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M. Obi and A. L. Lightner
Antibiotics
Metronidazole and ciprooxacin are the most commonly used antibiotics for the
treatment of perianal CD and remain a mainstay of treatment in acute treatment [4].
However few studies have been performed to evaluate their efcacy and use. A
meta- analysis of 15 clinical trials assessing the efcacy of antibiotics was performed and noted ciprooxacin was better than placebo (p=0.005) in treating perianal stulas in CD patients but not signicantly effective when looking at active CD
in general [28]. A subsequent randomized control trial (RCT) found that while their
data was insignicant, 10weeks of ciprooxacin treatment for perianal CD increased
remission (p=0.41) and response (p=0.43) as compared to those treated with metronidazole or a placebo [29]. Other broad spectrum antibiotics such as amoxicillinclavulanic acid have been utilized [30].
Overall, antibiotics provide a good rst- line therapy but treatment requires at
least 6–8weeks of therapy and more commonly patients only have symptom relief
without signicant stula closure with symptom recurrence after treatment has been
stopped [31, 32]. As such, antibiotics should be treated as an adjuvant therapy; additional treatment with other therapies including azathioprine [33] or iniximab [34]
produce a signicantly longer term healing response.
Immunomodulators
Thiopurines are purine analogues that work by deactivating key steps in T lymphocyte functioning that result in an inammatory response [35]. The two most commonly studied with stulizing CD are azathioprine (AZA) and 6- mercaptopurine
(6-MP; an active metabolite of AZA) which have been found to have a moderate
treatment effect. No direct prospective trials currently exist evaluating thiopurine
effect on stula closure but an early meta-analysis found as a secondary endpoint
that those treated with thiopurines had a response rate of 54% compared to a rate of
21% found in those given a placebo [36]. A more recent systematic review found no
signicant improvement in clinical outcomes or steroid free remission with AZA
and 6-MP as compared to placebo and methotrexate, respectively [37]. A prospective open label trial did show that, in combination with antibiotics, AZA had a signicantly improved response rate [33].
Calcineurin inhibitors, which reduce interleukin synthesis and thus subsequently
reduce T-cell activation, have also been utilized in the treatment of perianal CD
[38]. An RCT found that oral tacrolimus resulted in a signicantly higher (43% vs
8%; p=0.004) stula response rate but only a 10% actual closure rate which was
not signicant (p=0.86) compared to placebo. In addition, nephrotoxicity was a
signicant adverse effect of drug usage [39]. Topical tacrolimus has demonstrated
no signicant benet for stulizing CD [40]. Although all data is observational,
cyclosporine is another potential option for treatment especially in refractory disease. Early studies demonstrated signicant closure rates of up to 44% but were
consistently complicated by high relapse rates upon drug discontinuation and a
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notable number of adverse events limiting continued use [41, 42]. As such, calcineurin inhibitors have a potential role in combination therapy for refractory disease,
but should be used with caution due to side effects attributed to long term use.
Little evidence exists to support the use of methotrexate, a dihydrofolate reductase inhibitor that leads to decreased nucleic acid synthesis and increased T cell
apoptosis, for the treatment of stulizing CD despite evidence of its effectiveness in
luminal CD [43]. Two small retrospective reviews noted stula response rates ranging from 44–56% with complete closure in up to 31% [44, 45]. Further prospective
and larger studies still need to be done to conrm the potential role of methotrexate
for the treatment of stulizing CD.
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Biologics
With the introduction of anti- tumor necrosis factor (anti- TNF) therapy in the late
1990s, the medical management of perianal stulizing CD signicantly improved
and anti- TNF therapy is now considered the gold standard of care. Iniximab (a
monoclonal antibody that binds to TNF-α) remains the initial and most widely studied biologic, but adalimumab and certolizumab have growing evidence for induction and maintenance of remission of stulizing CD.
In 1999, Present etal. performed a placebo controlled trial with 5 mg/kg and
10mg/kg dosing of iniximab as an induction agent for stula closure. They found
at least 50% closure of the stula to have occurred in 56–68% of patients with complete closure noted in 38–55% of patients as compared to placebo with the 5mg
dosing producing higher response rates [46]. The subsequent ACCENT II trial evaluated iniximab as maintenance therapy. After 14weeks of iniximab induction
treatment with an observed 64% healing rate, those who subsequently received
5mg/kg iniximab every 8weeks had longer time to loss of response (>40weeks)
than placebo (14 weeks; p = 0.001) and achieved an additional 39% vs 19%
(p=0.009) complete closure rate by 54 weeks [47]. Iniximab therapy was also
found to reduce hospitalizations, need for surgery, and number of procedures compared to placebo [48]. Combination therapy with antibiotics and AZA has been
shown to be superior to iniximab alone for induction of steroid- free clinical remission [34, 37, 49], but this data remains conicting as sub-group analyses of the
ACCENT II trial demonstrated that concomitant immunosuppression with iniximab therapy did not improve response rates at 1year [47].
While no dedicated control trials have been performed for adalimumab, subgroup analyses in several RCTs have demonstrated its efcacy. In the CLASSIC I
trial, adalimumab’s effectiveness as induction therapy was evaluating after 4weeks
of therapy. Of the 299 patients in the study, 32 had perianal stulizing disease and
at 4weeks, the rate of stula improvement remission weren’t signicantly improved
although a positive trend did exist [50]. The GAIN trial evaluated CD patients who
previously failed iniximab and of the 14 patients who had stulizing disease, again
at 4weeks, no signicant improvement was found with adalimumab therapy [51].
Both these trials though were likely underpowered and had limited follow-up. The
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CHARM trial on the other hand evaluated 778 patients of which 117 had stulizing
disease and at 26weeks found a 30% rate of complete stula closure compared to
13% (p=0.043) in the placebo group. Additionally, those who had complete closure
underwent maintenance therapy and at 56weeks continued to have complete closure. At 2years, 90% had sustained closure [52, 53]. Iniximab has been found to
have similar effectiveness as adalimumab in treating perianal CD and studies have
also demonstrated adalimumab’s effectiveness in in treating patients who lost
response to iniximab [54, 55]. Combination with ciprooxacin has also proven to
be more effective than monotherapy [56].
Like adalimumab, there are no direct studies to assess the efcacy of certolizumab and overall fewer studies available. The PRECiSE trials demonstrated signicant improvement in complete closure rates at 26weeks compared to placebo
(36% vs 17%, p=0.038) [57]. Longer term follow-up demonstrated consistent efcacy of treatment [58].
Although anti-TNF therapy has signicantly improved healing rates for stulizing CD, work continues to be done to improve the treatment, and as such, new therapies have been developed and are under investigation. A sub-group analysis of the
GEMINI II trial evaluated vedolizumab (a biologic which prevents lymphocyte
adhesion to intestinal vascular endothelium) and reported a probability of stula
closure at 1year to be 33% as well as faster time to closure. While the sample size
was relatively small, the study did also nd that about half of the patients had previously failed anti-TNF therapy suggesting vedolizumab could be an effective refractory treatment [59]. An ongoing study, the ENTERPRISE trial, has described a
prospective trial for vedolizumab resulting in sustained improvement of stulizing
disease of up to 54% with clinically relevant improvement of stula drainage at
2weeks for refractory disease [60]. Ustekinumab (an anti- interleukin monoclonal
antibody) is the most recent biologic agent in development. No prospective trials
have been performed but a recent open label study has demonstrated promising
results in regards to stula closure [61].
M. Obi and A. L. Lightner
Hyperbaric Oxygen Therapy: AnAlternative Therapy
Studies have proposed that hypoxia contributes to the proliferation of an inammatory response and as such it is though that improved tissue oxygenation can lead to
reduction of pro-inammatory cytokine production, increase broblast proliferation, upregulate the hypoxia response pathways, and promote stem cell migration to
lead to improved wound healing [62, 63]. The therapy involves placing a patient in
a hyperbaric chamber where they can inhale 100% oxygen at a pressure of >1atm.
A 1994 study found 50% complete healing in 10 CD patients with refractory perianal stulizing disease after two courses of therapy [64]. A systematic review of
inammatory bowel disease patients showed an 88% response rate after therapy
[62]. Adverse events have been mild and related to barometric pressure alterations
and oxygen toxicity including middle ear trauma most commonly [63, 65]. In addition, concern exists that treatment effect might diminish once therapy is stopped.
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While not widely utilized or recently studied, prior ndings suggest hyperbaric oxygen could be considered a last-line and/or adjuvant option for perianal stulizing CD.
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Surgical Management
While medical management has improved over the years, response and remission
rates with medical management alone rarely surpass 50% [4]. As such, a combined
medical- surgical approach is widely viewed as the best treatment strategy. In the
PREFACE study, around 90% of patients underwent at least one surgical intervention (frequently seton placement or drainage procedures) consistent with prior estimates of the eventual need for surgery in this patient population [3, 66]. There
currently exists no standard medical- surgical treatment algorithm, although many
have been proposed, but the consistent overall treatment pathway remains to get
initial local sepsis control prior to optimal medical management [4].
It is important to note that the presence of a stula on its own is not an indication
for surgery [67]. Typically surgery is indicated if symptoms fail to respond to medical management, drainage results in poor quality of life, if they create a tract that
results in malabsorption or if they have connections to the genitourinary tracts [68].
While surgery can have denitive benets, the complication risk is also substantial
with the highest risk being that of incontinence [69]. In addition, iatrogenic injury
as well as poor wound healing are additional complications that must be considered
and counseled for when discussing the decision to proceed with surgical management. The choice of surgical procedure is largely based on location and complexity
of disease process.
Incision & Drainage (I&D)
I&Ds are the most common pre-operative intervention for the treatment of perianal
stulas [68]. Perianal abscess have been found to be present in over 80% of perianal
CD stulas [70]. It is unclear whether the abscess precedes the stula or develops as
a result of poor stula drainage. Surgical drainage has been found to signicantly
minimize the risk of septic complications as compared to waiting for spontaneous
drainage [71]. Typically, drainage is recommended prior to initiating any medical
therapy, especially immunosuppressives [12]. I&D is usually reserved for symptomatic abscesses >1 cm that could not otherwise be treated with medication
alone [72].
Seton
Setons serve to maintain patency of the stula tract to allow for adequate drainage
and decrease the risk of abscess formation and septic complications. Setons can
either be cutting (any seton, i.e. silk suture a non-absorbable multilament suture
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M. Obi and A. L. Lightner
type, meant to cut through tissue either mechanically or chemically) or non-cutting
(a loosely tied non-absorbable suture or vessel loop passed through the stula tract
that helps preserve integrity of the external anal sphincter). Cutting setons are typically not preferred due to their risk of anal incontinence [73]. Non-cutting setons
have a low incidence of recurrent abscesses or formation of new stulous branches
[74] although some studies have reported that sole treatment with setons results in
signicant re-intervention rate, hence with the evolution of biologics, specically
iniximab, several studies have reported the improved efcacy and healing rate with
dual therapy [20, 75, 76]. From a patient standpoint, setons have the disadvantage
of being rather uncomfortable and take time to achieve adequate healing. In addition, the risk of tract epithelization exists the longer the seton remains in place and
currently there is no consensus on when the optimal time is to remove a seton. The
ACCENT II study suggested seton removal after 2weeks but subsequently saw a
15% new abscess rate whereas Thornton etal. described similar long-term outcomes after over a year of seton presence [76, 77]. The recent PISA trial compared
long term seton placement (1year) vs a year of anti-TNF treatment and advancement ap vs LIFT procedure after 2months of anti-TNF treatment and found that
the long-term seton group underwent a higher rate of re-intervention suggesting
chronic seton treatment is not effective in CD patients [78]. Typically, seton removal
is recommended only after ongoing inammation has subsided, a signicant
decrease in drainage has been demonstrated, and induction of anti-TNF treatment
has been completed (Fig.2.3).
Fistulotomy vs Fistulectomy
Fistulotomy involves identifying the internal and external openings of the stula
tract via probe placement, identifying sphincter involvement, and with cautery or
sharp dissection, opening the tract along the length of the probe then with cautery,
Fig. 2.3 Seton placement
(blue vessel loop) and
abscess drainage (penrose
drain) in a CD patient with
complex perianal CD
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obliterating the epithelized tract and leaving the wound open to heal [79]. It is an
effective treatment for supercial, low intersphincteric, and in select low transsphincteric stulas with less than 33% sphincter involvement [12, 30]. Recurrence
rates remain low at about 15% [30]. Healing rates have been reported to be greater
than 80% in this population but decrease signicantly if performed in the setting of
active proctitis [80, 81]. In the setting of proctitis, primary management remains
seton placement with attempts for stula closure via stulotomy or other methods
performed only after endoscopic remission [12]. Despite high success rates, the risk
of incontinence remains signicant and found to be higher in patients with diarrhea,
short anal canals, signicant external sphincter involvement, and women with anterior stulas (as the anterior portion of the external sphincter is shorter) [82].
For high trans-sphincteric or suprasphincteric stulas, stulectomy with primary
sphincter reconstruction is an option. Like a stulotomy, the stula tract is divided
but additionally excised. Once the tract is excised, the sphincter is re-approximated
with absorbable sutures [79]. This procedure remains relatively new with few studies noting similar healing rates as stulotomy, recurrence rates of 1–10%, and rates
of incontinence ranging from 2–20% [83, 84]. Compared to stulotomy, healing
time has been found to be signicantly longer with similar complication rates. Thus,
when able, stulotomy remains the preferred procedure [85].
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Fibrin Glue andFistula Plug
Fibrin glue and stula plugs are benecial treatment methods because they avoid
the risk of sphincter injury. That being said, their efcacy has been challenged and
are thus not often used.
Fibrin glue is a mixture of thrombin and brinogen that results in brin clot formation when injected into a stula tract. This clot is thought to promote wound
healing via angiogenesis as the clot undergoes brinolysis over time [4]. A large
multicenter, open-label, RCT found clinical remission rates after brin glue injection to be 38% after 8weeks compared to only 16% in the observation group who
just had seton removal performed (p=0.04). Adverse events did not differ signicantly [86]. While results were promising, the limited follow-up time did not provide sufcient enough data to provide denitive recommendations regarding
treatment use. Subsequent studies had demonstrated increased success rates that
lasted for longer periods indicating its potential as a viable treatment for those without alternative options [87, 88].
Fistula plugs are bioprosthetic absorbable plugs made of substances such as collagen or porcine intestinal submucosa that are inserted into the internal stula opening and occasionally sutured in place. Typically, they are only utilized after adequate
drainage of the stula tract has been done (i.e. with seton placement). Success rates
vary from 20–90% dependent on ability of plug to remain in place and severity of
perianal disease [12]. The 2019 ECCO guidelines noted that anal stula plugs
shouldn’t be routinely utilized as a stula closure mechanism as seton removal was
found to be equally effective [88]. Two RCTs demonstrated that plug placement was
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M. Obi and A. L. Lightner
no more effective than seton removal or surgeon’s preference (i.e. stulotomy, cutting seton, ap, etc.), had similar adverse events, and additionally was associated
with higher costs [89, 90]. Of note, recurrence was found to be higher than with
other surgical methods for stula treatment [79]. Overall, the use of a stula plugs
is relatively safe and can be considered in certain patients bearing in mind cost and
varying success rates (Fig.2.4).
Endorectal Advancement Flap
In the setting of perianal stula disease without active proctitis or stenosis, endorectal advancement aps (ERAF) is an effective surgical treatment. The procedure
involves coring out the stula tract then mobilizing a rectal mucosal ap (either
elliptical, rhomboid, or U-shaped) to cover the internal stula opening thus closing
of the high pressure end of the stula. The external opening remains open to allow
it to drain and heal on its own. The method attempts to avoid damage to the sphincter complex and avoids the creation of an external wound that can be more challenging to heal [12, 20]. Multiple systematic reviews have demonstrated a success rate
of about 60% in CD patients, but have a 9% risk of incontinence when thicker aps
are utilized [92, 93]. Recurrence remains a signicant problem but ERAFs have the
benet of being utilized in the setting of prior stula surgery, although risk for failure increases with each additional attempt at ap creation [94]. Prior immunologic
treatment as well as adequate stula drainage have been shown to improve outcomes of ERAF [95] (Fig.2.5).
Fig. 2.4 Insertion of a stula plug through the
internal opening of an anal stula and pulled
out of the external opening until it is well
seated and can subsequently be secured.
(Adapted from Song [91])
ab c
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25
de
Fig. 2.5 Creation of an endorectal advancement ap. Full or partial thickness U-shaped ap of
rectal tissue advanced to remove the supercial opening of a stula tract and cover the tract.
(Adapted from Lightner etal. [96])
Ligation ofIntersphincteric Fistula Tract (LIFT) Procedure
The LIFT procedure was rst described by Rojanasakul etal. in 2007 for the treatment of trans-sphincteric stulas, and has subsequently been expanded to address
more complex stulas that cross the intersphincteric groove (ISG) [97]. A perineal
incision at the ISG is made, the intersphincteric tract is identied, and the internal
and external ends of the tract are suture ligated within the ISG. Distal to the ligation,
the tract is divided, which can be conrmed via injection of saline or hydrogen peroxide into the external opening, and any tract remnant is removed. The initial incision overlying the ISG is approximated with absorbable suture [79, 97]. Retrospective
studies have demonstrated healing rates of 40–90% with increased success in CD
patients with concurrent small bowel disease as opposed to colonic disease [88, 98,
99]. Gingold etal. performed a prospective study on CD patients and demonstrated
one-year healing rates of 67% without development of incontinence. They additionally demonstrated that long term healing was associated with lateral versus midline
incision location as well as longer stula length [100]. Recently published prospective data out of Cedars-Sinai Medical Center continues to demonstrate healing rates
of 65% in CD patients after a mean follow-up of 33months, indicating that the LIFT
procedure may be a viable treatment option in this patient population [101] (Fig.2.6).
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External opening
Intersphincteric plane
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Perianal incision
Anal fistula tract
Ligated fistula
ends
EAS
IAS
Internal opening
Fig. 2.6 Depiction of the dissection made in the ISG and subsequent view of the intersphincteric
tract meant to be ligated during the LIFT procedure. IAS internal anal sphincter. EAS external anal
sphincter. (Adapted from Lo and Sangar [102, 103])
Anal verge
M. Obi and A. L. Lightner
Fecal Diversion
Healing remains the most difcult outcome for perianal CD.Fecal diversion (i.e.
loop ileostomy or end colostomy) serves to divert stool thereby preventing further
contamination and inammatory response. The goal is to avoid the need for proctectomy and is indicated in severe refractory disease. A retrospective study demonstrated early remission in 81% of CD patients but also noted relapse in 68% of those
patients and only about 10% of patients were able to undergo eventual stoma reversal [104]. A subsequent meta- analysis demonstrated early response rates of about
64% and similar low success (17%) of restoration of continuity with about 27% of
those patients requiring re-intervention. In addition, there was no notable change in
clinical response between the pre- and post-biologic eras [105]. No RCTs exist
though comparing diversion with other surgical or medical interventions.
Unfortunately, a high percentage (about 41%) of those who undergo diversion ultimately require a proctectomy [30].
Proctectomy
Proctectomy is considered a last resort for the treatment of perianal CD in the setting of severe, refractory disease associated with concomitant rectal involvement
resulting in incontinence and worsening quality of life [68]. While biologics have
slightly diminished the need for proctectomy and have improved post-diversion restoration of continuity rates, up to 40% will still undergo a proctectomy to treat
perianal CD [12, 106]. One series described that patients underwent a median number of 12 operations over a median time of 6years prior to undergoing a proctectomy. The cited risks factors for eventual proctectomy include multiple prior
perineal procedures, prior fecal diversion, CD without rectal involvement, and CD
with proctitis [68]. The main risks of the surgery include, pelvic nerve damage,
presacral abscesses, chronic draining sinus formation and delayed wound healing
2 Surgical vs Medical Management of Symptomatic Anal Fistulas in Patients…
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[12]. Given the high risk for perineal wound complications, an intersphincteric dissection is recommended [107]. For patients with large perineal defects, further treatment with myocutaneous advancement aps (i.e. rectus abdominus ap transposition
and gracilis interposition) have also had success. A retrospective review in CD
patients with complex perianal stulas demonstrated an overall success rate of 64%
with signicant long-term efcacy noted at a median of 64-month follow up [108].
Rectus abdominus aps were found in subsequent studies to have better healing
rates than gracilis aps [109].
27
Emerging Therapies
Mesenchymal Stem Cells (MSCs)
Mesenchymal stem cells (MSCs) are an emerging therapy with early promising
results for the treatment of perianal stulizing CD. They are non-hematopoietic
multipotent cells that are precursors of connective tissue cells commonly found in
subdermal adipose tissue (obtained via liposuction) and bone marrow; no study has
directly compared adipose stem cells to marrow stem cells with regard to efcacy
[63, 110]. The exact mechanism of action is unknown, but MSCs are thought to
have anti-inammatory, immunomodulatory and broblast- like healing effects via
their inhibition of T cell proliferation and promotion of T regulatory cells and formation of granulation tissue [4, 8]. They can be injected around the stula opening
directly into the rectal mucosa or they can be injected into the stula tract along with
brin glue. The use of this product was rst described in a case report of a woman
with a refractory rectovaginal stula treated with MSCs and advancement ap with
complete healing observed after 1week and maintained at 3months [111]. GarcíaOlmo subsequently initiated the rst phase I clinical trial in Spain evaluating 4
patients who had autologous adipose tissue-derived stem cells injected intralesionally. Complete healing occurred in 75% by week 9 and no adverse events
occurred after an average of 22months of follow up [112]. A subsequent phase II
trial by the same group re-demonstrated a complete healing rate of 71% when MSCs
were combined with brin glue as compared to 16% in the brin glue only cohort
(p<0.001) [113]. An additional phase II study also determined there to be closure
rates of 82% at 8weeks after direct injection into the stula tract of MSCs mixed
with brin glue. A sustained healing rate of 88% was noted after 1year [20]. A
recent phase III trial out of Europe again evaluated adipose derived MSCs and their
effect on treatment- refractory, draining complex perianal stulas in CD patients. Of
the 107 patients who received MSCs, 53 (50%) compared to 34% of patients in the
placebo group achieved clinical remission (p=0.024). In addition, only 17% compared to 29% in the placebo group experienced treatment- related adverse events,
most notable anal abscess and proctalgia [114].
Most recently ADMIRE- CD, the largest phase III, multicenter, double blinded,
placebo controlled trial, is underway evaluating the efcacy and safety of adult
allogeneic expanded adipose- derived stem cells for the treatment of refractory
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