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Techniques in Coloproctology

, Volume 21, Issue 7, pp 501–519 | Cite as

Prognostic factors affecting outcomes in fistulating perianal Crohn’s disease: a systematic review

  • G. C. Braithwaite
  • M. J. LeeEmail author
  • D. Hind
  • S. R. Brown
Open Access
Review

Abstract

Background

One in three patients with Crohn’s disease will develop a perianal fistulae, and one third of these will achieve long-term healing or closure. A barrier to conducting well-designed clinical trials for these patients is a lack of understanding of prognostic factors. This systematic review sets out to identify factors associated with prognosis of perianal Crohn’s fistulae.

Methods

This review was registered on the PROSPERO database (CRD42016050316) and conducted in line with PRISMA guidelines along a predefined protocol. English-language studies assessing baseline factors related to outcomes of fistulae treatment in adult patients were included. Searches were performed on MEDLINE and Embase databases. Screening of abstracts and full texts for eligibility was performed prior to extraction of data into predesigned forms. Bias was assessed using the QUIPS tool.

Results

Searches identified 997 papers. Following removal of duplicates and secondary searches, 923 were screened for inclusion. Forty-seven papers were reviewed at full-text level and 13, 2 of which were randomised trials, were included in the final qualitative review. Two studies reported distribution of Crohn’s disease as a prognostic factor for healing. Two studies found that CARD15 mutations decreased response of fistulae to antibiotics. Complexity of fistulae anatomy was implicated in prognosis by 4 studies.

Conclusions

This systematic review has identified potential prognostic markers, including genetic factors and disease behaviour. We cannot, however, draw robust conclusions from this heterogeneous group of studies; therefore, we recommend that a prospective cohort study of well-characterised patients with Crohn’s perianal fistulae is undertaken.

Keywords

Crohn’s disease Perianal fistulae Prognosis Systematic review 

Introduction

Crohn’s disease (CD) is an inflammatory condition which can affect any part of the gastrointestinal tract. It is characterised by chronic inflammation all the way through the intestinal wall. Crohn’s disease typically follows one of three behaviour patterns: inflammation only, stricturing, and penetrating [1]. Penetrating disease is typically characterised by formation of a fistulae (an abnormal connection between two epithelial surfaces). This can happen between intestinal loops (enteroenteric), intestine, and skin (enterocutaneous), or the anorectum and buttock skin (perianal). The incidence of perianal fistulae in CD is around 30% [2].

A fistulae is typically managed with sepsis control, through incision and drainage of any abscess, placement of a seton, and immune modulation by drugs such as azathioprine or infliximab (anti-TNF-α therapy) [3, 4]. A number of alternative surgical procedures might also be considered [3]. In serious cases, a stoma might be offered, often as a prelude to proctectomy [4]. This condition can have a significant impact on patients’ quality of life [5, 6, 7]. As few as one in three patients will achieve long-term healing of their fistulae [8]. Consequently, health care costs of anal fistulae in CD are high due to drug therapies [9, 10]. It is not surprising that this condition has been identified as a research priority in two recent research priority setting exercises [11, 12].

The aetiology of CD is complex and multifactorial. Recent genomic studies have identified several loci of susceptibility [13, 14, 15]. Several of these genes are implicated in aberrant immune responses. Environmental factors such as smoking are thought to play a key part in disease behaviour [16], as in altered intestinal microbiome [17] [18]. These are baseline disease or demographic factors that might be implicated in disease behaviour and prognosis. On top of these systemic mechanisms, localised mucosal damage and aberrant or failed repair mechanisms likely contribute to persistence of fistulae [2, 19].

Randomised controlled trials (RCTs) are the gold standard in clinical research, and these are sorely needed to guide treatment of fistulating perianal CD. To design trials, we need to balance prognostic factors across study arms to limit confounding and produce reliable results [20].

The aim of the present study was to systematically review the literature and identify baseline prognostic factors relevant to the treatment of fistulating perianal CD.

Materials and methods

This review was registered on the PROSPERO database (CRD42016050316) and conducted in line with Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines using a predefined protocol.

The inclusion criteria were: publication during or after 1980; study size ≥50 patients with rectovaginal or perianal fistulae; fistulae cause by CD; patients aged 16 years or over; fistulae is baseline health state (startpoint [20]) of the study. Exclusion criteria were: CD without fistulae; paper only reports intervention as opposed to demographic or disease status; covariates; paper only includes treatment outcomes as opposed to analysing by demographic or disease status factors. Publications not in English were also excluded due to resource constraints.

Information sources were MEDLINE (1946 to October 26, 2016) and Embase (1974 to October 26, 2016) via Ovid. Searches, which used no limits, combined thesaurus and free-text terms (see Fig. 1).
Fig. 1

Search terms used in paper selection

Results from bibliographic databases were combined with papers through secondary searches of bibliographies and papers of known relevance identified by clinical topic experts, and duplicates removed. Titles and abstracts of citations were screened against the eligibility criteria (by GB), with secondary review and resolution of queries (by ML and DH). Potentially eligible full texts were retrieved and the process repeated, with reasons for rejection recorded.

Data were extracted into predesigned tables (by GB) and findings confirmed (by ML). We extracted data on demographics of the patients and specific details about their condition, including: age; gender; smoking status; duration of disease; location of disease; number of fistulae; treatments; and outcome data on ‘response’ or ‘healing’, that is :fistulae closure, no further discharge from fistulae, or no fistulae recurrence, however defined. Risk of bias (RoB) in individual studies was assessed by two reviewers (GB and ML) using the Quality In Prognosis Studies tool (QUIPS) tool [21]. This tool assesses 6 domains: study participation, study attrition, prognostic factor measurement, outcome measurement, study confounding, and statistical analysis and reporting. We recorded statistical methods used and summary measures, however presented, including odds ratios, relative risks, hazard ratios with confidence intervals, tests of significance (p values). We conducted a narrative (descriptive) synthesis with results structured by type of prognostic factor.

Results

The PRISMA study selection flow chart is shown in Fig. 2.
Fig. 2

PRISMA flow diagram

Study comparisons

Searches identified 997 papers. Following removal of duplicates and secondary searches, 923 were screened for inclusion. Forty-seven papers were reviewed at full-text level. Thirty-four papers were rejected at this stage for the following reasons: no prognostic factors reported (n = 11), <50 patients with fistulae caused by CD (n = 9), CD without fistulae (n = 4), fistulae was an endpoint (n = 3), development of fistulae was a factor in natural history of Crohn’s disease (n = 2), paper was a narrative review (n = 3), or paper was a systematic review (n = 2). This left 13 papers for qualitative review.

Study demography and design

Of the 13 studies identified, 2 were published between 1995 and the end of 1999 [22, 23], 7 between 2000 and the end of 2009 [24, 25, 26, 27, 28, 29, 30], and 4 between 2010 and 2014 [31, 32, 33, 34]. Studies and characteristics are summarised in Table 1.
Table 1

Summary of included papers and characteristics

Paper

Design

Population

Fistulae (number, anatomy)

Location of disease

Treatment

Bell [24]

Retrospective cohort

Male 41

78 perianal

74 colonic/ileocolonic

Rule based

  

Female 46

27 rectovaginal

12 small bowel

Medical (antibiotics, azathioprine, enteral, parenteral feeding)

  

Total = 86

169 fistulae 135 complex (80%)

74 colonic/ileocolonic

Simple surgery (drainage, fistulotomy, seton) [most common for simple and complex perianal]

  

Age (mean, range) years: 35 (20–91)

‘Simple’—superficial or intersphincteric

12 small bowel

Complex (resection, refunctioning stoma, proctectomy) [most common for rectovaginal]

   

‘Complex’—transsphincteric, suprasphincteric, or extraspincteric

74 colonic/ileocolonic

Other (advancement flap, primary repair)

    

12 small bowel

 
    

1 perianal

 
    

57 rectal involvement

 

Dewint [31]

RCT

Male 37

70 perianal (110 localisations) anatomy undefined

N/A

Random

  

Female 33

  

34 allocated to ciprofloxacin (and made it to completion)

  

Total = 70

  

36 allocated to placebo

  

Age (mean, range) years: 36.1 (18–70)

  

Randomisation was performed through a centralised randomisation schedule in a 1:1 ratio

  

Smokers 22 (12 in cipro., 10 in placebo)

   

Loffler [25]

Prospective cohort

Male 49

45 rectovaginal

Anorectal/rectovaginal 144

Rule based

  

Female 98

101 perianal

Colon 141

292 operations on 146 patients

  

Total = 147 (1 patient excluded)

Classified according to Parks et al.

 

38% major surgery, 62% minor surgery

  

Age (mean, range) years: 33 (17–68)

Extrasphincteric 34

 

Minor surgery (lay open-44, fistulae excision-41, fistulae curetting-25, seton drainage-71, fibrin glue application-1)

   

Suprasphincteric 24

 

Major 1 surgery (endorectal advancement flap-34, levatorplasty/sphincteroplasty-20)

   

Submucosal 22

 

Major 2 surgery (ostomy-17, Hartmann’s procedure-10, proctectomy/perianal resection-29)

   

Transsphincteric 21

  

Luna-Chadid [26]

Prospective cohort

Male 57

59 Perianal

Ileal 33

Rule based

  

Female 51

12 Rectovaginal/enterovesical

Colonic 19

All treated with infliximab

  

Total = 108

 

Ileocolonic 55

 
  

Age (mean) years: 38 Smokers: 54

Fistulae anatomy: Entereocutaneous or Perianal or Internal or Rectovaginal or Enterovesical 194 Localisations

  

Present [23]

RCT

Male 44

85 Perianal (anatomy not defined)

Ileum 14

Random

  

Female 50

 

Colon 26

Randomly assigned to infliximab or placebo

  

Total = 94

 

Both ileum and colon 54

 
  

Age (mean years: 37.2)

   

Gaertner [27]

Retrospective cohort

Male 105

226 Perianal, 254 Localisations Classified by method described by Parks et al.

Ileocecal 81

Rule based

  

Female 121

‘Complex’—if there are multiple fistulae tracts and extension of tracks above the dentate line

Perianal 62

Underwent operative treatment only (147) or operative treatment and infliximab (79)

  

Total = 226

Intersphincteric 103

Colon 51

 
  

Age (mean, range) years: 39 (16–83) Smokers 32

Transsphincteric 91

Small bowel 20

 
   

Complex 35

Terminal Ileum 12

 
   

Extrasphincteric 14

  
   

Suprasphincteric 11

  

Angelberger [59]

Prospective cohort

Male 28

54 Perianal Fistulae anatomy is not defined

Ileocolonic 39

Rule based

  

Female 24

 

Colonic 13

49 treated with ciprofloxacin

  

Total = 54

  

3 treated with metronidazole for 7 weeks

  

Age (mean, range) years: 36 (22–61)

   
  

29 smokers

   

Bougen [32]

Retrospective cohort

Male 61

158 perianal 28 simple 128 complex

Ileal 19

Rule based

  

Female 95

 

Colonic 63

IFX administrated

  

Total = 156

 

Ileocolonic 70

 
  

Age (mean) years: 30

 

Upper digestive tract 8

Episodic if administrated on relapse of symptoms

     

Scheduled if every 8 weeks

Dejaco [29]

Prospective cohort

Male 27

52 Perianal classified according to Parks et al. Superficial 2

Ileocolonic 39

Rule based

  

Female 25

Intersphincteric 17

Colonic 13

All treated with ciprofloxacin and/or metronidazole

  

Total = 52

Transsphincteric 14

  
  

Age (mean, range) years: 39 (22–63)

Suprasphincteric 2

  
  

Smokers 32

Extrasphincteric 1

  
   

Complex fistulae 7

  
   

Unclassified 9

  

Freire [33]

Prospective cohort

Male 87

203 perianal Classified as ‘simple’—superficial (intersphincteric or low transsphincteric), painless, with a single external opening and no evidence of rectovaginal involvement or anorectal stricture or ‘complex’—fistulae is located high (high transsphincteric, extrasphincteric, or suprasphincteric), may be associated with pain, can potentially involve multiple external openings, and may be associated with rectovaginal fistulae and/or anorectal stricture

N/A

Rule based

  

Female 116

  

Antibiotic treatment; all given metronidazole and 28 also received ciprofloxacin

  

Total = 203

   
  

Age (mean) years: 36.6

   
  

Male 35.9

   
  

Female 37.1

   

Haennig [34]

Prospective cohort

Male 39

12 Rectovaginal

Perineum 56

Rule based

  

Female 42

69 Perianal

Rectum 34

62 had surgery, drainage with a loose seton—all given infliximab for median of 4.9 months

  

Total = 81

Simple or complex according to the classification of the American Gastroenterology Association

Ileum 6

 
  

Age (mean) years: 31; BMI (kg/m2) = 20 Smokers 23

71 Complex

Colon 32

 
    

Ileocolonic 42

 

Makowiec [37]

Prospective cohort

Male 37

75 Perianal—14 Complex

Ileal 9

Rule based

  

Female 53

15 Anovaginal 50 Transsphincteric (includes 15 anovaginal)

Colitis 31

Standard treatment was a high dose of corticosteroid therapy

  

Total = 90

24 Subcutaneous

Ileocolitis 50

36 given prednisolone (6 also received azathioprine)

   

4 Intersphincteric

 

2 received azathioprine alone

   

11 Ischiorectal

 

These 38 were classified as receiving immunosuppressive therapy

   

1 Suprasphincteric

 

9 were given oral metronidazole

     

12 received steroids

Michelassi [30]

Prospective cohort

Male 102

51 fistulae in ano

N/A

Rule based

  

Female 122

20 Rectovaginal

 

Surgery for all patients

  

Total = 224

  

Setons used in fistulae

  

Age (mean, range) years: 38 (17–82)

   

BMI body mass index, N/A not available

All studies took place in the USA (n = 3) [23, 27, 30]) or Europe (Germany (n = 3) [22, 25, 28], France (n = 2) [32, 34], the UK (n = 1) [24], the Netherlands (n = 1) [31], Austria (n = 1) [29], Spain (n = 1) [26], and Portugal (n = 1) [33]). The institutional setting was a teaching hospital in all cases.

Ten of the studies were prospective: either observational (n = 8) [22, 25, 26, 28, 29, 30, 33, 34] or RCTs (n = 2) [23, 31]. The remaining 3 studies were retrospective [24, 27, 35]. The follow-up period for studies ranged from 7 weeks to 27.3 years.

Different statistical methods were used to evaluate results. The techniques used were Fisher’s exact test (n = 9) [23, 24, 25, 27, 28, 29, 30, 31, 33], Chi-square test (n = 7) [23, 25, 26, 27, 30, 31, 33], mean with standard deviation (n = 5) [26, 29, 31, 33, 34], Mann–Whitney U test (n = 4) [24, 28, 31], Kaplan–Meier method (n = 4) [22, 25, 32, 34], log-rank test (n = 4) [22, 25, 32, 34], Cox proportional hazards regression model (n = 3) [22, 32, 34], 95% confidence Intervals (n = 2) [26, 33], odds ratios (n = 2) [23, 33], Wilcoxon rank tests (n = 2) [22, 28], median with interquartile range (n = 2) [31, 32], log-likelihood ratio (n = 1) [26], Kruskal–Wallis test (n = 1) [25], Kolmogorov–Smirnov test (n = 1) [33], and Hardy–Weinberg test (n = 1) [33]. Statistical methods and potentially confounding variables recorded are shown in Table 2.
Table 2

Additional baseline demographics and statistical tests used to assess prognostic factors

Paper

Previous treatment

Other perianal manifestations or stoma

Time period

Follow-up (mean, range)

Duration of CD

Statistical methods

Bell [24]

N/A

N/A

Jan 1993–Dec 1994

5.5 years (7 weeks–27.3 years)

8 years (0–32 years)

Mann–Whitney U test (nonparametric comparisons). Fisher’s exact test for associations between data sets.

Dewint [31]

Concomitant use of thiopurine derivates, methotrexate, 5-aminosalicylic, oral corticosteroids

11 had previous stoma

Sept 2008–March 2011

24 weeks

N/A

Distributions between treatment groups were compared by X2 or the Fisher exact test. Continuous variables were summarised by using median and IQR or mean and SD, and their distributions between treatments were compared with Mann–Whitney test. Frequencies of response were compared between treatments using X2 or Fisher’s exact test

Loffler [25]

27 on immunosuppressants at time of trial

N/A

1991–2001

48 months

N/A

Using SAS software, difference in no. of operations between fistulae type was calculated by Kruskal–Wallis test. Number of protectomies according to fistulae type with Fisher’s exact test

Luna-Chadid [26]

Azathioprine 73

N/A

Oct 1999–March 2001

At least 4 weeks

9 years

Comparisons between independent proportions were carried out by Chi-square test

 

Corticosteroids 59

     
 

5-Aminosalicylates 81

     
 

Metronidazole 72

     
 

Ciprofloxacin 35

     

Present [23]

Corticosteroids 33

Previous stoma excluded

N/A

N/A

12.4 years

The primary analysis was performed with the intention-to-treat principle and included all patients who were assigned to treatment. 1. The Mantel–Haenszel Chi-square test for a linear dose response in the proportion of patients in whom the primary endpoint occurred. 2. If significant, Fisher’s exact test was used to compare the proportion of patients achieving the primary endpoint in each of the two infliximab groups with the placebo group. Odds ratios were used to assess the consistency of benefit of infliximab treatment. Analysis of the proportion of patients with complete response was performed with the same methods for analysis of the primary endpoint. Continuous variables were compared by analysis of variance of the van der Waerden normal scores

 

Mercaptopurine or azathioprine 38

     
 

Aminosalicylates 52

     
 

Antibiotics 28

     

Gaertner [27]

84 had previous surgery

N/A

March 1991–Dec 2005

30 months (6–216)

7 years (0.08–38)

Pearson Chi-squared and Fisher’s exact tests were performed to compare baseline patient characteristics and differences in healing between treatment groups. Fisher’s exact test was performed to compare differences in healing between patients based on type of fistulae, initial site of CD, and operative treatment. p < 0.05 was considered significant. All calculations were performed by using the GraphPad InStat 3 statistics programme

Angelberger [59]

31 previous surgery 5-aminosalicylic acid, sulphasalazine—21

N/A

N/A

N/A

3.9 years (0.1–26.4)

Fisher exact test for 2 × 2 frequency tables. Comparison of the HBD-2 gene copy number and number of draining fistulae between the patient groups was performed by the Wilcoxon signed rank test and Mann–Whitney U test, respectively. All calculations were done by SAS and SPSS statistical software

 

Steroids—11

     
 

Immunosuppressants-23

     

Bougen [32]

Major abdominal surgery 44 Purine analog 51

N/A

Jan 1998–Sept 2011

5 years

3.8 years (0–30)

Quantitative variables were described as median and percentile (IQR) Categorical variables were presented as counts and per cent of cohort. Four events were defined: events were analysed using survival analysis. Cumulative probabilities of fistulae closure, recurrence of PCD, or abscess were estimated using Kaplan–Meier method. To identify predictive factors, we performed a univariate analysis using the log-rank test. When considering the continuous variables for dichotomous analysis, cut-off values were determined using receiver operating characteristic analysis to reduce the risk of bias related to arbitrarily defined cut-off and identify the optimal cut-off using each outcome as a classification variable. To identify independent predictors of surgery using a multivariate analysis, all significant variables in the log-rank test were retained in the model and integrated into a Cox proportional hazards regression model

 

Methotrexate 6

     
 

Adalimumab 3

     
 

Concomitant:

     
 

Steroids—45

     
 

Purine analog—82

     
 

Methotrexate—8

     
 

Antibiotics—90

     

Dejaco [29]

Perianal surgery 32 Concomitant: Aminosalicylates

Previous stoma excluded

July 1999 –Feb 2002

28.1 months

11 years (2–35)

Results are expressed as the mean ± standard deviation. Comparison of PDAI scores, leucocyte counts, and C-reactive protein levels before and during treatment was analysed by the paired exact Wilcoxon signed rank test. For the detection of differences between response rates in patients receiving different types of medication, Fisher’s exact test was used. Multivariate logistic regression analysis was performed by SAS in order to assess the simultaneous effects of smoking, azathioprine administration, and duration of fistulising disease on treatment response at week 20

Freire [33]

Concomitant

N/A

N/A

N/A

N/A

Categorical variables were expressed as frequency and percentage, and corresponding contingency tables were analysed with Pearson’s Chi-square test or Fisher’s exact test, OR were determined with 95% CI. Continuous variables were summarised using mean ± standard deviation. These variables were tested for normal distributions using the Kolmogorov–Smirnov test. The Student’s t test was employed to compare means of continuous variables and normally distributed data; otherwise, the Mann–Whitney U test was applied. All variants studied were in Hardy–Weinberg equilibrium. Data were analysed using the Statistical Package for Social Sciences

 

5-Aminosalicylic acid = 34

     
 

Steroids = 6

     
 

Azathioprine (<3 months) = 9

     
 

Azathioprine (≥3 months) = 7

     

Haennig [34]

N/A

N/A

2000–2010

63.8 months (2–263)

N/A

Quantitative variables are given as mean ± SD and median with range. The time to complete closure and its relation to the duration of seton drainage or infliximab treatment was determined using the Kaplan–Meier method, and significance was demonstrated using the log-rank test. Cox uni- and multivariate analysis was used to determine the effect of clinical variables on closure. Factors significantly associated with closure in univariate analysis were applied to a restricted multivariate mode

Makowiec [37]

Previous surgery: 41 for intestinal disease

80 had abscesses

May 1989 –Oct 1992

22 months (6–44) Follow-up ended Dec 1993

8 years (0–22)

Inactivation of perianal fistulae and abscesses, healing, reopening, and symptomatic recurrence rates were analysed using Kaplan–Meier survival estimates. Patients were considered at risk until the event occurred (inactivation, healing, recurrence) or until the last follow-up examination. Factors influencing healing or symptomatic recurrence were analysed by log-rank and Wilcoxon rank tests (univariate analysis). The data underwent further independent analysis using multiple regression according to the proportional hazard model (Cox regression analysis)

 

69 for perianal fistulae or abscesses

7 stoma

    

Michelassi [30]

N/A

Perianal abscesses 36 Anal stenosis 40 Incontinence 11

Oct 1984–May 1999

N/A

N/A

All data were transcribed on a relational database software programme for subset query extraction and analysis. Where appropriate, nominal variables were compared by using Chi-square analysis or single-tailed Fisher exact test. Statistical calculations were made with the aid of a statistical software package (Minitab 10.1 for Windows; Minitab, Inc, State College, PA, USA

  

Stoma 5

    

CD Crohn’s disease, N/A not available, PDAI perianal disease activity index

Outcomes

Identified prognostic factors were related to various outcome measures defined differently in the 13 papers. Common outcome terms were healing, response, complete response, partial response, and recurrence. A summary of various definitions and common ‘headings’ used is presented in Table 3.
Table 3

Common outcome groups and definitions used

Common outcome measure

Definition given in paper

‘Healed’/‘healing’/‘complication healed’ (n = 4)

No discharge on history or examination, with healing of the external opening [24]

 

Complete closure of fistulae without sign of activity or pain for at least a month [37]

 

Complete healing or successful dilation of anal stenosis, after surgical intervention [30]

 

Non-defined [27]

Response (n = 3)

≥50% reduction in fistulas [31]

 

Maintained fistulae healing; PDAI 2.8 ± 2.4 [29]

 

Absence of fistulae drainage, even after compression for at least 4 weeks [33]

Complete response (n = 4)

The complete cessation of drainage from all fistulas despite gentle finger compression [26]

 

Absence of any draining fistulas [23]

 

Absence of any drainage fistulas despite gentle finger compression [28]

 

PDAI 0.8 ± 1.0 fistulae closure or absence of any draining fistulas despite gentle finger compression [29]

Partial response (n = 2)

At least 50% reduction from baseline in the number of fistulas or drainage for at least 4 consecutive weeks after the discontinuation of drug infusions [26]

 

Reduction of 50% or more from baseline in the number of draining fistulas [28]

Recurrence (n = 4)

Presence of fistulae openings among patient who experienced fistulae closure [32]

 

Reopening of a former track or presence of new fistulae after primary response [34]

 

Reappearance of active perianal fistulas or associated abscesses after prior inactivation or healing [37]

 

Recurrence of the same or different complication after a period of complete healing [30]

PDAI perianal disease activity index

Bias

Risk of bias findings are presented in Table 3. Overall risk of bias in the studies was judged to be low for 7 [26, 28, 29, 31, 32, 33, 34, 36] and moderate for 6 studies [23, 24, 25, 30, 37] [24]. Study attrition was typically low. The domains most commonly at high risk of bias were study confounding (n = 5) [22, 24, 25, 28, 30] and statistical analysis and reporting (n = 6) [26, 30, 31, 32, 33, 37]. This bias assessment is shown in Table 4.
Table 4

Risk of bias using QUIPS tool

 

Overall risk of bias

1. Study participation

2. Study attrition

3. Prognostic factor measurement

4. Outcome measurement

5. Study confounding

6. Statistical analysis and reporting

Bell [24]

Moderate

L

L

L

M

H

M

Dewint [31]

Low

L

L

M

L

M

H

Loffler [25]

Moderate

M

L

M

M

H

M

Luna-Chadid [26]

Low

L

L

H

L

L

H

Present [23]

Moderate

M

M

L

L

M

M

Gaertner [39]

Moderate

L

L

H

H

M

M

Angelberger [61]

Low

L

L

M

L

H

M

Bougen [32]

Low

L

L

L

M

L

H

Dejaco [29]

Low

L

M

M

L

L

M

Freire [33]

Low

L

L

L

M

L

H

Haennig [34]

Low

M

M

L

L

L

M

Makowiec [37]

Moderate

L

M

M

L

H

H

Michelassi [30]

Moderate

M

L

M

L

H

H

L low risk of bias, M moderate risk of bias, H high risk of bias

QUIPS Quality in Prognostic Studies

Prognostic factors

Prognostic factors were divided into those associated with patient characteristics, disease characteristics, and environmental characteristics. These are summarised in Table 5.
Table 5

Studies and prognostic factors assessed

Paper

Clinical endpoints

Significant prognostic factors

Insignificant prognostic factors

Bell [24]

‘Healed’—no discharge on history or examination, with healing of the external opening

Rectal Crohn’s made proctectomy more likely than those with no rectal involvement (p = <0.001)

Complex did not take significantly longer to heal than simple (p = 0.69)

 

‘Persistent fistulae’—not defined

Complex perianal took an average of 6 procedures over 2 or more years

The presence of a rectovaginal fistulae was not predictive of the need for a proctectomy (p = 0.25)

 

‘Maintenance with a seton’—not defined

 This is significantly more procedures than simple (3 treatments, p = 0.002)

No association between presence of rectal CD and rectovaginal fistulae (p = 0.085)

 

‘Sepsis’—if an abscess formed at the fistulae site

 This is significantly more than rectovaginal (3 treatments, p = 0.01)

 
 

‘None healed’ ‘death’

 This is significantly more procedures than abdominal wall (2 treatments, p = 0.0005)

 
  

This is significantly more time than internal fistulae (1 treatment, p = 0.002)

 
  

Complex fistulae took on average 42.8 months to heal

 
  

Rectovaginal fistulae took significantly shorter time to heal (median of 26 months) than perianal fistulae (p = 0.05)

 
  

Abdominal wall fistulae took significantly shorter time to heal (median of 6.3 months) than perianal fistulae (p = 0.0001)

 
  

Enteroenteric took significantly shorter time to heal (median of 9.4 months) than perianal fistulae (p = 0.03)

 

Dewint [31]

‘Response’ –

None

Sex (p = 0.74)

 

≥50% reduction in no. of fistulae

 

Race, Caucasian versus other (p = 0.39)

 

‘Remission’ –

 

Seton (p = 0.90)

 

100% closure of draining fistulae

 

Stoma (p = 0.30)

   

Smoker (p = 0.64)

   

Previous treatment with infliximab (p = 0.63)

Loffler [25]

‘Long-term success’—whether or not patients have fistulae persistence or recurrence over 60 months

98% of patients with anorectal or rectovaginal disease also had a manifestation in colon/rectum. This was significantly higher than in patients without anorectal or rectovaginal fistulae (p < 0.001)

Complex fistulae in comparison with simple fistulas, there was a strong trend to a difference in outcome of 5 years (p = 0.2113)

Luna-Chadid [26]

‘Complete response’—the complete cessation of drainage from all fistulas despite gentle finger compression

None

Age

 

‘Partial response’—at least 50% reduction from baseline in the number of fistulas or drainage for at least 4 consecutive weeks after the discontinuation of drug infusions

 

Sex

 

‘Response for rectovaginal fistulae’—closure documented by physical examination

 

Smokers

   

Duration of fistulising disease

   

(no p value given, just says the p value is not significant)

Present [23]

‘Complete response’—absence of any draining fistulae

Males (p < 0.001)are more likely than females (p = 0.28) to reach primary endpoint when in infliximab group as compared to placebo group

None

 

A fistulae was considered to be closed when it no longer drained despite gentle finger compression

  

Gaertner [27]

‘Healing’—not defined

None

There were no significant associations found between fistulae healing and the duration of CD, initial site of CD, previous fistulae disease, and cigarette smoking

Angelberger [59]

‘Complete response’ -absence of any draining fistulae despite gentle finger compression

Complete fistulae response was significantly higher in patients with NOD2/CARD15 wild type

Median HBD-2 gene copy number was not significantly different between the responders and non-responders (p = 0.92)

 

‘Partial response’—reduction of 50% or more from baseline in the number of draining fistulae

(p = 0.02)

Duration of perianal fistulating disease (p = 0.844)

   

Smoking (p = 0.239)

   

Association between complete response and median number of draining fistulae (p = 0.18)

   

Rate of patients with more than one draining fistulae (p = 0.32)

Bougen [32]

(1) Fistulae closure = absence of any draining by fistulae openings at one visit

Significant predictors of perianal fistulae closure: prior abdominal surgery

Sex (p = 0.12) HR 1.46 (95% 0.89–2.35)

 

(2) Recurrence of PCD = presence of fistulae openings among patient who experienced fistulae closure

(p = 0.0097) HR 0.43 (95% CI 0.21–0.8)

 
 

(3) Recurrence of abscess after IFX initiation

  
 

(4) Sustained fistulae closure for patients without any recurrence

  

Dejaco [29]

‘Response’—maintained fistulae healing, PDAI 2.8 ± 2.4

The duration of fistulising disease was a significant prognostic factor (p = 0.04)

Smoking (p = 0.3)

 

‘Complete Response’—PDAI 0.8 ± 1.0, fistulae closure or absence of any draining fistulae\despite gentle finger compression

  
 

‘No response’ –

  
 

PDAI 7.4 ± 3.1

  

Freire [33]

‘Response’—absence of fistulae drainage, even after compression for at least 4 weeks

Clinical response of perianal fistulae to antibiotics was significantly higher in patients without the CARD15 mutation (p = 0.041)

None

  

OR 8.16 (95% CI 0.97–68.74)

 

Haennig [34]

‘Clinical response’—complete closure of the fistulae track with no further discharge from the opening(s) on the gentle application of pressure

The time for closure of fistulae was significantly shorter for men than women (p = 0.03) HR 0.59 (95% CI 0.36–0.96)

Recurrence after initial fistulae closure—tobacco (p = 0.41)

 

‘Primary response’—closure had been sustained for at least 4 months

11.7 versus 21.0 months

Ileocolonic location of CD (p = 0.10)

 

‘Recurrence’—reopening of a former track or presence of new fistulae after primary response

The time for closure was significantly shorted for simple fistulae compared to complex fistulae (p < 0.001) HR 0.31 (0.16–0.62)

Rectovaginal fistulae (p = 0.24)

  

2 versus 15.3 months

 
  

Rectovaginal fistulae took a significantly longer time to close than perianal (p = 0.02) HR 0.44 (0.22–0.91)

 
  

12 versus 30.6 months

 

Makowiec [37]

‘Inactivation of perianal fistulas and abscesses’—cessation of purulent discharge from fistulae and disappearance of perianal pain

Ischiorectal and transsphincteric fistulae recurred more frequently than low fistulas (p = 0.007)

None

 

‘Healing’—complete closure of fistulae without sign of activity or pain for at least a month

Low fistulas had a better prognosis (higher healing rate) than transsphincteric

 
 

‘Reopening of fistulae’—reappearance of perianal fistulas after prior healing

or ischiorectal fistulas

 
 

‘Symptomatic recurrence’—reappearance of active perianal fistulae or associated abscesses after prior inactivation or healing

(p = 0.015)

 
  

The presence of rectal disease indicated that a patient was significantly more likely to have recurrence (p = 0.041)

 
  

Fistulae healed better in patients without than in those with rectal disease (p = 0.017)

 
  

If presence of stoma are more likely to heal (p = 0.005)

 

Michelassi [30]

‘Persistence’—persistence of a complication after surgical intervention

A patient is significantly less likely to heal from a perianal complication when there is rectal involvement (p < 0.05)

None

 

‘Development’—development of a complication different from the original one as a consequence of surgical intervention

49.1 versus 19.3%

 
 

‘Recurrence’—recurrence of the same or different complication after a period of complete healing

A patient is significantly more likely to heal when they have a single complication compared to having multiple complications (p < 0.05)

 
 

‘Complication healed’—complete healing or successful dilation of anal stenosis, after surgical intervention

48.6 versus 28.2%

 
 

‘Sepsis controlled’—anorectal sepsis controlled as consequence of surgery

Patients with rectal involvement had a significantly higher chance of proctectomy (p < 0.0001)

 
  

77.6 versus 13.6%

 
  

Patients with multiple complications had significantly higher chance of proctectomy (p < 0.05)

 
  

23 versus 10%

 

CD Crohn’s disease, PDA perianal disease activity index, PCD perianal Crohn’s disease

Patient characteristics

Two papers found that patient sex was significant. A RCT of infliximab versus placebo (n = 94) found that males were significant more likely than females to reach the primary endpoint (p < 0.001) versus (p = 0.28) [23]. Another paper (n = 81) found that time for closure of fistulae was significantly shorter for men than women, at 11.7 months versus 21.0 months (p = 0.03) [HR 0.59, (95% CI 0.36–0.96)] [34]. Three papers found sex had no significant association with outcome. One trial (n = 70) found sex was not significant to the ‘response’ of patients (p = 0.74) [31] and another (n = 108) found no difference between the sexes (p > 0.05) [26]. A retrospective study (n = 156) found that sex was not a significant prognostic factor. (p = 0.12) [HR 1.46, (95% CI 0.89–2.35)] [32]

Only 1 trial (n = 108) assessed age as a prospective factor and did not find it to be significant (p > 0.05) [26].

Race was evaluated in 1 study (n = 70) as ‘Caucasian versus other’ and was found not to be a significant predictor of healing (p = 0.39) [31].

Studies did not clearly report baseline/historic use of medications; this was reported as previous or current use of immunosuppression and therefore not included in this study.

Genetics

Two papers evaluated the clinical response of NOD2/CARD15 variant carriers versus wild-type patients to antibiotic therapy. One study (n = 54) found that that complete fistulae response was more likely with wild-type (33 vs. 0%, p = 0.02) [28]. The other (n = 203) found that those without the mutation were more likely to show clinical improvement when treated with antibiotics (7.7 vs. 40.5%, p = 0.041) [33]. Both of these studies relied on fistulae drainage and had small numbers in the variant carrier group; therefore, caution should be exercised in interpreting these results.

Disease duration and location

A prospective observational study (n = 52) found the duration of fistulating disease was a significant prognostic factor, although strength and direction of association was not clearly reported (p = 0.04) [29]. Two prospective studies found the duration of perianal fistulating disease was not significant—again measures used to assess this were not clear [26, 28]. A retrospective study (n = 226) found no significant associations between fistulae healing and the duration of CD [27].

Two papers reported patients with ileal CD only (in association with perianal disease) were significantly more likely to have better outcomes than those with other disease distributions. One RCT (n = 94) noted complete fistulae response was more likely in those with ileal and colonic disease (OR 5.1, p = 0.01) than those with isolated colonic disease (OR 2.3 p = 0.35) [23]. A retrospective study (n = 156) found patients with ileocolonic disease were more likely to achieve fistulae closure [HR 1.59 (1.08–2.34) p = 0.017] compared to those with colonic disease [HR 0.86 (0.58–1.27) p = 0.54] on univariate analysis [32]. On multivariate analysis, ileocolonic behaviour was positively associated with fistulae healing [HR 1.88 (1.08–3.32) p = 0.025]. This finding was not upheld by 1 prospective study (n = 81), and 1 retrospective study (n = 226) which found no association between fistulae healing and the initial site of CD [27, 34]. Three prospective studies found rectal involvement in CD was a predictor of poor fistulae healing [24, 25, 30].

Fistulae anatomy

Three papers identified complexity of fistulae anatomy as a prognostic factor. Prospective studies found that compared to simple fistulae, complex fistulae required more treatments (n = 86) (p = 0.02) [36] and took longer to heal (15.3 vs. 2 months) (n = 81) (p < 0.001) [HR 0.31 (95% CI 0.16–0.62)] [34]. A retrospective study (n = 156) demonstrated that simple fistulae was associated with fistulae closure [HR 2.53 (95% CI 1.43–4.45) (p = 0.006)] [32] Another study (n = 147) found a trend towards worse outcomes at 5 years for complex versus simple fistulae (p = 0.2113) [25].

One study (n = 224) found that a patient with multiple fistulae was less likely to achieve healing than a patient with a single fistulae [48.6 vs. 28.2% (p < 0.05)] [30]. This was not consistent across all studies [24, 25].

Presence of a rectovaginal fistulae was not thought to be a prognostic factor for overall perianal fistulae healing (n = 81) [27].

Environmental characteristics

Six studies evaluated smoking, and none of these found it to be a significant prognostic factor [26, 27, 28, 29, 31, 34]. This is summarised in Table 6.
Table 6

Studies assessing smoking as a prognostic factor in outcome of perianal Crohn’s fistulae

Study

Total patients (n)

Smokers (n)

p value

Prospective/retrospective

Dewint [31]

70

22

0.64

Prospective

Luna-Chadid [26]

108

54

>0.05

Prospective

Angelberger [28]

54

29

0.239

Prospective

Dejaco [29]

52

32

0.3

Prospective

Haennig [34]

81

23

0.41

Prospective

Gaertner [27]

226

32

>0.05

Retrospective

Discussion

To our knowledge, this is the first systematic review to assess prognostic factors in fistulating perianal CD. It has identified candidate prognostic factors including NOD2/CARD15, duration of fistulating disease, distribution of CD, and fistulae anatomy. These require further robust assessment before they can be used to inform research or clinical practice. The challenges to prognostic research in this field are many, including lack of standardised outcome measures and timing of outcome measurement.

The NOD2 and CARD15 variant genes had a significant association with fistulae response to antibiotics in 2 studies [28, 33]. Prior work has found associations between disease severity and expression of the various alleles, particularly with aggressive luminal disease requiring early and repeated surgery [38, 39, 40]. This suggests that these are plausible factors related to the prognosis of fistulating perianal CD, although there is insufficient evidence presented at this point to understand strength of association, or modulating factors.

Duration of fistulating disease was significant in 1 study (with unclear direction), but not in 2 others. Long-standing fistulae have been shown to undergo epithelialisation and behave in a similar fashion to skin, and this may reduce the ability to heal [41, 42, 43]. If track epithelialisation is the underlying mechanism, then it may be reasonable to consider fistulae duration as a prognostic factor (or a proxy of a prognostic factor).

Disease distribution is possibly a prognostic factor, with ileal disease associated with a better prognosis and colonic or rectal disease associated with a worse prognosis. Guidelines advocate early assessment for proctitis in Crohn’s fistulae, as this impacts clinical strategy and outcome [4, 44, 45]. Proctitis has been associated with higher rates of proctectomy in previous studies, suggesting that this factor has a role in predicting outcomes in these patients [46].

The behaviour of the fistulating process is most likely a factor in healing, both in terms of complexity and number. Those with complex anatomy (multiple branching tracks crossing large proportions of the anal sphincter) are at risk of recurrent sepsis [47]. Unfortunately, terminology used to define ‘complex’ and ‘simple’ is not standard across the literature. Complexity of fistulae anatomy is more than location and number of branches. Magnetic resonance imaging offers the ability to assess volume and length of fistulae tracks [48]. It is plausible that a longer or large-volume fistulae track could take longer to heal than a short- or low-volume track. This is potentially an important prognostic marker and therefore would merit further assessment.

Patient demographics including sex may not have a role to play; the majority of studies reviewed found no relationship between sex and outcome, and those that did identify statistical differences obtained conflicting results. This may reflect sampling issues.

None of the studies reviewed found that smoking was a significant prognostic factor in fistulae outcomes. Smoking has been shown to be associated with poor disease control, and smoking cessation is widely advised in CD [49, 50, 51]. Given this, it is interesting that it is not a significant factor here. This could be for a number of reasons: bias of design of studies through definition of smoking (patient reported vs. carbon monoxide testing), or size or sampling of patients; that there is no mechanistic role for smoking in the formation of perianal fistulae; or that disease is already ‘bad’ and smoking has no additive effect.

The number of prognostic factors identified was limited by the number of studies reporting baseline factors with appropriate analysis. Even if cohorts had been well described, it would not have been possible to perform a meta-analysis in this setting as there was little consistency across study endpoints. There were 5 major groups of outcome (healed, response, complete response, partial response, recurrence), with an average of 4 definitions for each outcome. Definition of recurrence was fairly consistent across studies. The definition of healed included an asymptomatic fistulae, a non-draining fistulae on compression, and a change in the perianal disease activity index (PDAI). These are relatively subjective measures; even the PDAI has subjective elements [52], at a single time point. It is clear that there are issues to be addressed before further studies are undertaken to investigate this further.

There are limitations to consider in this review. Initial screening by a single reviewer to select studies and extract data increased the possibility that relevant reports were discarded [53, 54]. Despite this, we had multiple checks in place to support the single reviewer process, including screening of discarded abstracts for key papers by a second reviewer. This, coupled with support from clinical topic experts and a robust bibliography search, meant that we were confident that we had identified the majority of papers reporting prognostic factors.

This study used a broad search strategy to identify as many candidate papers as possible and used a tool appropriate for the assessment of prognostic factors (QUIPS). The validity of the findings is supported by the prognostic role of some reported factors in other aspects of inflammatory bowel disease. There are diminishing marginal returns from the use of databases additional to MEDLINE and Embase, with some such as CINAHL rarely retrieving unique references for many topic areas [55, 56]. For this reason, we believe our search strategy is associated with a low risk of bias.

It is important that any future prognostic study captures the above factors and uses a standardised well-defined outcome measure. A well-conducted cohort study will allow all the above factors to be properly assessed using appropriate multivariate statistical models [57, 58]. Given the prevalence and incidence of perianal CD, it might be possible to use the resulting data to inform novel study designs. Clear understanding of confounding factors might allow for trials within cohorts, Bayesian modelling or interrupted time series as alternatives to classical trial designs.

Conclusions

This systematic review has identified potential prognostic markers for outcomes in fistulating perianal CD, including genetic factors and disease behaviour. We cannot, however, draw robust conclusions from this heterogeneous group of studies. We recommend that future studies include well-characterised cohorts and use a consistent endpoint for reporting.

Notes

Funding

This work was supported as part of a Grant from the Bowel Disease Research Foundation.

Compliance with ethical standards

Conflict of interest

The authors have no conflicts of interest to declare.

Ethical approval

This article does not contain any studies with human participants or animals performed by any of the authors.

Informed consent

Informed consent was not required for this study as it used secondary sources only.

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© The Author(s) 2017

Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.

Authors and Affiliations

  • G. C. Braithwaite
    • 1
  • M. J. Lee
    • 1
    • 2
    Email author
  • D. Hind
    • 3
  • S. R. Brown
    • 2
    • 3
  1. 1.University of Sheffield Medical SchoolSheffieldUK
  2. 2.Department of General SurgeryNorthern General HospitalSheffieldUK
  3. 3.Clinical Trials Research UnitUniversity of SheffieldSheffieldUK

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