collect long-term registry data throughout the disease course to better characterize FPCD and help physicians identify early at-risk patients. The results described reflect initial management of FPCD mainly based upon conventional therapies; the infrequent use of anti-TNFs in the study population may reflect an intentional delay in use necessitated by a requisite for surgery after FPCD diagnosis, and less stringent supporting data and recommendations from guidelines during the study period. P. Wils has received lecture fees plus travel expenses from Takeda, Ferring, and AbbVie, and travel expenses from Ferring, AbbVie, Hospira, Janssen, Biogaran, and Takeda. A. Leroyer and C. Gower-Rousseau have no financial disclosures or potential conflicts of interest to disclose. M. Fumery has received lecture and consulting fees from AbbVie, MSD, Takeda, Ferring, Janssen, Tillots, Boehringer Ingelheim, Gilead, and Celgene. A. Fernandez-Nistal is an employee of Takeda. B. Pariente has received consulting fees from AbbVie, MSD, Takeda, Janssen, Lilly, Pfizer, and Biogaran, and lecture fees from AbbVie, MSD, Takeda, Janssen, and Ferring. This work was supported by Takeda Pharmaceuticals International. The EPIMAD registry is supported by grants from Lille Amiens and Rouen University Hospitals, Inserm, Santé Publique France, The Digest Science Foundation and the Association François Aupetit.

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