Review

Digestion 2020;101(suppl 1):43–57 Received: November 16, 2019

Accepted: February 6, 2020
DOI: 10.1159/000506364 Published online: March 13, 2020

Treatment Algorithms for Crohn’s Disease

Michael Christian Sulz a Emanuel Burri b Pierre Michetti c
     

Gerhard Rogler d Laurent Peyrin-Biroulet e Frank Seibold f

     

on behalf of the Swiss IBDnet, an official working 
group of the Swiss Society of Gastroenterology
a Department
of Gastroenterology and Hepatology, Kantonsspital St. Gallen, St. Gallen, Switzerland;
b Gastroenterology
and Hepatology, University Medical Clinic, Cantonal Hospital Baselland, Liestal, Switzerland;
c Centre de Gastroentérologie Beaulieu SA and Division of Gastroenterology, Lausanne University Medical Center,
 

Lausanne, Switzerland; d Department of Gastroenterology and Hepatology, University Hospital Zurich and Zurich
 

University, Zürich, Switzerland; e Department of Gastroenterology and Inserm U954, Nancy University Hospital, Lorraine
 

University, Vandoeuvre-Lès-Nancy, France; f Praxis Balsiger Seibold und Partner, Crohn Colitis Zentrum, Bern und
 

Université de Fribourg, Gastroenterologie, Bern, Switzerland

Keywords antitumor necrosis factor (TNF) experienced with ongoing

Algorithms · Crohn’s disease · Decision making · inflammation. The definitive role of vedolizumab and
Inflammatory bowel disease · Treatment ustekinumab is not yet fully clarified. However, with the ad-
vantage of good safety profiles over TNF-inhibitors, these
drugs will be more frequently used in the near future, also as
Abstract first-line biologicals, compared to TNF-inhibitors. Concern-
Background: Treatment of Crohn’s disease (CD) patients is ing treatment of fistulizing disease, the knowledge of the
complex as therapy choices depend on a variety of factors, exact anatomy of the fistula is of major importance. An inter-
such as location and severity of inflammation, disease be- disciplinary discussion involving gastroenterologists, sur-
havior (inflammatory, stricturing or penetrating) but also co- geons, and in some cases gynecologists may help to opti-
morbidities, extra-intestinal manifestations, the patient’s mize the treatment plan. Regarding the postsurgical setting
age, and previous therapies. Subsequently, the choice of in CD patients, according to the very recent Cochrane Net-
treatment should be tailored to the individual patient. Sum- work meta-analysis, mesalazine should be at least posi-
mary: This article gives the reader therapy algorithms as a tioned equivalent to thiopurines and TNF-inhibitors, as
guide through different CD scenarios to support the physi- shown in our algorithm. © 2020 S. Karger AG, Basel
cian’s decision making. New compounds introduced in CD
therapy in recent years justify such an update on standard
approaches. Ustekinumab and vedolizumab and their posi-
tions within the treatment options are discussed. Fistulizing Introduction
perianal disease and postoperative medical prophylaxis are
depicted in separate chapters with own algorithms. Key Crohn’s disease (CD) is a chronic inflammatory bowel
Messages: In recent years, a variety of new drugs became disease (IBD) with relapsing and remitting symptoms that
available to treat patients with CD – especially those who are may lead to bowel damage and disability over time. There-

[email protected] © 2020 S. Karger AG, Basel Michael Christian Sulz

www.karger.com/dig Department of Gastroenterology and Hepatology
Kantonsspital St. Gallen, Rorschacher Strasse 95
CH–9007 St. Gallen (Switzerland)
E-Mail michael.sulz @ kssg.ch
fore, early diagnosis and adequate treatment should be Table 1. Montreal classification [1]
achieved. Any part of the gastrointestinal tract can be af-
fected by CD, the most common being the terminal ileum Age at diagnosis
A1 below 16 years
and the colon. The disease phenotype is described by the A2 between 17 and 40 years
Montreal classification (Table 1) that categorizes CD pa- A3 above 40 years
tients according to their age at diagnosis, location of the Location
disease, and disease behavior [1]. The prospectively vali- L1 ileal
L2 colonic
dated Lemann Damage Score might better represent accu-
L3 ileocolonic
mulating bowel damage over time [2, 3]. However, to date, L4 isolated upper disease*
there is no uniform reference standard to measure the inte- Behavior
gral disease burden in clinical practice. Indicators of severe B1 nonstricturing, nonpenetrating
disease course include smoking, sustained debilitating B2 stricturing
B3 penetrating
symptoms, repeated flare-ups, development of penetrating
p perianal disease modifier†
or stricturing lesions, need for repeated steroid treatment,
and need for surgery [4]. Symptoms do not always correlate The Montreal classification characterizes the phenotype of CD
well with objective assessment such as endoscopy, cross- according to the patient’s age at diagnosis, the location of inflamma-
sectional imaging, or noninvasive biomarkers. Addition- tion within the gastrointestinal tract, and also the disease behavior.
ally, symptom scoring systems used in clinical trials (e.g., * L4 is a modifier that can be added to L1–L3 when upper gas-
trointestinal disease is coexistent.
CD activity index) are not reliable measures of the underly- † “p” is added to B1–B3 when concomitant perianal disease is
ing inflammation and consequently have almost no role in present.
clinical practice. Fecal calprotectin may act as surrogate A, age at diagnosis; L, location of disease; B, behavior of disease;
marker of luminal intestinal inflammation as it correlates p, perianal disease; CD, Crohn’s disease.
well with endoscopic disease activity [5, 6]. Endoscopy can
reliably visualize mucosal inflammation and grade disease
activity but may be difficult to achieve in case of small-bow- Table 2. Indicators for severe disease/disease progression [4, 10]
el involvement. However, CD is a transmural disease that
may be more reliably assessed with cross-sectional imaging Indicator
(computed tomography, magnetic resonance imaging) or Young age at diagnosis
ultrasonography (US) [7, 8]. In clinical trials, patients are Corticoid steroids necessary at time of diagnosis
stratified into mild, moderate, or severe disease activity at a Early stricturing or penetrating disease (B2 and/or B3a)
certain point in time with clinical scoring systems, for ex- Ileal or ileocolonic disease location (L1 or L3a)
ample, CD activity index. However, these scores do not as- Rectal disease
Severe upper gastrointestinal disease (L4a)
sess overall disease burden and the patient’s risk profile. Perianal disease
Clearly, there is a need for validated indices of severity [9]. Severe endoscopic lesions
Not only the abovementioned disease parameters but Smoking
also the patient’s age, relevant comorbidities, possible ex- Positive antimicrobial markers
tra-intestinal manifestations, previous therapies, and the NOD2-mutation (risk for ileal disease/risk of surgery)
presence of complicated disease risk factors [4, 10] (Table a According to the Montreal classification (Table 1).
2) impact the individual therapeutic decision. Patient’s This table shows a list of indicators that are associated with a
perception to treatment and also to the disease is one of severe disease course and disease progression in patients with CD.
the most important aspects to achieve good treatment ad- CD, Crohn’s disease; NOD2, nucleotide-binding oligomeriza-
herence [11]. Thus, the possibility to simplify CD treat- tion domain-containing protein 2.
ment is limited. Nevertheless, more general recommen-
dations certainly are possible and can be summarized in
respective algorithms for CD treatment that support the lished updates (January 2020) [12–14] and are expert
physician’s decision to treat the patient as best as possible. based opinions (without voting). A systematic review of
The algorithms presented in this manuscript should point the literature was not repeated (but done for the ECCO
out the practicability of this review. They are based on the guidelines). Based on the current literature, we aimed to
guidelines of the European Crohn’s and Colitis Organiza- position recently approved drugs such as ustekinumab
tion (ECCO) and include also their very recently pub- and vedolizumab within the therapy algorithm.

44 Digestion 2020;101(suppl 1):43–57 Sulz et al.

DOI: 10.1159/000506364
 Table 3. List of medications for CD [15]

Agent Dosage

5-Aminosalicylic acid
Mesalazine Above 2.4 g/day
Corticosteroids
Budesonide 9 mg/day
Prednisone 0.75–1 mg/kg body weight/day
Immunosuppressive agents
AZA 2–2.5 (max. 3) mg/kg body weight/day
6-MP 1–1.5 mg/kg body weight/day
MTX 10–25 mg per week + 5 mg folic acid
Antibiotics
Metronidazol 1,000–1,500 mg/day
Ciprofloxacin 1,000 mg/day
Biologicals
Adalimumab (Humira®/Hyrimoz®/Amgevita®) Subcutaneous injection
Week 0: 160 mg
Week 2: 80 mg
Week 4: 40 mg
Then, every other 2 weeks: 40 mg
Infliximab (Remicade®/Inflectra®/Remsima®) Infusion over 30–90 min
Week 0: 5 mg/kg
Week 2: 5 mg/kg
Week 6: 5 mg/kg
Then, every 8 weeks: 5 mg/kg
Certolizumab pegol* (Cimzia®) Subcutaneous injection
Week 0: 400 mg
Week 2: 400 mg
Week 4: 400 mg
Then, every 4 weeks: 400 mg
Vedolizumab (Entyvio®) Infusion over 30 min
Week 0: 300 mg
Week 2: 300 mg
Week 6: 300 mg
Then, every 8 weeks: 300 mg
Ustekinumab (Stelara®) Infusion week 0
≤55 kg 260 mg
55 to <85 kg 390 mg
>85 kg 520 mg
Then 90 mg subcutaneous injection
after 8 weeks then every other 12 (or 8) weeks

* Certolizumab pegol is only approved in the United States and in Switzerland.

This table gives an overview of currently available drugs for the treatment of CD, grouped in mesalazine, cor-
ticosteroids, immunosuppressives, antibiotics (if indicated), and various biologicals. Common dosages are given.
Biologicals which are not yet approved are not considered in this publication.
CD, Crohn’s disease; AZA, azathioprine; 6-MP, 6-mercaptopurine; MTX, methotrexate.

Medical Therapy for CD duction of corticosteroids achieved reduction of mortal-

ity in CD patients, this treatment is associated with many
Historically, treatment of CD has relied mainly on cor- well-known undesired adverse effects and therefore not
ticosteroids and immunosuppressive medication with useful for long-term treatment. Two decades ago, the
thiopurines (azathioprine [AZA]/5-mercaptopurin [5- treatment armentarium was extended by infliximab, the
MP]) or methotrexate (MTX; Table 3). Though the intro- first tumor necrosis factor (TNF)-inhibitor, especially for

Treatment Algorithms for CD Digestion 2020;101(suppl 1):43–57 45

DOI: 10.1159/000506364
patients with severe disease course and those who were treatment with corticosteroids, immunosuppressives, or
refractory or intolerant to immunosuppressives [16]. anti-TNF therapy. Ustekinumab has shown to be effec-
However, therapy with TNF-inhibitors is still challenging tive in inducing and maintaining remission [29, 30], with
as 20–40% of patients have primary nonresponse to the higher response rates in TNF-naïve than in TNF-experi-
drug and 23–46% experience secondary loss of response enced patients (54–58% vs. 34%, respectively) [31]. In the
over time [17]. In addition, approximately 5% of patients updated ECCO guideline [13], ustekinumab has an ex-
suffer from anti-TNF induced psoriasis [18] or lupus-like panded position within the approved biologicals as it can
syndrome. Challenges also remain in treating elderlies also be used as a first-line biological – such as vedolizum-
who have significant comorbidities (e.g., heart failure) or ab. Again, the ECCO guideline does not give recommen-
patients with a history of malignancy. dation where to prefer ustekinumab over TNF-inhibitors
Over the last couple of years, a number of new drugs or over vedolizumab as first-line option. In our opinion,
have been developed and approved based either on inhi- ustekinumab has its particular place as first-line biologi-
bition of immune cell trafficking or on inhibition of cyto- cal, especially in patients with psoriasis and CD. Further-
kine signaling [19–22]. Vedolizumab, a monoclonal anti- more, this drug is a suitable option in patients who have
body directed against α4β7 integrin, has been approved developed severe TNF-induced psoriasiform disease [18].
for the treatment of patients with moderate-to-severe UC However, at least to date, TNF-inhibitors are less ex-
or CD who have inadequate response, loss of response or pensive (especially since biosimilars are available), and
intolerance to conventional therapy with corticosteroids, the clinical experience with TNF-inhibitors is much
immunosuppressives, or anti-TNF therapy. It is effective greater compared to the new biologicals. The safety pro-
in the induction and maintenance of remission in refrac- file of both ustekinumab and vedolizumab seems favor-
tory and luminal CD [23]. In real-world CD cohorts, clin- able, but long-term safety still needs to be confirmed in
ical remission and response rates after induction therapy postmarketing studies.
(usually evaluated at week 14) ranged from 24–36% to
49–64%, respectively, [24–27]. Vedolizumab prevents
circulating immune cells from homing to the mucosa and Therapy Algorithm for Endoluminal CD
is gut-selective through interactions with mucosal adhe-
sion molecules. This may be a specific advantage in long- The therapy algorithm for endoluminal CD (Fig.  1)
term safety [28] and may also explain the longer period of guides the reader through different endoluminal CD sce-
time to induce remission (12–16 weeks), compared to narios. Ustekinumab and vedolizumab and their posi-
TNF-inhibitors. Therefore, vedolizumab is not the ideal tions within the treatment options are discussed.
choice in patients with severe CD who are acutely ill According to the ECCO guidelines [12, 13], budesonide
where fast response to treatment is needed. In the latest (initially 9 mg) orally is the best treatment option for
ECCO guideline [13], the position of vedolizumab is mildly active localized ileo-cecal disease to induce remis-
adapted as it is now also clearly recommended to be used sion which can be achieved in up to 60% of patients after
for induction and remission in patients with moderate to a therapy course over 8 weeks [37, 38]. For moderately
severe CD with inadequate response to conventional active localized ileo-cecal disease, either budesonide or
therapy with immunosuppressives. In other words, it is systemic oral corticosteroids are recommended. Usually,
recommended as a first-line biological. However, the budesonide 9 mg daily is somewhat less effective than oral
ECCO guideline does not discuss in detail which patients systemic steroids (relative risk [RR] 0.85, 95% CI 0.75–
should be commenced on vedolizumab or anti-TNF in- 0.97), especially in severe disease (RR 0.52, 95% CI 0.28–
hibitors. In our opinion, vedolizumab is suitable as a first 0.95); however, oral budesonide is associated with less
choice biological in elderlies with comorbidities and ele- side effects (RR 0.64, 95% CI 0.54–0.76) [39, 40]. System-
vated risk of infection and patients with history of malig- ic corticosteroids are suitable in colonic and small bowel
nancy, where safety is of particular concern. CD to induce remission [12].
Ustekinumab is a monoclonal IgG1 antibody against For decades, mesalazine has been used to achieve re-
the p40 subunit of interleukin-12 (IL-12) and IL-23 that mission in CD. Still nowadays, mesalazine is often pre-
targets T-helper cell pathways which promote the accu- scribed; up to one-third of patients in the Epi-IBD cohort
mulation of inflammatory cells within the intestine. It was treated with mesalazine [41]. However, the latest
was approved for the treatment of patients with moder- ECCO guidelines [13] suggest not to use mesalazine (or
ate-to-severe CD who have failed or were intolerant to sulphasalazine) for CD treatment due to lack of support-

46 Digestion 2020;101(suppl 1):43–57 Sulz et al.

DOI: 10.1159/000506364
 Moderate to severe disease +Antibiotic,
Mild disease Patients with
if indicated
Ileo-cecal: budesonide% Systemic corticosteroids high risk for
mesalazine (>2.4 g/day) +/– disease
as alternative option+ AZA/6-MP/MTX progression#

Assessment of response after 2

weeks; tapering of corticosteroids

Maintain Steroid-dependent:
In selected remission Steroid-refractory:
Tapering of steroids within
patients: with Active disease despite (oral)
16 weeks impossible or
No medication AZA/6-MP/ corticosteroids during 4
recurrence within 12 weeks
MTX weeks
after stopping steroids

Assessment of response Choose any biological (vedolizumab

every 10–12 weeks not recommended if EIM present
and/or faster response necessary)

Surgery to be Anti-IL12/23
Anti-TNF& Anti-integrin
discussed ustekinumab
+/– vedolizumab
(especially in (prefer in selected
AZA/6-MP/MTX (prefer in elderlies
localized cases with
(prefer combo-therapy, and/or hx
ileo-cecal co-existent
if possible) of malignancy)
disease) psoriasis)

Assessment of response every 10–12 weeks (symptoms, calprotectin and US)

Insufficient Intolerance or
response or loss primary
of response non response

1. Optimize by escalation (dose

Change to other Maintain
escalation or/and interval reduction) Surgery
anti-TNF& or to remission
2. Add AZA/6-MP, if possible to be
other class of with selected
3. Change to other class of evaluated
biologicals agent
biologicals

Assessment of response
every 10–12 weeks

Response/remission

No response/no remission/recurrence

Fig. 1. Therapy algorithm for endoluminal CD [12, 13, 23, 29, 30, indicated. + For more details, see main text. % Budesonide: corti-
32–36]. To keep this algorithm as simple as possible and for rea- ment multi matrix is not approved for treatment of CD. # Table 1:
sons of repetition and similarity, location and extent of inflamma- indicators for severe disease/disease progression. & Anti-TNF: in-
tion (localized ileo-cecal, colonic, and extensive small bowel dis- fliximab and its biosimilars (Remicade®/Inflectra®/Remsima®);
ease) are not specifically represented. Also, for reasons of simplic- Adalimumab and its biosimilars (Humira®/Hyrimoz®/­
ity, the severity of inflammation (mild/moderately severe/severe) Amgevita®); CertolizumabPegol (Cimzia®), only approved in
is not differentiated. However, high-risk situation for progressive Switzerland and USA. CD, Crohn’s disease; AZA, azathioprine; IL,
disease and steroid-dependent/steroid-refractory inflammation interleukin; 6-MP, 6-mercaptopurine; MTX, methotrexate; TNF,
are discussed as separate entities. Surgery as a therapeutic option tumor necrosis factor; EIM, extraintestinal manifestations; US,
in endoluminal CD treatment is integrated in the algorithm, where ­ultrasonography.

Treatment Algorithms for CD Digestion 2020;101(suppl 1):43–57 47

DOI: 10.1159/000506364
ing data. The working group performed a meta-analysis that in the placebo arm [p < 0.05]) [45, 46]. The literature
of 7 randomised trials comparing mesalazine (5 studies) shows that combined treatment with infliximab and
and sulphasalazine (2 studies), published in the supple- AZA (at least 6 months) is more effective than infliximab
ments [13]. The Cochrane Network meta-analyses are in- alone to induce and maintain remission without steroids
consistent: A recent Cochrane Network meta-analysis by (SONIC trial) [46, 47]. Of course, the treating physician
Coward et al. [42] demonstrated a significant benefit for has to bear in mind the patient’s individual situation
high-dose mesalazine (above 2.4 g daily) over placebo ­including safety profile. However, it must be stated that a
(OR 2.29, 95% CI 1.58–3.33). However, another Network significant reduction of surgery rates up to 40% has also
meta-analysis could not confirm such a dose effect [43]. been shown for thiopurines [48].
Indeed, it has to be mentioned that the ECCO recommen- Generally, treatment in patients with extensive small
dation is stated as “weak” and based only on moderate bowel disease (defined as involvement of >100 cm small
evidence. Furthermore, a risk-benefit analysis has not bowel) should be more aggressive [49] and TNF-inhibi-
been performed. According to the meta-analysis, mesala- tors should be early started, also in combination with im-
zine is well tolerated [13]. In our opinion, mesalazine may munosuppressives, if possible [50]. Early start of anti-
still be a treatment option and may be offered to patients TNF therapy is more effective in extensive disease than a
who refuse repetitive steroids or do not want to escalate late start [51, 52]. The CHARM trial with adalimumab
therapy toward immunosuppressives or biologicals. could show that 60% of patients with CD <2 years of du-
Local mesalazine (rectal foam/enema) in left-sided CD ration reached clinical remission, compared to 40% (p <
colitis is not recommended by the ECCO guidelines, due 0.05) of patients who had a longer duration of disease
to lack of convincing data [12, 13]. This treatment has not [51].
been studied in randomized controlled studies. To date, As mentioned, recently, new biologicals became avail-
budesonide multi matrix with a colonic delivery technol- able, such as the anti-α4β7-integrin monoclonal antibody
ogy is not (yet) approved for CD. vedolizumab, and the IL-12/23 p40 antibody ustekinu­
Generally, the response of induction therapy should be mab.  The updated ECCO guideline [13] recommends
clinically assessed after 2 weeks. Usually, tapering of cor- them to be used also as first-choice biologicals. Vedolizu­
ticosteroids starts after 2 weeks. In selected cases (first mab (and also ustekinumab) may be preferred over TNF-
flare and mild localized disease), no further therapy may inhibitors in elderly patients or in patients with history of
be considered (ECCO statement 5 C; [12]). A population- malignancy, as these drugs have a very good safety profile.
based study investigated the outcome of first steroid However, one needs to bear in mind that vedolizumab is
treatment in CD patients and revealed that 80% of the not effective against extraintestinal manifestations and is
patients had a primary response within 30 days of therapy also not suitable when a fast response should be expected.
(48% with complete remission; 32% with partial re- Furthermore, ustekinumab is the preferred biological
sponse). Of those, 55% had prolonged response within agent in p
­ atients with coexistent psoriasis (see above).
1 year. However, 45% had either a course of relapses or Certainly, it is important to recognize patients who are
stayed steroid dependent [44]. Therefore, in around half steroid-dependent (defined as relapse within 12 weeks
of the patients, a concomitant therapy with either immu- during tapering or tapering within 16 weeks impossible)
nosuppressive agents (AZA/6-MP or MTX) or biological or refractory to steroids (defined as nonresponse within
treatment must be considered as a steroid-sparing con- 4 weeks). In those patients, biological therapy should be
cept. Patients with several indicators predictive for a se- initiated [53].
vere disease course (Table 2) should be early commenced Patients with early relapses and frequent flares during
on a biological treatment. When TNF-inhibitors have be- immunosuppressive therapy should be commenced on
come available, early start of anti-TNF therapy in these biological treatment (see below). Alternatively, surgical
patients increasingly became common practice, given the resection can be discussed or evaluated, especially in lo-
fact that continued treatment with either infliximab or calized disease and in those patients who still have active
adalimumab has been associated with a substantial reduc- inflammation despite experience with all TNF-inhibitors
tion in hospitalisation (with adalimumab every other and other biologicals.
week: 52 and 48% relative reductions in 12-month risk of Monitoring of patients with CD is important and is
all-cause and CD-related hospitalisation, respectively) recommended by the ECCO guidelines [8]. In patients
and surgery for CD (major surgery rate in the adalim- who reached clinical and biochemical remission, moni-
umab every other week arm almost 7 times lower than toring aims at early flare recognition [8]. According to

48 Digestion 2020;101(suppl 1):43–57 Sulz et al.

DOI: 10.1159/000506364
the ECCO guidelines fecal calprotectin can be used to Esophageal and gastroduodenal disease: According to
detect relapse before clinical symptoms occur. The mon- the ECCO statement 5 H, mild esophageal or gastroduo-
itoring time interval should be between 3 and 6 months denal disease may be treated with proton pump inhibitors
depending upon duration of remission and current only [12]. However, it needs to be mentioned that CD in
therapy [8]. Other than in North America, in Europe, the proximal gut is associated with a worse prognosis
especially in Germany and Switzerland, monitoring of [57]. Therefore, in general, more aggressive treatment
IBD patients with US is much more common and fre- should be recommended. Evidence-based therapy is
quently performed by many gastroenterologists in clin- mainly based on case series [58, 59]. Many clinicians add
ical practice. A German prospective multicenter study a proton pump inhibitor to conventional induction ther-
found that bowel US can be used to monitor disease ac- apy and have a low threshold for starting anti-TNF ther-
tivity in patients with active CD [54]. This method seems apy than for disease elsewhere.
to be a useful follow-up method to evaluate early trans-
mural changes in disease activity, in response to medical
therapy [54]. Hence, US is implemented as one of the Therapy Algorithm for Fistulizing Disease
monitoring instruments in our therapy algorithm
(Fig. 1). The knowledge of the exact anatomy of the fistula is of
In case of inadequate response or loss of response, dif- major importance in order to plan the treatment. An in-
ferent options can be chosen to optimize the treatment: terdisciplinary discussion involving gastroenterologists,
Serum trough levels of biologicals, especially of TNF-in- surgeons, and in some cases gynecologists may help to
hibitors, can be monitored and dosage adapted if re- optimize the treatment plan.
quired, also called therapeutic drug monitoring (TDM). The proper assessment of fistulae by magnetic reso-
It is also possible to optimize the TNF-inhibitor therapy nance imaging, endosonography, and exploration under
based on clinical judgement only, without measuring anesthesia allows to differentiate between simple perianal
drug trough levels or anti-TNF antibodies. The updated fistulae and complex fistulae according to Sandborn et al.
ECCO guideline commented on this aspect that there is [60] (Fig. 2). Complicated fistulae can be considered as a
currently no evidence to recommend for or against the risk factor for poor prognosis and should therefore be ag-
use of TDM to improve the clinical outcome [13]. This gressively treated. These complex fistulae are: high (high
statement is based on the only randomized controlled, means involving > 2/3 of the external sphincter) inter-
multicenter study with 69 patients that showed no sig- sphincteric, high transsphincteric, suprasphincteric, and
nificant difference in improving clinical response be- extrasphincteric, may have multiple openings and may be
tween the TDM-group and the symptom-based group associated with an abscess, proctitis, rectal stricture, or
(57.6 vs. 52.8%; RR 1.09, 95% CI 0.71–1.67; p = 0.81) [55]. may be connected with the bladder or vagina [60]. Any
Overall, despite the limited evidence, TDM might bring a anterior fistula in women is generally considered com-
cost-saving benefit [56]. Adding AZA/5-MP or MTX plex due to potential genital complications [61]. In con-
could be another step to increase efficacy of TNF-inhibi- trast, simple fistulae are low fistulae that involve superfi-
tors, especially in patients treated with infliximab. In case cial tissue and include subcutaneous and intersphincteric
of antibody formation against the TNF-inhibitor which and intrasphincteric fistulae that remain below the den-
was used (e.g., infliximab), a switch to another one (e.g., tate line, have a single opening, and are not associated
adalimumab or certolizumab pegol; certolizumab pegol with perianal complications [60, 61].
approved for CD in Switzerland and United States) would It is compulsory to rule out a perianal abscess first;
be recommended (switch within class). perianal pain is almost always associated with an abscess.
In patients with primary nonresponse despite ade- If suspected or already detected, urgent exploration un-
quate dosage or intolerance to the drug, an alternative der anesthesia combined with drainage performed by a
TNF-inhibitor or another class of biologicals (vedolizu­ colorectal surgeon is the treatment of choice to prevent
mab or ustekinumab) must be selected. The preference the destruction of undrained local sepsis. Furthermore,
should be given to change the mechanism of action. procto-sigmoidoscopy should be performed to search for
Especially in localized ileo-cecal disease, surgery is also active luminal disease. If detected, it must be treated
a reasonable option in patients who deny medical treat- achieving and maintaining remission [32].
ment options (due to any reason) or in those who are not An asymptomatic simple fistula does not need treat-
compliant toward medical therapy. ment. When symptomatic, a simple fistula may be treated

Treatment Algorithms for CD Digestion 2020;101(suppl 1):43–57 49

DOI: 10.1159/000506364
 Perianal fistula Search/rule out local
Recto-sigmoidoscopy
sepsis rectal pain/
assess for proctitis
fever/induration
Classify type of fistula: simple or complex
Medical assessment with MRI/EUS/EUA EUA + drainage
management of abscess
+ antibiotics

Simple fistula Complex fistula

Antibiotics (metronidazol or ciprofloxacin) Seton◊ and antibiotics and

Fig. 2. Management of fistulizing perianal and/or seton◊ (or fistulotomy) anti-TNF (or AZA/6-MP)
disease [10, 12, 14, 32, 33, 36, 61]. Simple
fistulae: Low fistulae that involve superfi- Continue
cial tissue and include subcutaneous and maintenance
therapy
intersphincteric and intrasphincteric fistu-
lae that remain below the dentate line, have Anti-TNF and/or AZA/6-MP
a single opening and are not associated with If indicated,
and/or
perianal complications. Complex fistulae: no more drugs
seton◊
are high (high means involving >2/3 of the
external sphincter) intersphincteric, high
transsphincteric, suprasphincteric, and ex-
trasphincteric, may have multiple open- Rule out again
ings, and may be associated with an abscess, abscess and/or
Response/remission
proctitis, rectal stricture or may be connect- stenosis
ed with the bladder or vagina. ◊ Seton: Se- No response/no remission/
ton, not cutting. AZA, azathioprine; EUA, recurrence
examination under anesthesia; EUS, endo-
scopic ultrasonography; 6-MP, 6-mercap- Evaluate diverting stoma
topurine; MRI, magnetic resonance imag-
ing; TNF, tumor necrosis factor.

conservatively (with antibiotics) and/or surgically by fis- and reduce symptoms, although they may need to be re-
tulotomy (seton) after abscess formation has been ruled placed at some time. Loose setons can also serve as a
out. In case of nonresponse, anti-inflammatory therapy bridge between medical therapy and the definitive surgi-
(either with immunosuppressives or with TNF-inhibi- cal treatment. Cutting setons are not recommended in the
tors) should be added to gain healing [32]. treatment of perianal CD as they are a method of fistu-
Complex fistulae should be primarily treated with se- lotomy implicating a risk of sphincter injury [63].
tons and/or antibiotics and a biological treatment (usu- Fistulectomy should only be used in selected cases due
ally a TNF-inhibitor) [14]. A systematic review of hetero- to the risk of fecal incontinence [32]. In severe therapy-
geneous retrospective studies revealed that the combina- refractory fistulizing disease, fecal diversion with colos-
tion of surgical and medical therapy may have a beneficial tomy or ileostomy may be evaluated. Often, this option is
healing effect of perianal fistulae compared with surgery not easy to discuss with the individual patient. However,
or medical therapy alone [59, 62]. To date, randomized sometimes it is the only way to prevent further structural
controlled trials or prospective studies comparing anti- damage and to increase the healing of complex fistulae. It
TNF treatment alone versus anti-TNF and surgery com- has to be stated that the fistula healing rate and stoma clo-
bined to treat complex perianal CD fistulae are not avail- sure rate are limited [14]. For details concerning defini-
able [14]. If the treatment plan aims for fistula closure, the tive surgical treatments, it is referred to Gecse et al. [63],
seton must be removed, often toward the end of the in- Adegbola et al. [64], and the updated ECCO guideline
duction phase of the TNF-inhibitor [63]. However, opti- [14].
mal timing of removal is unknown. One option is to keep Several medications are used for the treatment of fistu-
loose setons permanently in situ to control local sepsis lae. Antibiotics such as metronidazole and ciprofloxacin

50 Digestion 2020;101(suppl 1):43–57 Sulz et al.

DOI: 10.1159/000506364
seem to be helpful and are frequently used to treat the infec- To date, there are only few data available regarding the
tious complications of fistulizing disease. Only small stud- efficacy of ustekinumab in perianal CD. However, a
ies are available, most of them showing that the therapeutic French multi-center observational study (Bio-LAP)
effect is limited to the time of antibiotic treatment. Antibi- showed that ustekinumab appears as a fairly effective ther-
otics are useful to alleviate symptoms, but usually, they do apeutic option in perianal refractory CD [70]. Among pa-
not induce complete healing in complex fistulae [32]. Ac- tients with setons at the time ustekinumab was started,
cording to the updated ECCO guideline, antibiotics have no successful seton ablation during follow-up was possible in
role as monotherapy in closing fistulae [13]. Bacteria show 29/88 (33%) [73]. In a recent systematic review and meta-
increasing rates of resistance to ciprofloxacin; therefore this analysis of 27 controlled trials, a moderate-quality evi-
medication will have limited use in the future [65]. Steroids dence was found to support the efficacy of ustekinumab
have not shown to play a role in the treatment of fistulae; to induce fistula remission (RR 1.77, 95% CI 0.93–3.37)
they even may enhance septic complications. Thiopurines [74]. However, no difference was found for maintenance
have been used in the treatment of fistula; however, there of remission, compared to placebo. Currently, the updat-
are limited data. A meta-analysis of 5 randomized, placebo- ed ECCO guideline stated that the evidence for ustekinum-
controlled trials which assessed perianal fistula closure only ab is insufficient for fistula healing [13]. For vedolizumab,
as a secondary endpoint revealed that thiopurines were ef- only low-quality evidence was found in this meta-analysis
fective in inducing fistula closure (OR of response 4.44) [74]. Clearly, more studies are needed to define the role of
[66]. However, a substantial number of patients needed to ustekinumab and also vedolizumab related to other bio-
stop this treatment due to side effects [66]. Due to lack of logical therapies for the management of refractory peri-
data, the updated ECCO guideline suggested against using anal fistulizing CD. However, these biologicals may be
thiopurine monotherapy for fistula closure [13]. used in TNF-refractory patients, or where TNF-inhibitors
TNF-inhibitors are the medical mainstay in fistula are contraindicated and luminal activity is also ongoing.
treatment. The data from Present et al. [67] showed a sig- Recently, several studies about fistula curettage and
nificant closure and response rate to infliximab. Howev- mesenchymal stem cell therapy have been published and
er, it needs to be mentioned that the study endpoints were analyzed in a recent recent systematic review and meta-
somewhat imprecise. The ECCO working groups per- analyis (23 studies with 696 patients) [75], showing sig-
formed a meta-analysis of the existing data showing that nificant results concerning fistula closure (overall 80%
infliximab was clearly effective in inducing (RR 3.57, 95% success rate). However, the 4 randomized controlled tri-
CI 1.38–9.25) and maintaining (RR 1.79, 95% CI 1.10– als (483 patients) revealed a closure rate of 64% (vs. 37%
2.92) clinical fistula healing [13]. The ECCO guideline in the control arm). The uncontrolled studies in this anal-
clearly recommends infliximab as first-line biological for ysis most likely lead to overestimate the efficacy of this
treating complex fistulizing CD [13]. Also adalimumab – novel therapy. However, safety data are good and the re-
although less strongly – is suggested to use for this indica- lapse rate is low. This costly treatment needs to be evalu-
tion by the ECCO guideline [13]. Adalimumab has shown ated in clinical practice and should be currently limited
to be effective in fistula closure in about 40% of cases [68]. to refractory difficult to treat cases. Overall, complex peri-
In a small pediatric cohort, the fistula closure rate was anal fistulizing disease remains a challenging and limiting
44% [69]. The combined treatment with adalimumab and condition to treat. Further work is needed to optimize
ciprofloxacin seems to be superior to an anti-TNF treat- management in this special group of CD patients.
ment only; however, the positive effect is limited to the
time the antibiotic is taken [70]. Adalimumab should be
used in patients with previous infliximab failure as shown Algorithm for Postsurgical Prophylaxis
by the CHOICE trial [71]. Compared to the former ECCO
guideline, the updated one does not support a decision for Unfortunately, for the majority of CD patients, surgery
or against the use of thiopurines combined with TNF- is not curative. The cumulative rate of symptomatic (clin-
inhibitors to enhance the effect of anti-TNF in complex ical) recurrence is high (at 3 years approximately 50%)
fistulizing disease [13]. A meta-analysis in 2015 based on [76]. Endoscopic assessment of the neoterminal ileum (il-
11 randomized controlled trials revealed no apparent eocolonoscopy) is strongly recommended as gold stan-
benefit from the above combined therapy as regards par- dard for the diagnosis of postoperative endoscopic recur-
tial (OR 1.25, 95% CI 0.84–1.88) or complete fistula clo- rence by the ECCO guidelines within the first year after
sure (OR 1.1, 95% CI 0.68–1.78) [72]. surgery (EL2 [32]), based on the modified Rutgeert-Score

Treatment Algorithms for CD Digestion 2020;101(suppl 1):43–57 51

DOI: 10.1159/000506364
 After bowel resection Smoker? yes

Metronidazole 500 mg 2–3×/day Strongly recommend to stop

for 3 months after surgery smoking; refer to professional
(or ornidazole) cessation support

Low risk High risk

First resection-fibrostenotic Previous resection(s) – perforating/penetrating
disease – non-smoker/stopped disease – smoker – extensive small bowel
smoking disease – residual active disease

Watchful Naïve to thiopurine Previously treated with Intolerance to

waiting (AZA/6-MP) thiopurines pre-surgery thiopurines

AZA/6-MP Anti-TNF*
Continue AZA/6-MP
(mesalazine as (mesalazine as
post-surgery
alternative option+) alternative option+)

Monitoring with fecal calprotectin and ultrasonography

Ileocolonoscopy 3–6 months after surgery

No or mild disease Moderate disease activity Severe disease activity

Fig. 3. Management of postoperative CD activity Deep aphtoid ulcers Diffuse ileitis or stenosis
[12, 32, 33, 36, 79–81, 89]. Prevention of re- Rutgeert-score ≤2 or Rutgeert-score 2 Rutgeert-score 3 or 4
currence is a relevant aspect of the postsur-
gical management in CD patients. A per-
sonalized risk stratification with tailored Watchful waiting 1. If not yet treated, start with thiopurine (or anti-TNF)
monitoring with fecal 2. If already under treatment: escalate/optimize (dose
therapy is of relevance. Furthermore, the
calprotectin and optimization and/or add new medication (e.g.,
status of previous therapy and the patient’s ultrasonography anti-TNF)
attitude toward medical treatment should
be considered. *  Prefer adalimuab [89];
+ for more details, see main text. AZA, aza-
Ileocolonoscopy 18 months after surgery
thioprine; 6-MP, 6-mercaptopurine; TNF,
tumor necrosis factor.

[76]. The endoscopic recurrence rate is even higher and a­ lgorithm presented in this publication is based on the
predicts future clinical relapse. A meta-analysis showed an available literature and our opinion and should help the
endoscopic recurrence rate of 58% (95% CI 51–65%) 1 reader as a recommendation in daily practice (Fig. 3).
year (median) after surgery in the placebo groups of post- A general prophylaxis with metronidazole (500 mg
operative maintenance trials [77]. Therefore, prevention 2–3 x/day; or ornidazole) limited to 3 months is easy to
of recurrence is an important part of the postsurgical perform. Despite limited data and only moderate toler-
management in CD patients. In this setting, a personal- ance, this prophylaxis commenced directly after surgery
ized risk stratification with tailored therapy is eligible. is still recommended by the ECCO guidelines [32] and
However, despite a number of guidelines including the also by the recent consensus guidelines of the British So-
ECCO, the British Society of Gastroenterology, and ciety of Gastroenterology [36]. Endoscopic recurrence at
­American College of Gastroenterology guidelines [32, 36, 1 year was reduced by a 3-month metronidazole course,
78], a robust algorithm for the prevention and treatment but not sustained beyond 12 months [80]. Decision mak-
of postoperative recurrence is not yet established. The ing in the postoperative setting is based on several factors,

52 Digestion 2020;101(suppl 1):43–57 Sulz et al.

DOI: 10.1159/000506364
mainly on the individual risk factors leading to the con- evidence to determine which treatment is safest or most
stellation of either “low risk” or “high risk” (Fig. 3). Smok- effective in preventing clinical and endoscopic relapse be-
ing as the only modifiable risk factor is well replicated and cause of very low certainty of evidence [89]. Partially, these
associated with a 2-fold and a 2.5-fold increase in clinical new data conflict with recommendations of the current
and endoscopic recurrence, respectively, after surgery guidelines [32]. For example, the ECCO guidelines recom-
among smokers versus nonsmokers [82]. It has been mend thiopurines or TNF-inhibitors as drug of choice to
shown that smoking cessation is correlated with a de- prevent postsurgical recurrence (EL2 [32]). High-dose me-
creased risk of postoperative recurrence [83, 84]. It is of salazine is only declared as an option for patients with an
note that each smoking patient should be counseled about isolated ileal resection (EL2 [32]). In contrast, according to
the importance to quit smoking. Professional cessation the new network meta-analysis, there is only for mesala-
support (counseling, pharmacotherapy, or nicotine re- zine and adalimumab some evidence to prevent clinical
placement therapy) should be offered with efforts (Fig. 3). relapse [89]. Based on these data, mesalazine should be at
In patients with low risk (first resection, fibrostenotic least positioned equivalent to thiopurines and TNF-inhib-
disease, and nonsmoker), no further medical prophylaxis itors as shown in our algorithm (Fig. 3).
may be opted. In high-risk situations (≥1 previous resec- The choice of medical prophylaxis should also con-
tion, perforating disease, and smoker-status), prophylaxis sider the patient’s attitude toward medical treatment.
with TNF-inhibitors and/or immunosuppressives (thio- Even in a high-risk situation, some patients prefer not to
purines) are recommended as agents of choice by both, the take medication after surgery, especially when they are
ECCO and the American Gastroenterological Association feeling well or they fear possible side effects of medica-
guidelines [32, 85]. A more precise recommendation for tions. Compared to thiopurines and TNF-inhibitors, me-
the prevention of postoperative CD recurrence is missing salazine has a better overall safety profile which might be
in the guidelines. In 2014, a Cochrane review revealed that an argument to think of it. Alternatively, patients who are
thiopurines had lower clinical relapse rates compared with naïve to thiopurins can be commenced on AZA (or
placebo (RR 0.74, 95% CI 0.58–0.94), but with low-quality 6-MP). In patients who had been preoperatively already
evidence [86]. However, a large placebo-controlled trial on thiopurins, thiopurins are continued. In case of thio-
called TOPPIC (240 patients randomized to 6-MP at 1 mg/ purine intolerance, anti-TNF therapy is commenced
kg/day versus placebo after surgery, follow-up for 3 years) (Fig. 3). According to the new Cochrane Network meta-
showed a small but not significant effect of treatment (clin- analysis, adalimumab will probably have a stronger posi-
ical recurrence rate: 13% in the 6-MP group versus 23% in tion among the availale TNF-inhibitors [89].
the placebo group, requiring medical or surgical interven- In case the first postoperative endoscopic assessment
tion [p = 0.07]) [87]. Interestingly, 60% of patients in the shows no or mild inflammation (Rutgeert-Score <2), pro-
6-MP group had subtherapeutic levels at week 49. A sub- phylaxis may be stopped. In cases of relevant mucosal in-
group analysis revealed that 6-MP had a significant effect flammation (Rutgeerts 2 or above), escalation needs to be
in reducing clinical recurrence in smokers compared with considered: Either starting medical treatment or switching
nonsmokers (p interaction = 0.018). Regarding TNF-in- from mesalazine to thiopurines or from thiopurines to TNF-
hibitors, the largest randomized placebo-controlled trial inhibitors or escalating the dosage of TNF-inhibitors. The
(called PREVENT; 297 patients with ileocolic resection strategy to use endoscopy in the decision making is mainly
and ileocolonic anastomosis and increased risk of recur- based on the data of the POCER trial, a large randomized
rence, infliximab 8 weekly versus placebo) confirmed that clinical trial which provided evidence that endoscopy can
TNF-inhibitors were effective to prevent postoperative re- guide postoperative CD management to lower the risk of
currence [88]. Although endoscopic recurrence was sig- recurrence [79]. The POCER trial compared an active care
nificantly lower (22%) in the infliximab group than in the model using endoscopic assessment at 6 months postopera-
placebo group (51%; p < 0.001), the primary endpoint of tively with standard care (no colonoscopy at 6 months). All
this study, defined as clinical recurrence up to week 76, was patients received metronidazole for 3 months postopera-
not met (recurrence rates 13% for the infliximab group tively; high-risk patients received thiopurines (or adalim-
and 20% for the placebo group; p = 0.097). umab in case of purine intolerance). In the case of 6-month
Obviously, the newest Cochrane Network meta-analy- endoscopic recurrence treatment step-up in the active care
sis published in September 2019 [89] puts current guide- group was performed: to thiopurine, fortnightly adalimum-
line recommendations on postoperative medical manage- ab with thiopurine, or weekly adalimumab, respectively. At
ment into a new perspective. These data reveal insufficient 18 months endoscopic recurrence was 49% in the active

Treatment Algorithms for CD Digestion 2020;101(suppl 1):43–57 53

DOI: 10.1159/000506364
group versus 67% in the standard care group (p = 0.03) and Disclosure Statement
clinical recurrence was 27 and 40%, respectively (p = 0.08)
M.C.S. has received consultant and/or speaker fees from
[79]. Thirty-nine percent of patients in the active care group ­ bbVie, Ferring, MSD, Janssen, Pfizer, Takeda, UCB. E.B. has
A
had a step up in treatment based on the results of the colo- received consultant and/or speaker fees from Abbvie, Janssen,
noscopy at 6 months. Out of this patient group, 38% had MSD, Norgine, Pfizer, Pierre Fabre, Takeda. P.M. received in the
achieved endoscopic remission at the next colonoscopy at last 5 years consulting fees from Calypso, Ferring Pharmaceuti-
18 months. Furthermore, it is of note that a relevant portion cals, Merck Serono, MSD, Nestlé Health Sciences, Pfizer, Take-
da, UCB Pharma, and Vifor Pharma and lecture fees from
(41%) of patients in endoscopic remission at 6 months was ­AbbVie, Ferring Pharmaceuticals, Hospira, MSD, Takeda, UCB
documented with endoscopic recurrence just 1 year later (at Pharma, and Vifor Pharma. G.R. has consulted to Abbvie, Au-
18 months). Therefore, continued monitoring is important. gurix, BMS, Boehringer, Calypso, Celgene, FALK, Ferring, Fish-
In clinical practice, endoscopic assessment may be repeated er, Genentech, Gilead, Janssen, MSD, Novartis, Pfizer, Phadia,
18 months after surgery. In general, regular monitoring with Roche, UCB, Takeda, Tillots, Vifor, Vital Solutions and Zeller;
G.R. has received speaker’s honoraria from Astra Zeneca,
US and fecal calprotectin may be recommended. ­AbbVie, FALK, Janssen, MSD, Pfizer, Phadia, Takeda, Tillots,
UCB, Vifor and Zeller; G.R. has received educational grants and
research grants from Abbvie, Ardeypharm, Augurix, Calypso,
Closing Remarks and View on Emerging Therapies FALK, Flamentera, MSD, Novartis, Pfizer, Roche, Takeda, Til-
in CD lots, UCB and Zeller. L.P.-B. has received personal fees from
AbbVie, Janssen, Genentech, Ferring, Tillots, Pharmacosmos,
Celltrion, Takeda, Boerhinger Ingelheim, Pfizer, Index Pharma-
In recent years, a variety of new drugs became available ceuticals, Sandoz, Celgene, Biogen, Samsung Bioepis, Alma,
to treat patients with CD – especially those who are anti- Sterna, Nestle, Enterome, Allergan, MSD, Roche, Arena, Gilead,
TNF experienced with ongoing inflammation. Mean- Hikma, Amgen, BMS, Vifor, Norgine; Mylan, Lilly, Fresenius,
while, vedolizumab and ustekinumab are more clearly Oppilan Pharma, Sublimity Therapeutics, Applied Molecular
Transport, OSE Immunotherapeutics, Enthera, as well as grants
positioned not only as second-line but also as first-line from Abbvie, MSD, Takeda. Stock options: CTMA. F.S. has no
biologicals besides TNF-inhibitors. With the advantage conflicts of interest to declare.
of good safety profiles (compared to TNF-inhibitors),
these drugs will be more frequently used in the near fu-
ture. Certainly, it will be also a discussion whether vedol-
izumab will be a better option than AZA prior to anti- Funding Sources
TNF treatment, especially in elderly male patients with This work is not funded.
higher risk of lymphoma. However, this would negative-
ly impact the health costs in IBD-patients.
Certainly, the therapy algorithm of CD depicted in this
article will be complemented by a variety of further Author Contributions
emerging drugs which might be approved in the near fu- M.C.S. wrote the manuscript. All other authors critically re-
ture, such as risankizumab and mirikizumab, anti-p19 viewed it and approved the final draft.
antibodies with selective activity against IL-23, and Janus
kinase inhibitors, such filgotinib and upadacitinib as oral
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