Next Article in Journal
Prevalence of Non-Alcoholic Fatty Liver Disease and Its Impact on Fibrosis Risk in Inactive Chronic Hepatitis B Patients: Insights from a Cross-Sectional Study
Previous Article in Journal
Omentoplasty for Cervical Lymphocele after Aortic Arch Replacement
Previous Article in Special Issue
The Microbiome in Inflammatory Bowel Disease
 
 
Search for Articles:
Title / Keyword
Author / Affiliation / Email
Journal
Article Type
 
 
Advanced Search
 
Section
Special Issue
Volume
Issue
Number
Page
 
Journals
JCM
Volume 13
Issue 16
10.3390/jcm13164734
jcm-logo
Submit to this Journal Review for this Journal Propose a Special Issue
► Article Menu

Article Menu

share Share announcement Help format_quote Cite question_answer Discuss in SciProfiles thumb_up
...
Endorse textsms
...
Comment
first_page
settings
Order Article Reprints
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:
Background:
Systematic Review

Fistulizing Perianal Disease as a First Manifestation of Crohn’s Disease: A Systematic Review and Meta-Analysis

by
Liesbeth Jozefien Munster
1,2,*,
Giulia Louise Emilia Mönnink
1,2,
Susan van Dieren
2,
Marco William Mundt
3,
Geert Renaat Alfons Maria D’Haens
4,
Willem Adrianus Bemelman
2,
Christianne Johanna Buskens
2 and
Jarmila Dagmara Wendelien van der Bilt
1,2,*
1
Department of Surgery, Flevoziekenhuis, 1315 RA Almere, The Netherlands
2
Department of Surgery, Amsterdam UMC (Location VUMC), 1081 HV Amsterdam, The Netherlands
3
Department of Gastroenterology and Hepatology, Flevoziekenhuis, 1315 RA Almere, The Netherlands
4
Department of Gastroenterology and Hepatology, Amsterdam UMC (Location VUMC), 1081 HV Amsterdam, The Netherlands
*
Authors to whom correspondence should be addressed.
J. Clin. Med. 2024, 13(16), 4734; https://doi.org/10.3390/jcm13164734
Submission received: 30 May 2024 / Revised: 16 July 2024 / Accepted: 17 July 2024 / Published: 12 August 2024
(This article belongs to the Special Issue Editorial Board Members’ Collection Series: Inflammatory Bowel Disease)
Browse Figures
Versions Notes

Abstract

:
Background: Incidences of perianal fistulas (PAFs) as a first manifestation of Crohn’s disease (CD) vary widely in the literature. Aim: To analyse the percentage of patients with a PAF preceding CD diagnosis and assess the time to diagnosis. Methods: A systematic literature search was conducted. Studies reporting on patients with a PAF preceding CD diagnosis were identified. Primary outcomes were the (weighted) percentage of patients with CD with a PAF preceding CD and their time to CD diagnosis. Secondary outcomes were the (weighted) percentage of patients with CD with a PAF preceding CD diagnosis in predefined patient subgroups, including (1) sex (men vs. women), (2) ethnicity (Asian vs. non-Asian), and (3) age (paediatric (0–18 y) and patients with elderly onset CD (>60 y) vs. adult patients (18–60 y)). Results: Seventeen studies were included (34,030 patients with CD). In the overall CD population, a PAF preceded CD in 8.6% [95%CI; 5.72; 12.71] with a weighted mean time to CD diagnosis of 45.9 (31.3) months. No studies reported details on sex differences in patients with a PAF as a manifesting sign of CD. In Asian populations, a PAF preceded CD in 17.66% [95%CI; 11.45; 26.25], which was significantly higher when compared with non-Asians (4.99% [95%CI; 3.75; 6.60], OR:3.99, p < 0.0001). In adolescents, an incidence of 9.17% [95%CI; 5.92; 13.93] was found with significantly lower incidences in paediatric patients (6.38% [95%CI; 1.84; 19.85], OR:0.53, p < 0.0001), and elderly-onset patients (3.77% [95%CI; 1.68; 8.25], OR:0.44, p = 0.0035). Conclusions: This systematic review shows that in the literature, almost 10% of patients present with a PAF as a first manifestation of CD, with a mean time to diagnosis of almost four years. These results emphasise that increased clinical awareness is needed.

1. Introduction

Perianal fistulas (PAFs) are common in Crohn’s disease (CD) and are regarded as one of the most debilitating symptoms of the disease [1,2,3,4]. Approximately one-third of all patients with CD will be confronted with a PAF during the disease course, either before or after their CD diagnosis [1,5]. Reported incidences of CD related PAFs and timing of manifestations seem to vary widely within studies and various subgroups of patients (disease phenotype, patient’s country of origin, and age) [6,7]. Perianal symptoms may precede intestinal symptoms in CD for many years and may occur without any luminal signs [8,9,10,11,12,13]. Interestingly, time to CD diagnosis in patients with a PAF as a first manifestation is reported to be much longer than in patients presenting with luminal complaints [14,15]. Moreover, the literature states that the presence of PAFs at CD diagnosis is associated with a poor prognosis and an elevated risk of a disabling and complex disease course [16,17]. It was shown that combining anti-tumour necrosis factor (anti-TNF) therapy with surgical closure offers the highest chance of radiological healing, which nowadays is assumed to be the highest therapeutic goal for all PAF patients [18,19,20,21,22]. Correspondingly, a long diagnostic delay will result in delayed initiation of appropriate therapy, probably impacting outcomes [18], not only for the perianal disease but also with increased risk of bowel stenosis and need for surgical intervention in case of luminal disease [16].
Studies specifically focusing on patients with PAF as a manifesting sign of CD are limited, and it is difficult to draw firm conclusions on the true incidence of PAF as a first manifestation. Moreover, the relevance for daily clinical practice and its impact on long-term outcomes remains unknown. This current study aimed to analyse the percentage of patients with a PAF preceding CD diagnosis and assess their time to diagnosis by reviewing the current literature. In addition, the impact of time to diagnosis on long-term clinical outcomes was analysed.

2. Materials and Methods

2.1. Search Strategy

A systematic literature search was conducted for articles reporting on patients with a PAF preceding CD diagnosis according to PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-analyses) guidelines [23]. A detailed protocol was registered in the PROSPERO database (ID: CRD42022365616). Guided by an experienced medical librarian, the search was conducted in the following databases: Pubmed, EMBASE, Cochrane, and Web of Science. The search strategy included (MeSH) terms and free text related to or describing ‘Crohn’s disease’, ‘perianal diseases’, ‘diagnosis’, and/or ‘incidence’ or ‘prevalence’. No study date restrictions were applied. Animal studies, case reports, reviews, letters, conference abstracts, editorials, and comments were excluded. The final search was conducted on 28 August 2023. A detailed report of the search strategy is provided in Supplementary Table S1.

2.2. In-And Exclusion Criteria

Studies meeting the following criteria were included: (1) concerning a general CD cohort as the study population, (2) describing patients with a PAF preceding CD diagnosis [24] (i.e., PAF first), and (3) including >10 patients with CD.
In case different articles used the same study population in their analysis (e.g., same database and the same period of time), only one was included to prevent overrepresentation of the study population in the analysis.
Studies were excluded when they (1) did not distinguish between the type of perianal lesion (e.g., skin tag, PAF, PAA, fissure, or haemorrhoid), (2) included rectovaginal fistulas, (3) reported on the incidence of CD-related PAFs in a general PAF cohort solely, or (4) were in languages other than English or Dutch (due to logistic reasons).

3. Outcomes

Primary outcomes were the percentage of patients with a PAF preceding CD diagnosis (presented as a weighted mean percentage) and their associated time to diagnosis. Secondary outcomes were the (weighted) percentage of patients with CD with a PAF preceding CD diagnosis in predefined patient subgroups, including (1) sex (men vs. women), (2) ethnicity (Asian vs. non-Asian), and (3) age (paediatric (0–18 y) and patients with elderly onset CD (>60 y) vs. adult patients (18–60 y)). Additionally, time to diagnosis was correlated to length of follow-up (to correct for possible confounding) and long-term clinical outcomes. The quality of all studies was assessed by the use of the Newcastle Ottawa scale (NOS) [25].

3.1. Study Selection and Data Extraction

Two reviewers (GM and LM) screened titles and abstracts independently by the use of Rayyan [26]. Any disagreements in the selection process were resolved by discussion, and if necessary, a third researcher (JB) was consulted. After title and abstract screening, full texts were screened, and articles were evaluated in-depth to include studies specifically describing patients with a PAF preceding CD diagnosis and, if mentioned, their time to diagnosis (including the correlation between time to diagnosis and long-term clinical outcomes if reported).
Study characteristics (author, year of publication, country of publication, study design, study span, data source, study cohort, percentage of patients with CD used in the analysis, CD cohort subtypes) and patient characteristics (age and gender) were extracted. All data were recorded in a Microsoft Excel database (Microsoft Office version 2016). All missing data were reported and were handled by only analysing available data in the literature.

3.2. Statistical Analysis

Categorical data were presented as counts and percentages. Continuous data were presented as median and interquartile range (IQR) or means and standard deviation (SD). Time to diagnosis reported as median was converted to approximated mean values using a method suggested by Wan et al. [27] To standardise time units used in different studies, all data were converted to months before analysis. Meta-analyses were performed to calculate a weighted mean percentage [CI 95%] using the inverse variance method and a random effect model for the primary and secondary outcomes. Heterogeneity among the included studies was evaluated by computing the inconsistency index (I2). Values >50% indicated significant heterogeneity [28]. A Pearson’s correlation coefficient (r) was determined to assess the relationship between the number of patients with PAF first and the total number of patients with CD. Univariate analyses were used to determine the odds ratios (ORs) and 95% confidence intervals (CIs) of the variables associated with a PAF preceding CD. In case different studies were compared, a meta-regression on the random effects was performed. A two-tailed p-value of less than 0.05 was considered significant. All analyses were performed using Statistical Package for the Social Sciences (SPSS) for Windows (version 28, IBM Crop., Armonk, NY, USA) and RStudio for Windows (version 4.2.1).

4. Results

4.1. Study Selection

In the final search, a total of 6590 articles were retrieved. After the removal of duplicates, 3792 abstracts were included for screening. A total of 451 articles remained eligible for full-text screening. Among these, sixteen articles reported specifically on unique cohorts of patients with a PAF preceding CD diagnosis [29,30,31,32,33,34,35,36,37,38,39,40,41,42,43,44]. Cross-referencing yielded one additional article [45], which was included in the final analysis, resulting in a total of seventeen articles to be included. A comprehensive visual representation of the study selection process is presented in Figure 1.

4.2. Study Characteristics and Quality Assessment

Comprehensive study details of all seventeen studies included are summarised in Table 1. All studies (n = 17) were of a retrospective nature, of which nine were conducted in a multicenter setting. The studies included a total of 34,030 patients with CD (35% male), with cohort sizes ranging from 63 patients [32] to 12,905 patients [29]. The majority of studies report on adult patients. Two studies primarily focused on elderly onset CD [31,40], while two other studies exclusively concerned paediatric patients with CD [32,35]. Overall quality of the studies was moderate to good. Especially the length of follow-up and the adequacy of follow-up were lacking or insufficiently reported in most studies. For an overview of the results of the critical appraisal, see Supplementary Table S2.

4.3. PAF First in Patients with CD and Time to Diagnosis of CD

Seventeen studies reported on patients with a PAF as the first manifestation within the general CD cohort (Table 1) [29,30,31,32,33,34,35,36,37,38,39,40,41,42,43,45,46]. The study population comprised 34,030 patients with CD, with 2343 experiencing a PAF prior to their CD diagnosis. The incidence of a PAF before CD diagnosis ranged from 3 to 33% with a weighted mean of 8.59% [95% CI; 5.72; 12.71], r = 0.838, n = 17, p =< 0.001, Figure 2). Among the included studies, seven provided information on the time to diagnosis of CD after PAF manifestation. Five of these studies presented the time to diagnosis as either median (IQR/range) and/or mean (SD) values and were included in the analysis [33,36,41,42,44]. Four studies defined preceding diagnosis as the development or diagnosis of a PAF prior to CD diagnosis, and one study specifically described it as the development of a PAF > 6 months prior to CD diagnosis [42]. Time to diagnosis of CD ranged from 10.8 (15.8) months [36] to 106.75 (72.7) months [44], with a weighted mean time to diagnosis of 45.9 (31.3) months. In Supplementary Table S3, an overview of the (converted) times to diagnosis is provided.

4.4. PAF First and Sex

Although four studies reported on male predominance for PAF in general [40,42,44,45], no studies reported details on sex differences specifically in patients with a PAF as a manifesting sign of CD.

4.5. PAF First and Ethnicity

A subanalysis was performed to compare the proportion of PAF-first patients in Asian populations as compared to non-Asian populations. Seven Asian studies identified a total of 1187 patients with a PAF first among 7676 patients with CD, resulting in a weighted mean of 17.66% [95% CI; 11.45; 26.25], Figure 3a [30,35,36,40,42,44,45]. This was significantly higher (OR 3.99 [95% CI; 3.66; 4.34], p < 0.0001) than the 4.99% [95% CI; 3.75; 6.60] found in the analysis of ten non-Asian studies, Figure 3b [29,31,32,33,34,37,38,39,41,43].

4.6. PAF First and Age

Three studies, either focusing on paediatric patients or concerning paediatric subcohorts, were included [29,32,35]. When assessing the proportion of children with a PAF first as a fraction of all paediatric patients with CD (n = 2.318), a weighted mean of 6.38% [95% CI; 1.84; 19.85] was found, which was significantly lower when compared with 9.17% [95% CI; 5.92; 13.93] in patients from 18–60 years who served as reference (OR 0.53 [95% CI; 0.43; 0.66], p < 0.0001). In addition, two studies that addressed a PAF first in patients with elderly-onset CD (>60 years) revealed a weighted mean of 3.77% [95% CI;1.68; 8.25] [31,40], which was also significantly lower than the results as shown in the reference group (OR 0.44 [95% CI 0.25; 0.76], p = 0.0035, Figure 4).

4.7. Time to Diagnosis Correlated to Length of Follow-Up

Supplementary Figure S1 shows the percentage of patients with a PAF prior to CD diagnosis plotted against mean follow-up in years. It was shown that the eventual percentage of patients with a PAF prior to CD diagnosis was not correlated to the length of follow-up of included studies.

4.8. Impact of Time to Diagnosis on Long-Term Clinical Outcomes

Six studies reported on clinical outcomes in patients with perianal CD [33,36,39,42,43,45]. One study showed that patients with perianal CD had a significantly increased likelihood of undergoing (major) abdominal surgeries (including ostomy and proctectomy/proctocolectomy) [43]. Two other studies identified PAF prior to CD diagnosis as a poor prognostic factor [36,45] and suggested that early CD diagnosis could improve outcomes. However, no details were provided, and no correlation between time to diagnosis and clinical outcomes was reported. The remaining three studies presented fistula recurrences but did not discriminate fistula-first patients from the overall CD fistula population [33,39,42].

5. Discussion

This systematic review shows that a PAF as a first manifestation of CD occurs in 8.6% of all patients with CD, equaling around one-third of all patients with CD-related PAF. The weighted mean time to CD diagnosis in these patients was long, with an estimation of 45.9 (31.3) months. The percentage of patients with a PAF as a first manifestation was higher in the Asian population as compared with the non-Asian population (18% versus 5%, respectively), and adult patients with CD as compared with paediatric patients with CD and patients with elderly-onset CD (9% versus 6% and 4%, respectively).
The percentage of patients with a PAF as a manifesting sign of CD in this study is considerably higher than those reported in a recent systematic review by Tsai et al. [46], which investigated the cumulative incidence of perianal disease. In that study, it was reported that 3.8% (based on five studies, 95% CI 1.9–7.3%) of patients with CD developed perianal disease prior to luminal CD diagnosis. A possible explanation for this difference is that the current study included seventeen studies reporting on patients with a PAF first within the general CD cohort, which may have led to a more reliable percentage.
Time to CD diagnosis in patients with a PAF as a first manifestation is reported to be much longer than in patients presenting with luminal complaints [14,15]. Although none of the included studies provided details on the correlation between time to diagnosis and long-term clinical outcomes, several reports suggested that longer delays were associated with worse clinical outcomes [14,47], which underscores the need for action and the development of screening tools for early identification of patients at high risk of having CD. In addition, the start of adequate therapy will also be beneficial on the QoL of these patients, as fistula impact is known to be substantial, with symptoms such as faecal incontinence, rectal pain, and swelling affecting patients’ daily lives and sexual activity [48,49].
Recently, the International Organization for the Study of Inflammatory Bowel Disease (IO-IBD) identified ‘Red Flags’ suggestive for patients with CD, showing that a non-healing or complex PAF was strongly associated with the diagnosis of CD (OR 50.7) (95% CI 6.7–382.7) (p < 0.0001) [50]. Unfortunately, it remains challenging in clinical practice to be attentive to underlying CD in patients who present with a PAF as the sole manifestation. Despite that new insights in treatment for CD-related PAF combining anti-TNF therapy and surgical closure have improved prognosis, overall outcomes remain suboptimal, impacting both QoL and healthcare costs [19,20,21,22]. Awareness of this problem needs to be raised, as it not only leads to diagnostic delays but also mainly affects young adults who are in the midst of their socioeconomic lives [33,36]. The findings in this study underscore that a substantial part of patients with CD have PAF prior to CD diagnosis.
An interesting finding was that patients originating from Asian countries showed higher percentages of patients presenting with a PAF as the manifesting symptom of CD as compared with patients originating from non-Asian countries. A recent systematic review investigating the influence of ethnicity on phenotype and outcome in IBD showed that Asian and African patients with CD had more perianal involvement compared with Caucasian and/or Hispanic patients [6]. In addition, a large study on the disease phenotype of Korean paediatric patients with CD found that they had a higher probability of experiencing PAF at diagnosis than their peers from Europe (44.8% vs. 8.2%, p < 0.001) [7]. A potential explanation is that TNFSF15 polymorphisms (a so-called IBD gene that is upregulated in lymphocytes as well as in macrophages of the intestinal lamina propria in patients with CD), which are common in Asian populations, are independent predictive risk factors for the development of PAF, and are therefore associated with a higher risk of PAF [51,52]. Nevertheless, more research on the influence of ethnicity on disease phenotype needs to be conducted.
This study also demonstrated that paediatric patients presented less often with a PAF as a first manifestation of CD, which conforms to the literature stating that the risk of having CD increases with age when presenting with perianal disease [53,54,55,56,57]. In line with this, Roskam et al. [54] showed that the risk of CD in infants presenting with perianal disease solely is low. Moreover, it was shown that paediatric patients often present with isolated (ileo-)colonic disease without perianal involvement, which may have led to the lower percentages of patients with a PAF as a first manifestation [55]. Also, this study showed that PAF as a manifesting sign was frequently less seen in patients with elderly onset CD, which also conforms to the literature showing that patients with elderly onset CD were more likely to present with a colonic disease phenotype without involvement of the perianal region [56].
One of the major strengths of this study was that this study included a general population of patients with CD, which is most likely to be encountered in daily clinical practice. While, to our knowledge, this systematic review is the first to investigate the percentage of patients with CD with a PAF prior to CD diagnosis and their time to diagnosis, there are several limitations inherent to its design. Heterogeneity between studies was high with respect to cohort size, follow-up time, and quality. To avoid heterogeneity due the various definitions of perianal CD (which might also include fissures, skin tags, etc.), it was decided to only include studies presenting results of patients with PAF prior to CD diagnosis and no other perianal diseases. Unfortunately, the specific timeframe for ‘prior to diagnosis’ was not always specified, which may have contributed to the high heterogeneity rates in this study. However, it was shown that cohort sizes, as well as the length of follow-up in all studies, had no effect on the correlation between patients with a PAF first and the total CD cohort in all (sub)analyses. Still, as with all systematic reviews, it is important to interpret results with caution as all included studies were of retrospective design and its inherent limitations. Additionally, the quality assessment was of limited value due to the inapplicability of some of the questions in the NOS critical appraisal. In the current study, it was shown that the eventual percentage of patients with a PAF prior to CD diagnosis was not correlated to the length of follow-up, which is remarkable since literature states that a longer disease period is associated with an increased probability of developing PAF [57]. Since the majority of all included studies did not elaborate on follow-up periods, it may be possible that the percentage of patients with CD presenting with a PAF as a first manifestation is an underestimation of the real number of patients.
In conclusion, this systematic review shows that in the literature, almost 10% of patients present with a PAF as a first manifestation of CD with a substantial delay in diagnosis. These results emphasise that increased clinical awareness is warranted in order to decrease delay in CD diagnosis.

Supplementary Materials

The following supporting information can be downloaded at: https://www.mdpi.com/article/10.3390/jcm13164734/s1, Figure S1: Proportion of patients with a PAF prior to CD diagnosis plotted against mean follow-up; Table S1: Search strategy; Table S2: Overview of the critical appraisal results. NA = not applicable; Table S3: Time to diagnosis of CD after PAF manifestation as reported in studies and converted to a mean time to diagnosis in months using the method by Wan et al. [27]. * = median delay as was reported in the study; y = years; m = months; d = days; NR = not reported; sample size = number of patients in whom time to CD diagnosis was reported.

Author Contributions

L.J.M. and G.L.E.M. collected the data, performed the statistical analyses, and drafted the manuscript. S.v.D. provided help with statistical analysis. S.v.D., M.W.M., G.R.A.M.D., W.A.B., C.J.B. and J.D.W.v.d.B. all revised the manuscript for important intellectual content and approved the final version of this review for publication. All authors have read and agreed to the published version of the manuscript.

Funding

This research received no external funding.

Data Availability Statement

The authors of this manuscript confirm that the data supporting the findings of this systematic review are available within this manuscript or in its Supplementary Materials. Additional details can be provided upon request.

Conflicts of Interest

There are no conflicts of interest for this project or any of the involved authors.

References

  1. Adegbola, S.O.; Dibley, L.; Sahnan, K.; Wade, T.; Verjee, A.; Sawyer, R.; Mannick, S.; McCluskey, D.; Yassin, N.; Phillips, R.K.S.; et al. Burden of disease and adaptation to life in patients with Crohn’s perianal fistula: A qualitative exploration. Health Qual Life Outcomes 2020, 18, 370. [Google Scholar] [CrossRef] [PubMed]
  2. Carr, S.; Velasco, A.L. Fistula-in-Ano. In StatPearls; StatPearls Publishing LLC: St. Petersburg, FL, USA, 2024. [Google Scholar]
  3. Gold, S.L.; Cohen-Mekelburg, S.; Schneider, Y.; Steinlauf, A. Perianal Fistulas in Patients with Crohn’s Disease, Part 2: Surgical, Endoscopic, and Future Therapies. Gastroenterol. Hepatol. 2018, 14, 521–528. [Google Scholar]
  4. Zhou, Z.; Ouboter, L.F.; Peeters, K.; Hawinkels, L.; Holman, F.; Pascutti, M.F.; Barnhoorn, M.C.; van der Meulen-de Jong, A.E. Crohn’s Disease-Associated and Cryptoglandular Fistulas: Differences and Similarities. J. Clin. Med. 2023, 12, 466. [Google Scholar] [CrossRef] [PubMed]
  5. Schwartz, D.A.; Pemberton, J.H.; Sandborn, W.J. Diagnosis and treatment of perianal fistulas in Crohn disease. Ann. Intern. Med. 2001, 135, 906–918. [Google Scholar] [CrossRef] [PubMed]
  6. Shi, H.Y.; Levy, A.N.; Trivedi, H.D.; Chan, F.K.L.; Ng, S.C.; Ananthakrishnan, A.N. Ethnicity Influences Phenotype and Outcomes in Inflammatory Bowel Disease: A Systematic Review and Meta-analysis of Population-based Studies. Clin. Gastroenterol. Hepatol. 2018, 16, 190–197.e111. [Google Scholar] [CrossRef] [PubMed]
  7. Kang, B.; Kim, J.E.; Jung, J.H.; Choe, J.Y.; Kim, M.J.; Choe, Y.H.; Kim, S.; Koh, H.; Lee, Y.M.; Lee, J.H.; et al. Korean Children and Adolescents with Crohn’s Disease Are More Likely to Present with Perianal Fistulizing Disease at Diagnosis Compared to Their European Counterparts. Pediatr. Gastroenterol. Hepatol. Nutr. 2020, 23, 49–62. [Google Scholar] [CrossRef] [PubMed]
  8. McKee, R.F.; Keenan, R.A. Perianal Crohn’s disease—Is it all bad news? Dis. Colon Rectum 1996, 39, 136–142. [Google Scholar] [CrossRef] [PubMed]
  9. Pescatori, M.; Interisano, A.; Basso, L.; Arcanà, F.; Buffatti, P.; Di Bella, F.; Doldi, A.; Forcheri, V.; Gaetini, R.; Pera, A.; et al. Management of perianal Crohn’s disease. Results of a multicenter study in Italy. Dis. Colon Rectum 1995, 38, 121–124. [Google Scholar] [CrossRef] [PubMed]
  10. Schwartz, D.A.; Loftus, E.V., Jr.; Tremaine, W.J.; Panaccione, R.; Harmsen, W.S.; Zinsmeister, A.R.; Sandborn, W.J. The natural history of fistulizing Crohn’s disease in Olmsted County, Minnesota. Gastroenterology 2002, 122, 875–880. [Google Scholar] [CrossRef] [PubMed]
  11. Nordgren, S.; Fasth, S.; Hultén, L. Anal fistulas in Crohn’s disease: Incidence and outcome of surgical treatment. Int. J. Color. Dis. 1992, 7, 214–218. [Google Scholar] [CrossRef]
  12. Scharl, M.; Rogler, G.; Biedermann, L. Fistulizing Crohn’s Disease. Clin. Transl. Gastroenterol. 2017, 8, e106. [Google Scholar] [CrossRef] [PubMed]
  13. Gecse, K.B.; Sebastian, S.; Hertogh, G.; Yassin, N.A.; Kotze, P.G.; Reinisch, W.; Spinelli, A.; Koutroubakis, I.E.; Katsanos, K.H.; Hart, A.; et al. Results of the Fifth Scientific Workshop of the ECCO [II]: Clinical Aspects of Perianal Fistulising Crohn’s Disease-the Unmet Needs. J. Crohn’s Colitis 2016, 10, 758–765. [Google Scholar] [CrossRef] [PubMed]
  14. Nguyen, V.Q.; Jiang, D.; Hoffman, S.N.; Guntaka, S.; Mays, J.L.; Wang, A.; Gomes, J.; Sorrentino, D. Impact of Diagnostic Delay and Associated Factors on Clinical Outcomes in a U.S. Inflammatory Bowel Disease Cohort. Inflamm. Bowel Dis. 2017, 23, 1825–1831. [Google Scholar] [CrossRef] [PubMed]
  15. Thomas, T.; Chandan, J.S.; Harvey, P.R.; Bhala, N.; Ghosh, S.; Nirantharakumar, K.; Trudgill, N.J. The Risk of Inflammatory Bowel Disease in Subjects Presenting With Perianal Abscess: Findings From the THIN Database. J. Crohn’s Colitis 2019, 13, 600–606. [Google Scholar] [CrossRef] [PubMed]
  16. Schoepfer, A.M.; Dehlavi, M.A.; Fournier, N.; Safroneeva, E.; Straumann, A.; Pittet, V.; Peyrin-Biroulet, L.; Michetti, P.; Rogler, G.; Vavricka, S.R. Diagnostic delay in Crohn’s disease is associated with a complicated disease course and increased operation rate. Am. J. Gastroenterol. 2013, 108, 1744–1753, quiz 1754.. [Google Scholar] [CrossRef] [PubMed]
  17. Beaugerie, L.; Seksik, P.; Nion-Larmurier, I.; Gendre, J.P.; Cosnes, J. Predictors of Crohn’s disease. Gastroenterology 2006, 130, 650–656. [Google Scholar] [CrossRef] [PubMed]
  18. Lee, M.J.; Freer, C.; Adegbola, S.; Elkady, S.; Parkes, M.; Hart, A.; Fearnhead, N.S.; Lobo, A.J.; Brown, S.R. Patients with perianal Crohn’s fistulas experience delays in accessing anti-TNF therapy due to slow recognition, diagnosis and integration of specialist services: Lessons learned from three referral centres. Color. Dis. 2018, 20, 797–803. [Google Scholar] [CrossRef] [PubMed]
  19. Meima-van Praag, E.M.; van Rijn, K.L.; Wasmann, K.; Snijder, H.J.; Stoker, J.; D’Haens, G.R.; Gecse, K.B.; Gerhards, M.F.; Jansen, J.M.; Dijkgraaf, M.G.W.; et al. Short-term anti-TNF therapy with surgical closure versus anti-TNF therapy in the treatment of perianal fistulas in Crohn’s disease (PISA-II): A patient preference randomised trial. Lancet Gastroenterol. Hepatol. 2022, 7, 617–626. [Google Scholar] [CrossRef] [PubMed]
  20. Meima-van Praag, E.M.; Becker, M.A.J.; van Rijn, K.L.; Wasmann, K.; Stoker, J.; D’Haens, G.; Ponsioen, C.Y.; Gecse, K.B.; Dijkgraaf, M.G.W.; Spinelli, A.; et al. Short-term anti-TNF therapy with surgical closure versus anti-TNF therapy alone for Crohn’s perianal fistulas (PISA-II): Long-term outcomes of an international, multicentre patient preference, randomised controlled trial. EClinicalMedicine 2023, 61, 102045. [Google Scholar] [CrossRef] [PubMed]
  21. Chen, G.; Pedarla, V.; Null, K.D.; Cazzetta, S.E.; Khan, Q.R.; Schwartz, D.A. Health Care Costs and Resource Utilization Among Patients With Crohn’s Disease With and Without Perianal Fistula. Inflamm. Bowel Dis. 2022, 28, 870–877. [Google Scholar] [CrossRef] [PubMed]
  22. Spinelli, A.; Yanai, H.; Girardi, P.; Milicevic, S.; Carvello, M.; Maroli, A.; Avedano, L. The Impact of Crohn’s Perianal Fistula on Quality of Life: Results of an International Patient Survey. Crohn’s Colitis 360 2023, 5, otad036. [Google Scholar] [CrossRef] [PubMed]
  23. Page, M.J.; McKenzie, J.E.; Bossuyt, P.M.; Boutron, I.; Hoffmann, T.C.; Mulrow, C.D.; Shamseer, L.; Tetzlaff, J.M.; Akl, E.A.; Brennan, S.E.; et al. The PRISMA 2020 statement: An updated guideline for reporting systematic reviews. BMJ 2021, 372, n71. [Google Scholar] [CrossRef] [PubMed]
  24. Silverberg, M.S.; Satsangi, J.; Ahmad, T.; Arnott, I.D.; Bernstein, C.N.; Brant, S.R.; Caprilli, R.; Colombel, J.F.; Gasche, C.; Geboes, K.; et al. Toward an integrated clinical, molecular and serological classification of inflammatory bowel disease: Report of a Working Party of the 2005 Montreal World Congress of Gastroenterology. Can. J. Gastroenterol. 2005, 19 (Suppl. A), 5a–36a. [Google Scholar] [CrossRef] [PubMed]
  25. Lo, C.K.; Mertz, D.; Loeb, M. Newcastle-Ottawa Scale: Comparing reviewers’ to authors’ assessments. BMC Med. Res. Methodol. 2014, 14, 45. [Google Scholar] [CrossRef] [PubMed]
  26. Ouzzani, M.; Hammady, H.; Fedorowicz, Z.; Elmagarmid, A. Rayyan—A web and mobile app for systematic reviews. Syst. Rev. 2016, 5, 210. [Google Scholar] [CrossRef] [PubMed]
  27. Wan, X.; Wang, W.; Liu, J.; Tong, T. Estimating the sample mean and standard deviation from the sample size, median, range and/or interquartile range. BMC Med. Res. Methodol. 2014, 14, 135. [Google Scholar] [CrossRef] [PubMed]
  28. Higgins, J.P.; Thompson, S.G.; Deeks, J.J.; Altman, D.G. Measuring inconsistency in meta-analyses. BMJ 2003, 327, 557–560. [Google Scholar] [CrossRef] [PubMed]
  29. Atia, O.; Focht, G.; Lujan, R.; Ledder, O.; Greenfeld, S.; Kariv, R.; Dotan, I.; Yanai, H.; Gabay, H.; Balicer, R.; et al. Perianal Crohn Disease Is More Common in Children and Is Associated With Complicated Disease Course Despite Higher Utilization of Biologics: A Population-based Study From The epidemiology group of the Israeli IBD Research Nucleus (epiIIRN). J. Pediatr. Gastroenterol. Nutr. 2022, 74, 788–793. [Google Scholar] [CrossRef] [PubMed]
  30. Chun, J.; Im, J.P.; Kim, J.W.; Lee, K.L.; Choi, C.H.; Kim, H.; Cheon, J.H.; Ye, B.D.; Kim, Y.H.; Kim, Y.S.; et al. Association of Perianal Fistulas with Clinical Features and Prognosis of Crohn’s Disease in Korea: Results from the CONNECT Study. Gut Liver 2018, 12, 544–554. [Google Scholar] [CrossRef] [PubMed]
  31. Danielou, M.; Sarter, H.; Pariente, B.; Fumery, M.; Ley, D.; Mamona, C.; Barthoulot, M.; Charpentier, C.; Siproudhis, L.; Savoye, G.; et al. Natural History of Perianal Fistulising Lesions in Patients With Elderly-onset Crohn’s Disease: A Population-based Study. J. Crohn’s Colitis 2020, 14, 501–507. [Google Scholar] [CrossRef] [PubMed]
  32. Davidson, P.M.; McLain, B.I.; Beasley, S.W.; Stokes, K.B. Perianal disease in childhood crohns-disease—Frequency, characteristics, and prognostic-significance. Pediatr. Surg. Int. 1992, 7, 174–176. [Google Scholar] [CrossRef]
  33. Göttgens, K.W.; Jeuring, S.F.; Sturkenboom, R.; Romberg-Camps, M.J.; Oostenbrug, L.E.; Jonkers, D.M.; Stassen, L.P.; Masclee, A.A.; Pierik, M.J.; Breukink, S.O. Time trends in the epidemiology and outcome of perianal fistulizing Crohn’s disease in a population-based cohort. Eur. J. Gastroenterol. Hepatol. 2017, 29, 595–601. [Google Scholar] [CrossRef] [PubMed]
  34. Hellers, G.; Bergstrand, O.; Ewerth, S.; Holmström, B. Occurrence and outcome after primary treatment of anal fistulae in Crohn’s disease. Gut 1980, 21, 525–527. [Google Scholar] [CrossRef] [PubMed]
  35. Jin, W.S.; Park, J.H.; Lim, K.I.; Tchah, H.; Ryoo, E. Significance of Perianal Lesion in Pediatric Crohn Disease. Pediatr. Gastroenterol. Hepatol. Nutr. 2018, 21, 184–188. [Google Scholar] [CrossRef] [PubMed]
  36. Mizushima, T.; Ota, M.; Fujitani, Y.; Kanauchi, Y.; Iwakiri, R. Diagnostic Features of Perianal Fistula in Patients With Crohn’s Disease: Analysis of a Japanese Claims Database. Crohn’s Colitis 360 2021, 3, otab055. [Google Scholar] [CrossRef] [PubMed]
  37. Molendijk, I.; Nuij, V.J.; van der Meulen-de Jong, A.E.; van der Woude, C.J. Disappointing durable remission rates in complex Crohn’s disease fistula. Inflamm. Bowel Dis. 2014, 20, 2022–2028. [Google Scholar] [CrossRef] [PubMed]
  38. Qari, Y.A. Clinical Characteristics of Crohn’s Disease in a Cohort from Saudi Arabia. Saudi J. Med. Med. Sci. 2022, 10, 56–62. [Google Scholar] [CrossRef] [PubMed]
  39. Rubín de Célix Vargas, C.; Algaba, A.; Guerra, I.; Serrano, Á.; Pérez-Viejo, E.; Aulló, C.; Bermejo, F. Resources used in the treatment of perianal Crohn’s disease and the results in a real-life cohort. Gastroenterol. Hepatol. 2018, 41, 353–361. [Google Scholar] [CrossRef] [PubMed]
  40. Song, E.M.; Kim, N.; Lee, S.H.; Chang, K.; Hwang, S.W.; Park, S.H.; Yang, D.H.; Byeon, J.S.; Myung, S.J.; Yang, S.K.; et al. Clinical characteristics and long-term prognosis of elderly-onset Crohn’s disease. Scand. J. Gastroenterol. 2018, 53, 417–425. [Google Scholar] [CrossRef] [PubMed]
  41. Thia, K.T.; Sandborn, W.J.; Harmsen, W.S.; Zinsmeister, A.R.; Loftus, E.V., Jr. Risk factors associated with progression to intestinal complications of Crohn’s disease in a population-based cohort. Gastroenterology 2010, 139, 1147–1155. [Google Scholar] [CrossRef] [PubMed]
  42. Weng, M.T.; Lin, K.L.; Huang, Y.L.; Karki, C.; Hong, J.L.; Bennett, D.; Arnold Chan, K.; Wei, S.C. Epidemiology, Disease Course, and Clinical Outcomes of Perianal Fistulas and Fissures Crohn’s Disease: A Nationwide Population-Based Study in Taiwan. Crohn’s Colitis 360 2023, 5, otad035. [Google Scholar] [CrossRef] [PubMed]
  43. Wewer, M.D.; Zhao, M.; Nordholm-Carstensen, A.; Weimers, P.; Seidelin, J.B.; Burisch, J. The Incidence and Disease Course of Perianal Crohn’s Disease: A Danish Nationwide Cohort Study, 1997-2015. J. Crohn’s Colitis 2021, 15, 5–13. [Google Scholar] [CrossRef] [PubMed]
  44. Ye, B.D.; Yang, S.K.; Cho, Y.K.; Park, S.H.; Yang, D.H.; Yoon, S.M.; Kim, K.J.; Byeon, J.S.; Myung, S.J.; Yu, C.S.; et al. Clinical features and long-term prognosis of Crohn’s disease in Korea. Scand. J. Gastroenterol. 2010, 45, 1178–1185. [Google Scholar] [CrossRef] [PubMed]
  45. Park, S.H.; Yang, S.K.; Park, S.K.; Kim, J.W.; Yang, D.H.; Jung, K.W.; Kim, K.J.; Ye, B.D.; Byeon, J.S.; Myung, S.J.; et al. Long-term prognosis of crohn’s disease and its temporal change between 1981 and 2012: A hospital-based cohort study from Korea. Inflamm. Bowel Dis. 2014, 20, 488–494. [Google Scholar] [CrossRef] [PubMed]
  46. Tsai, L.; McCurdy, J.D.; Ma, C.; Jairath, V.; Singh, S. Epidemiology and Natural History of Perianal Crohn’s Disease: A Systematic Review and Meta-Analysis of Population-Based Cohorts. Inflamm. Bowel Dis. 2022, 28, 1477–1484. [Google Scholar] [CrossRef] [PubMed]
  47. Pellino, G.; Sciaudone, G.; Selvaggi, F.; Riegler, G. Delayed diagnosis is influenced by the clinical pattern of Crohn’s disease and affects treatment outcomes and quality of life in the long term: A cross-sectional study of 361 patients in Southern Italy. Eur. J. Gastroenterol. Hepatol. 2015, 27, 175–181. [Google Scholar] [CrossRef] [PubMed]
  48. Rencz, F.; Stalmeier, P.F.M.; Péntek, M.; Brodszky, V.; Ruzsa, G.; Gönczi, L.; Palatka, K.; Herszényi, L.; Schäfer, E.; Banai, J.; et al. Patient and general population values for luminal and perianal fistulising Crohn’s disease health states. Eur. J. Health Econ. 2019, 20 (Suppl. 1), 91–100. [Google Scholar] [CrossRef] [PubMed]
  49. Panes, J.; Reinisch, W.; Rupniewska, E.; Khan, S.; Forns, J.; Khalid, J.M.; Bojic, D.; Patel, H. Burden and outcomes for complex perianal fistulas in Crohn’s disease: Systematic review. World J. Gastroenterol. 2018, 24, 4821–4834. [Google Scholar] [CrossRef] [PubMed]
  50. Danese, S.; Fiorino, G.; Mary, J.Y.; Lakatos, P.L.; D’Haens, G.; Moja, L.; D’Hoore, A.; Panes, J.; Reinisch, W.; Sandborn, W.J.; et al. Development of Red Flags Index for Early Referral of Adults with Symptoms and Signs Suggestive of Crohn’s Disease: An IOIBD Initiative. J. Crohn’s Colitis 2015, 9, 601–606. [Google Scholar] [CrossRef] [PubMed]
  51. Yang, S.K.; Lim, J.; Chang, H.S.; Lee, I.; Li, Y.; Liu, J.; Song, K. Association of TNFSF15 with Crohn’s disease in Koreans. Am. J. Gastroenterol. 2008, 103, 1437–1442. [Google Scholar] [CrossRef] [PubMed]
  52. Yang, D.H.; Yang, S.K.; Song, K.; Hong, M.; Park, S.H.; Lee, H.S.; Kim, J.B.; Lee, H.J.; Park, S.K.; Jung, K.W.; et al. TNFSF15 is an independent predictor for the development of Crohn’s disease-related complications in Koreans. J. Crohn’s Colitis 2014, 8, 1315–1326. [Google Scholar] [CrossRef]
  53. Goddard, G.R.; Lim, I.I.P.; Cheng, Y.C.; Velazco, C.S.; Jenkins, T.; Rosen, N.G.; Kotagal, M.; Garrison, A.P.; Falcone, R.; Rymeski, B.; et al. A child presents with perianal symptoms—How often is this Crohn’s disease? J. Pediatr. Surg. 2021, 56, 1618–1622. [Google Scholar] [CrossRef]
  54. Roskam, M.; de Meij, T.; Gemke, R.; Bakx, R. Perianal Abscesses in Infants Are Not Associated With Crohn’s Disease in a Surgical Cohort. J. Crohn’s Colitis 2020, 14, 773–777. [Google Scholar] [CrossRef] [PubMed]
  55. Heyman, M.B.; Kirschner, B.S.; Gold, B.D.; Ferry, G.; Baldassano, R.; Cohen, S.A.; Winter, H.S.; Fain, P.; King, C.; Smith, T.; et al. Children with early-onset inflammatory bowel disease (IBD): Analysis of a pediatric IBD consortium registry. J. Pediatr. 2005, 146, 35–40. [Google Scholar] [CrossRef] [PubMed]
  56. Ananthakrishnan, A.N.; Shi, H.Y.; Tang, W.; Law, C.C.; Sung, J.J.; Chan, F.K.; Ng, S.C. Systematic Review and Meta-analysis: Phenotype and Clinical Outcomes of Older-onset Inflammatory Bowel Disease. J. Crohn’s Colitis 2016, 10, 1224–1236. [Google Scholar] [CrossRef] [PubMed]
  57. Park, S.H.; Aniwan, S.; Scott Harmsen, W.; Tremaine, W.J.; Lightner, A.L.; Faubion, W.A.; Loftus, E.V. Update on the Natural Course of Fistulizing Perianal Crohn’s Disease in a Population-Based Cohort. Inflamm. Bowel Dis. 2019, 25, 1054–1060. [Google Scholar] [CrossRef] [PubMed]
Jcm 13 04734 g001
Figure 1. Study selection process according to PRISMA guidelines [23].
Figure 1. Study selection process according to PRISMA guidelines [23].
Jcm 13 04734 g001
Jcm 13 04734 g002
Figure 2. Forest plot on the weighted mean percentage of PAF first in patients with CD [29,30,31,32,33,34,35,36,37,38,39,40,41,42,43,44,45]. PAF = perianal fistula; CD = Crohn’s disease; CI = confidence interval; p = significance.
Figure 2. Forest plot on the weighted mean percentage of PAF first in patients with CD [29,30,31,32,33,34,35,36,37,38,39,40,41,42,43,44,45]. PAF = perianal fistula; CD = Crohn’s disease; CI = confidence interval; p = significance.
Jcm 13 04734 g002
Jcm 13 04734 g003
Figure 3. (a) Forest plot on the weighted percentage of PAF first in patients with CD in Asian cohort studies [30,35,36,40,42,44,45]. PAF = perianal fistula; CD = Crohn’s disease; CI = confidence interval; p = significance. (b) Forest plot on the weighted percentage of PAF first in patients with CD in non-Asian cohort studies (reference group) [29,31,32,33,34,37,38,39,41,43]. PAF = perianal fistula; CD = Crohn’s disease; CI = confidence interval; p = significance.
Figure 3. (a) Forest plot on the weighted percentage of PAF first in patients with CD in Asian cohort studies [30,35,36,40,42,44,45]. PAF = perianal fistula; CD = Crohn’s disease; CI = confidence interval; p = significance. (b) Forest plot on the weighted percentage of PAF first in patients with CD in non-Asian cohort studies (reference group) [29,31,32,33,34,37,38,39,41,43]. PAF = perianal fistula; CD = Crohn’s disease; CI = confidence interval; p = significance.
Jcm 13 04734 g003
Jcm 13 04734 g004
Figure 4. (a) Forest plot on the weighted percentage of PAF first in paediatric patients [29,32,35]. PAF = perianal fistula; CD = Crohn’s disease; CI = confidence interval; p = significance. (b) Forest plot on the weighted percentage of PAF first in patients 18–60 years (reference group) [29,30,33,34,36,37,38,39,40,41,42,43,44,45]. PAF = perianal fistula; CD = Crohn’s disease; CI = confidence interval; p = significance. (c) Forest plot on the weighted percentage of PAF first in patients with elderly-onset CD (>60 years) [31,40]. PAF = perianal fistula; CD = Crohn’s disease; CI = confidence interval; p = significance.
Figure 4. (a) Forest plot on the weighted percentage of PAF first in paediatric patients [29,32,35]. PAF = perianal fistula; CD = Crohn’s disease; CI = confidence interval; p = significance. (b) Forest plot on the weighted percentage of PAF first in patients 18–60 years (reference group) [29,30,33,34,36,37,38,39,40,41,42,43,44,45]. PAF = perianal fistula; CD = Crohn’s disease; CI = confidence interval; p = significance. (c) Forest plot on the weighted percentage of PAF first in patients with elderly-onset CD (>60 years) [31,40]. PAF = perianal fistula; CD = Crohn’s disease; CI = confidence interval; p = significance.
Jcm 13 04734 g004
Table 1. Overview of the included studies.
Table 1. Overview of the included studies.
AuthorYearCountryStudy DesignSingle or MulticenterStudy Span (y)Data SourceCD Patients (n)Subtypes CD Cohort Subtypes CD Cohort (n, %) Age (y)Male (n, %)PAF Prior to CD Diagnosis (n, %)Diagnostic Delay (Median)Follow-Up (Median)
Atia et al. [29]2022IsraelRetrospective population-based cohort studyMulticenter2005–2019 epi-IIRN12,905(1) Adults;
(2) children		(1) 10,719 (83)
(2) 2186 (17)		(1) 34.4 (13.8) *;
(2) 14.1 (3.5) *		(1) 6646 (62);
(2) 1661 (76)		(1) 473/10,719 (4.4);
(2) 76/2186 (3.5) 		NR7.8 y
[IQR 4.2–11.0]
Chun et al. [30]2018KoreaRetrospective cohort studyMulticenter1982–2008CONNECT study database1193NANA26.9 (11.9) *840 (70.4)318/1193 (26.7)NR8.77 y
(1.0 to 25.8) **
Danielou et al. [31]2020FranceRetrospective population-based cohort studyMulticenter1988–2006EPIMAD registry372NANA70.1 [65.2–76.4]142 (38.2)11/372 (3)NR6 y
[IQR 3–10]
Davidson et al. [32]1992Australia Retrospective cohort studySingle center1971–1987Medical records63NANA12 [3–16]11 (17.5)2/63 (3.2)NRNR
Göttgens et al. [33]2016The NetherlandsRetrospective population-based cohort studyMulticenter1991–2011IBDSL registry1162(1) Without PAF/RVF;
(2) only PAF;
(3) RVF		(1) 995 (85.6);
(2) 150 (12.9);
(3) 17 (1.5)		(1) 38.5 (16.3) *;
(2) 32.3 (12.5) *;
(3) 37.3 (15.1) *		(1) 375 (37.7);
(2) 59 (39.3);
(3) 0 (0)		49/1162 (4.2)0.8 y
[0.2–2.7]		8.7 y
(5.7) **
Hellers et al. [34]1980SwedenRetrospective cohort studyMulticenter1955–1974Medical records826NANANR379 (45.9)45/826 (5.4)(1) >2 y prior to CD diagnosis (19);
(2) 6 m > and >2 y (26)		9.4 y
(0.5–22.5) **
Jin et al. [35]2018KoreaRetrospective cohort studySingle center2000–2014Medical records69(1) CD with perianal lesions;
(2) CD without perianal lesions		(1) 54 (78.2);
(2) 15 (21.7)		15.451 (73.9)13/69 (18.8)14 mNR
Mizushima et al. [36]2021JapanRetrospective cohort studyMulticenter2013–2019JMDC Co., Ltd., claims database 1426(1) PAF after CD;
(2) CD after PAF;
(3) PAF + CD †;
(4) CD only		(1) 43 (3.0);
(2) 188 (13.2);
(3) 43 (3.0);
(4) 1152 (80.8)		(1) 27.1 (12.7) *;
(2) 25.7 (10.5) *;
(3) 26.9 (13.6) *;
(4) 35.9 (15.7) *		(1) 39 (90.7);
(2) 169 (89.9);
(3) 36 (83.7)
(4) 757 (65.7)		188/1426 (13.2)10.8 m
(15.8) **		≥12 m
Molendijk et al. [37]2014The NetherlandsRetrospective cohort studySingle center1980–2000Medical records436NANA 22.8 [4.0–68.7] *NR44/436 (10.1) * NRNR
Park et al. [45]2014KoreaRetrospective cohort studySingle center1981–2012Medical records2043(1) 1981–2000;
(2) 2001–2005;
(3) 2006–2012 		(1) 363 (17.8);
(2) 611 (29.9);
(3) 1069 (52.3)		23 [9–75] *1462 (71.6)(1) 70/363 (19.3);
(2) 118/611 (19.3);
(3) 201/1069 (18.8)		NR80 m
(1–381)
Qari [38]2022Saudi ArabiaRetrospective cohort studySingle center2012–2018Medical records245NANA26.3 [14–73] *125 (51)25/245 (10.2)NRNR
Rubín de Célix Vargas et al. [39]2018Spain Retrospective cohort studySingle center2004–2016 Medical records300NANANR36 (12)8/300 (2.7)NRNR
Song et al. [40]2018KoreaRetrospective matched case-control studySingle center1989–2016Asan IBD registry243(1) Elderly onset;
(2) Middle-age onset;
(3) Young onset		(1) 27 (11.1);
(2) 108 (44.4);
(3) 108 (44.4)		26.0 [21.0–34.1] *161 (66.3)(1) 2/27 (7.4);
(2) 15/108 (13.9);
(3) 29/108 (26.9)		NR67.8 m
[IQR 40.5–120.8]
Thia et al. [41]2010USARetrospective cohort studyMulticenter1970–2004Medical records (Olmsted County Database)306NANA30.2 [3–142]*150 (49)15/306 (4.9) 38 m
[range, 3–142]		8.4 y
[2 d–35.9 y]
Weng et al. [42]2023TaiwanRetrospective cohort studyMulticenter2000–2017Taiwan’s National Health Insurance Research Database2424(1) With pCDl;
(2) without pCD		(1) 358 (14.8);
(2) 2066 (85.2)		(1) 33.7 (14.9); (2) 44.9 (21.8)(1) 284 (79.3);
(2) 1248 (60.4)		141/2424 (5.8)(1) 1266
[756–2237];
(2) 1611 d
(1213) **		Not clearly reported
Wewer et al. [43]2021DenmarkRetrospective cohort studyMulticenter1997–2015National Patient Registry9739(1) Without pCD;
(2) with pCD		(1) 7927 (81.4);
(2) 1812 (18.6)		(1) 39.6 [27.0–57.0] *;
(2) 32.8 [24.1–46.2] *		(1) 3317 (41.8);
(2) 903 (49.8)		408/9739 (4.2)NR8.2 y
[4.1–13.3]
Ye et al. [44]2010KoreaRetrospective cohort studySingle center1991–2007Medical records278NANA23 [9–74] *191 (68.7)92/278 (33.1)32 [2–361] m71 m
[1–210]
Data provided as n (%). * = age at CD diagnosis; ** = mean (SD); IBD = Inflammatory Bowel Disease; CD = Crohn’s disease; PAF = perianal fistula; pCD = perianal Crohn’s disease; NA = not applicable, NR = not reported; y = year; m = month; † = same month.
Disclaimer/Publisher’s Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content.

Share and Cite

MDPI and ACS Style

Munster, L.J.; Mönnink, G.L.E.; van Dieren, S.; Mundt, M.W.; D’Haens, G.R.A.M.; Bemelman, W.A.; Buskens, C.J.; van der Bilt, J.D.W. Fistulizing Perianal Disease as a First Manifestation of Crohn’s Disease: A Systematic Review and Meta-Analysis. J. Clin. Med. 2024, 13, 4734. https://doi.org/10.3390/jcm13164734

AMA Style

Munster LJ, Mönnink GLE, van Dieren S, Mundt MW, D’Haens GRAM, Bemelman WA, Buskens CJ, van der Bilt JDW. Fistulizing Perianal Disease as a First Manifestation of Crohn’s Disease: A Systematic Review and Meta-Analysis. Journal of Clinical Medicine. 2024; 13(16):4734. https://doi.org/10.3390/jcm13164734

Chicago/Turabian Style

Munster, Liesbeth Jozefien, Giulia Louise Emilia Mönnink, Susan van Dieren, Marco William Mundt, Geert Renaat Alfons Maria D’Haens, Willem Adrianus Bemelman, Christianne Johanna Buskens, and Jarmila Dagmara Wendelien van der Bilt. 2024. "Fistulizing Perianal Disease as a First Manifestation of Crohn’s Disease: A Systematic Review and Meta-Analysis" Journal of Clinical Medicine 13, no. 16: 4734. https://doi.org/10.3390/jcm13164734

Note that from the first issue of 2016, this journal uses article numbers instead of page numbers. See further details here.

Article Metrics

Back to TopTop