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ABSTRACT:
Background: The term inflammatory bowel disease (IBD) encompasses two clinical entities:
ulcerative colitis (UC) and Crohn’s disease (CD), which reflectreflects the characteristic of
clinical manifestations between patients, and within individuals over time. Optimal
Aim and Sscope: We aimed to provide a condensed guideline of IBD management for
based on the most up-to-date information at the time of writing, and will be updated on a
regular basis.
Furthermore, the current recommendations are not intended to be used as rigid therapeutical
guidelines. They are also not meant to take the place of practicing physician’s clinical
judgement; instead, they are meant to assist and advise health care practitioners who are
Materials and Mmethods: Theseis guidelines for the management of inflammatory bowel
diseaseIBD in adults and children was developed by the Saudi Ministry of Health in
collaboration with the Saudi gastroenterology association (SGA) and Saudi society of clinical
1
A literature review of the current publications, and international guidelines regarding the
management of IBD was performed. A total of 145 evidence and expert opinion-based
recommendations for diagnosis and treatment of UC and CD were proposed, and further
– High, if further research very unlikely to change confidence in the estimate of effect;
– Low, if further research very likely to have an important impact on confidence in the
A summary of the current IBD treatment goals and algorithms can be consulted as a
Results: The consensus includes 145 statements focused on diagnosis and medical treatment
options of IBD.
The group supported the use of serological biochemical markers (i.e., fecal calprotectin), ileo-
colonoscopy with multiple biopsies, and cross-sectional imaging as important tools for a
definitive diagnosis. Moreover, several international scoring systems were proposed in order
The group reached agreement upon the positioning of corticosteroids therapies, exclusive
biologic agents, as important treatment options of for IBD in (both UC and CD). Based on
consensus, the treat-to-target (TTT) strategy was chosen as the core treatment strategy for
2
Conclusions:
differential diagnoses should be made with enteric infections, intestinal TB, or primary
immune deficiency.
Table of Contents
Chapter 1. Diagnosis of Crohn’s disease (CD) and ulcerative colitis (UC).........................................................3
General considerations.....................................................................................................................................3
Ulcerative colitis Diagnosis...............................................................................................................................8
Crohn’s disease Diagnosis................................................................................................................................9
Classification of inflammatory bowel disease...............................................................................................12
Composite clinical and endoscopic disease activity in UC...........................................................................15
Endoscopic disease activity in UC..................................................................................................................16
The Pediatric Crohn’s Disease Activity Index (PDCAI).............................................................................18
Treatment Goals..............................................................................................................................................18
Treatment Algorithm......................................................................................................................................25
Crohn’s disease................................................................................................................................................26
Perianal Fistulizing Disease............................................................................................................................30
Ulcerative Colitis.............................................................................................................................................31
Biologics............................................................................................................................................................36
The use of biologics in moderate to severe UC.............................................................................................36
The use of biologics in moderate to severe CD.............................................................................................36
Sequencing of medications..............................................................................................................................40
Interventions based on therapeutic drug monitoring for patients with IBD and loss of response to anti-
TNF agents.......................................................................................................................................................41
Chapter 2. Special Patient population.................................................................................................................45
Using of biologics in pregnancy......................................................................................................................45
Diagnostic workup of children with suspected IBD.....................................................................................50
3
Medical Management of UC...........................................................................................................................55
ASA and Enemas.............................................................................................................................................55
Oral Corticosteroids........................................................................................................................................56
Immunosuppressants......................................................................................................................................57
Biologics............................................................................................................................................................58
General considerations for using Biologics...................................................................................................60
Medical management of Crohn’s disease in pediatrics (CD)......................................................................62
Aminosalicylates..............................................................................................................................................62
Corticosteroids.................................................................................................................................................63
Exclusive Enteral Nutrition............................................................................................................................64
Immunosuppressants......................................................................................................................................65
Anti–Tumor Necrosis Factor Biologic Therapy...........................................................................................66
References:.......................................................................................................................................................70
Statement 1: There are no precise diagnostic criteria for diagnosing Crohn’s disease (CD) or
unclear etiopathology, but common clinical manifestations. The most representative entities
inflammation starting distally in the rectum, with continuous extension proximally for a
variable distance, often with an abrupt demarcation between inflamed and non-inflamed
condition with variable age of onset, disease location, and behavior (2).
The diagnosis of IBD is not restricted to a certain criterion; however, the diagnosis is
4
parameters (3). Genetic and serological testing are not recommended as there is limited
Although the diagnosis of IBD can be challenging, some of the presenting symptoms
may raise the suspicion of IBD. These may include hematochezia, diarrhea, tenesmus, and
abdominal cramping (5). Some enteric infections such as E. coli, Salmonella, Shigella,
Yersinia, and Campylobacter, and certain parasitic infections, such as amebiasis, may present
with similar symptoms, therefore it must be excluded before a final diagnosis of IBD is made
(6).
Statement 2: We recommend using the Red Flags Score (RFS) to help differentiate irritable
The Red Flags Score (RFS) is a screening method developed to identify patients with
who are at a higher risk of having IBD rather than IBS (7). Danese et al., developed a 21-
items survey which was administered to healthy subjects, patients with irritable bowel
syndromeIBS (non-CD group) and patients with recently diagnosed (<18 months) CD (7).
The authors concluded that a minimum Red Flags indexRFS value of 8 was highly predictive
of CD diagnosis with sensitivity and specificity bootstrap estimates of 0.94 (95% confidence
interval 0.88–0.99) and 0.94 (0.90–0.97), respectively. Moreover, the association between
A more recent study, from Saudi Arabia, outlined the association between an elevated
RFS and the lack of specialized gastroenterological evaluation, thus appealing for early
5
Statement 3: Genetic and serological tests are not currently recommended for the
Genetic and serological testing are not recommended as there is limited evidence
supporting their role in confirming IBD diagnosis (4). Serological markers could be used in
order to support a diagnosis of IBD, though the accuracy of the best available tests is rather
(pANCA) in inflammatory bowel disease (IBD), and to evaluate their discriminative ability
UC and CD (10). The authors concluded that ASCA and pANCA antibodies are specific, but
Likewise, genetic testing does not allow diagnosis of IBD, but further research could evaluate
Statement 4: Fecal calprotectin is a non-invasive disease activity measure that may be used
to screen for IBD, assess treatment response, evaluate symptoms, and predict recurrence.
endoscopic indices of disease activity, and thus allow serial monitoring of disease activity
6
and of treatment success, and can even serve in predicting clinical recurrence or sustained
remission (13-16).
necessary for suspected IBD. If the patient has severe acute colitis, sigmoidoscopy is
preferred.
diseases of the large bowel disease, as itnd allows direct mucosal visualization, biopsy, and
therapeutic intervention of the colon and terminal ileum. During ileocolonoscopy, tTwo
biopsies should be taken through ileo-colonoscopy from the inflamed areas in order to
diagnose UC and CD. Additional biopsies from the uninflamed areas, and every segment of
the colon, including that of the rectum, especially for the diagnosis of UC, could be used to
morphology and acute inflammatory process (17). In this case, biopsies of inflamed and
uninflamed regions are required. Sigmoidoscopy with biopsies may offer a suitable
alternative in patients with severe UC due to the high risk of perforation (18). Later on, after
Statement 6: There are no endoscopic features unique to CD or UC. The most important
involvement with clear demarcation of inflammation and rectal involvement. The most
7
The colonoscopy findings usually show UC as a continuously inflamed segment
involving the distal rectum and extending proximally, loss of vascular markings, granularity,
and friability of the mucosa., as well as dDeep ulcers and bleeding are associated with more
ulcerations (both aphthous and linear), antral thickening, presence of fistulae, and strictures
(20).
architectural distortion, and chronic inflammation are necessary to make the diagnosis of
Histological examination of the mucosa plays an important role during the diagnosis
of IBD. For example, iInfectious colitis is distinguished from IBD by the presence of intact
crypt morphology and acute inflammatory process whereas features of chronicity such as
crypt architectural distortion, and chronic inflammation are necessary to make the diagnosis
of IBD (17). Histological features can also aid in differentiating between UC and CD through
the presence of patchy disease, and granulomas which are suggestive of CD rather than UC
(21). However, in UC patients, basal plasmacytosis has been identified as the characteristic
histological feature with the best predictive value for UC diagnosis (22). At least one month
Magnetic Resonance (MR), Computed Tomography (CT), and small bowel ultrasonography
(SBUS) when radiological evaluation of the small bowel is required for IBD patients.
8
To assess the small bowel, either magnetic resonance enterography (MRE) or
require the patient to drink a large volume of neutral contrast, which is used to help highlight
inflammation, strictures, ulcers, and cobble stoning of the intestinal wall (23). Cross-sectional
imaging can also identify extraluminal findings such as fistulae and mesenteric thickening.
A recent meta-analysis showed that the sensitivity and specificity for CTE were 87%
(95% confidence interval [CI], 78%–92%) and 91% (95% CI, 84%–95%), respectively, for
CTE, and 86% (95% CI, 79%–91%) and 93% (95% CI, 84%–97%), respectively, for MRE
(24).
because disease monitoring usually occurs on a lifelong basis for patients with IBD and the
cumulative dose of radiation can be significant across decades. In contrast, MRE often
requires the patient to stay in a small, enclosed space, which cand induce claustrophobia.
MRI is also the best current technique to evaluate perianal disease (25), with a 97%
sensitivity, and 96% specificity for the diagnosis of anal fistulae in CD (26).
Computed Tomography (CT) has advantages that include lower cost, less procedure
time, more suitable procedure, widespread availability, less need for anesthesia, and it is
more suitable for patients with contraindications for MRI. Additionally, CT scanning is more
Ultrasonography also avoids the use of ionizing radiation in the evaluation of the
bowel, and is primarily used to diagnose bowel wall thickening or differential diagnosis
89% and a specificity of 94.3% in the assessment of patients with known CD, but is less
9
Ulcerative colitis Diagnosis
More than 90% of patients with active UC report having rectal bleeding. Associated
symptoms generally reflect the severity of mucosal disease, and may differ according to
Loose stools for more than 6 weeks differentiates extensive UC from most cases of
infectious diarrhea (30). Patients with active disease also complain of rectal urgency and
ulcerative colitisUC.
Statement 10: In individuals suspected of having UC, stool testing is recommended to rule
out enteric infection including special testing for Clostridium difficile (C. diff) infection.
assayed for Clostridium difficile (C. diff) because the presence of an infection with this
pathogen is a major risk factor for complications, hospitalization, and mortality (31).
Moreover, numerous studies have outlined the link between C. diff Clostridium difficile
(35). C. diff C. difficile isolates should be characterized based on their toxin profile and
10
Statement 11: If UC is identified by sigmoidoscopy, a future complete ileo-colonoscopy is
recommended to determine the extent and severity of inflammation and to diagnose rule out
CD.
to confirm the diagnosis, extent and severity of disease by means of full ileo-colonoscopy,
usually within the first year, as this can differentiate between UC and Crohn’s diseaseCD,
provide data for further prediction of the disease’s outcome and risk stratification for
Statement 12: In Saudi Arabia, tThe differential diagnosis of intestinal tuberculosis (ITB)
Patients with ileocecal CD can be misdiagnosed with ITB due to similarities in the
skin test, antibodies to TBpositive interferon gamma release assay (IGRA) for TB, abdominal
lymphadenopathy, ascites, transverse appearing ulcers, and a patulous ileocecal valve are all
Previous research suggested that ITB lesions were both inflammatory and
proliferative, but in CD, the entire thickness of the intestinal wall was implicated in both
11
inflammation and ulceration (39). CD lesions were wider, and rectal lesions were frequent,
compared tobut ITB lesions that were limited to the right colon (39).
In ITB, necrotic lymph node and contiguous ileocecal involvement are common. A
meta-analysis conducted by Du et al. comprising 692 patients showed that the most reliable
and ITB,ITB; however, several key elements found on colonoscopy, serologyical, and
radiological examinations can help the differential diagnosis between the two entities.
include: anorectal lesions, longitudinal ulcers, aphthous ulcers, and cobblestone appearance
(41). Patients with intestinal TB usually have involvement of fewer than four segments of the
colon, patulous ileocecal valve, transverse ulcers, and scars or post-inflammatory polyps (41).
Additionally, a positive ASCA serology and proximal small bowel disease may
indicate CD, while a positive quantiferon IGRA test and typical pulmonary lesions could
point out to TB (42). TB PCR performed on intestinal biopsies may aid in the distinction
Patients with IBD who have upper gastrointestinal symptoms such as nausea,
dyspepsia, and vomiting will benefit from upper GI endoscopy (44). The debate about the use
continuing, especially due to recent evidence that suggests a higher prevalence of upper GI
12
intestinal biopsies is difficult, upper GI endoscopy with evidence of focal gastritis from
Statement 14: If ileo-colonoscopy is normal, in a patient suspected of having CD, EGD and
histopathological examination may support the diagnosis of CD (45). Moreover, the use of
Statement 15: Small intestine video capsule endoscopy (VCE) is an alternative choice to
cross-sectional imaging for patients with a clinical apprehension of CD and a normal ileo-
colonoscopy.
abnormalities in the small bowel. The diagnostic capabilities of VCE appear to be superior to
MRE or small intestine contrast ultrasound (SICUS) when evaluating the proximal small
Statement 16: We recommend assessing the risk of retention prior to using VCE when
swallowing disorders (47, 48). Data on retention rates in patients with CD varies from 2% to
13% in patients with established CD, to approximately 1.5% in patients with suspected CD
(49). If small bowel stenosis is not firmly excluded, a patency capsule can be used to confirm
13
Statement 17: The diagnosis of CD should be suspected if three or more ulcers were found
in the small intestine after excluding the use of non-steroidal anti-inflammatory drugs within
a month of testing.
Limited data exists regarding the number of ulcerations found during enteroscopy that
are suggestive of CD. A study by Mow et al., reported that multiple ulcerations (≥3
ulcerations) found using wireless capsule enteroscopy were considered diagnostic for CD,
patients with negative upper and lower endoscopy and features suspicious of CD on MRI or
Monteiro et al., outlined that 25% of patients with unclassified IBD were found to
have small bowel involvement consistent with CD on VCE examination, but approximately
one third (37%) of them remained unclassified during further follow-up (51). This data
supports the need for further assessment of device-assisted enteroscopy as a diagnostic tool
for CD.
Statement 19: CD should be suspected in patients who have recurrent perianal abscesses or
complicated fistulae.
frequent in patients with isolated colonic involvement (52). Clinical and imaging findings are
From this point of view, there are two types of fistulae: simple, if they are superficial,
have a single external opening, and lack evidence of complications, or complex, if they are
14
high, have multiple external openings, and are associated with abscesses, rectovaginal
patients with perianal CD to assess disease extent, severity, presence of internal openings,
Statement 20: We recommend using the Montreal classification for adults and the Paris
classification for pediatric patients to describe the disease’s phenotype in patients with UC.
The Montreal classification was introduced as an attempt to describe the extent and
behavior of CD in more detail, and includes a classification system for UC (55). Since its
introduction, several studies have assessed the inter-observer reliability and validity of the
Montreal classification, and concluded that the inter-observer agreement was good for disease
location, but only moderate/fair for upper gastrointestinal involvement. Moreover, the
Montreal didn’t appear to be a reliable classification system for disease severity in ulcerative
colitisUC (56).
E1 Ulcerative proctitis
E2 Left-sided UC (distal to splenic flexure)
E3 Extensive (proximal to
S2 Moderate UC
15
S3 Severe UC
Severity
The Paris classification of UC (Table II) evaluates the disease’s extent that is
classified into E1, E2, E3 and E4. In E1, ulcerative proctitis, the inflammation is confined to
the rectum. In E2, the inflammation involves a portion of the colorectum that is distal to the
splenic flexure. While in E3, inflammation extends distal to the hepatic flexure, and in E4 the
inflammation extends proximal to hepatic flexure (57). Disease extent should be confirmed
by mapping biopsies, as endoscopic appearance may undervalue the true extent. Determining
disease extent is critical for prognosis, and the risk for undergoing colectomy. Disease
extension is dynamic, and it may progress or regress with time. In the Paris classification of
UC (table I), the severity of the disease is only classified to either S0 (never severe) or S1
(ever severe); the disease is considered severe when the Pediatric Ulcerative Colitis Activity
Statement 21: We recommend using the Harvey Bradshaw index (HBI) to assess for and
16
Vote: 90% strongly agreed; high-quality evidence
disease activity in ileocolonic Crohn's diseaseCD (59, 60). A HBI score less than 5 is defined
as clinical remission, HBI between 5 and 7 as mild disease, HBI between 8 and 16 as
Statement 22: We recommend using the Simple Endoscopic Score for Crohn’s Disease
SES-CD score is based on the evaluation of five defined bowel segments (rectum,
sigma + descending colon, transverse colon, ascending colon, and terminal ileum), and in
these segments the presence and size of ulcerations and the extent of the inflammatory area
and stenosis are assessed, then classified in severity as a score of 0–3. The scores for each
individual segment are added together as a sum score (Table III) (61).
Table III: Simple Endoscopic Score for Crohn’s Disease (SES-CD) (61)
Severity 0 1 2 3
Ulcerations none aphtoidAphthous Large ulcers Very large ulcers
(<0.,5 cm)
Ulcerated none <10% 10 – 30% >30%
surface
Inflamed none <50% 50 – 75% >75%
surface
Stenosis none singleSingle, multipleMultiple, notNot passable
passable passable
17
Statement 23: In clinical practice, we recommend using the Mayo score for UC as a
The Mayo Score is a hybrid between clinical and endoscopic variables; stool
and daily activities of the patient are assessed (Table IV) (62). In studies, a decrease of the
score by 3 or more is usually taken as therapeutic success. For the assessment of endoscopic
mucosal response, the endoscopic subscore is most often used, and mucosal healing is
diagnosed with an endoscopic subscore of 0 or 1 (but subscore 1 can mean clearly visible
0 1 2 3
Stool frequency 0 1–2 3–4 >5
(aboveAbove-
average)
Bleeding noneNone mild moderate severe
Sigmoidoscopy inactiveInactiv mild moderate severe
e
Overall physician Nnormal mild moderate severe
assessment
Daily activities normalNormal slightly significantly massively
Statement 25: We recommend using the Pediatric Ulcerative Colitis Activity Index (PUCAI)
to evaluate the disease severity and to monitor treatment in children with UC.
18
The PUCAI is a validated, objective measure of clinical outcome developed to
standardize the reporting of UC disease activity in the pediatric population (Table V) (63).
The PUCAI score has been primarily used within the gastroenterology literature to
characterize disease activity and the effects of medical treatment (64, 65). It is based on 6
quantifiable items easily obtained from a patient’s history, without need for a subjective
Item Points
Abdominal pain
No pain 0
Rectal bleeding
None 0
stools 20
Formed 5
Partially formed 10
Completely unformed
0–2 5
19
3–5 10
6–8 15
>8
wakening 0
No 10
Yes
Activity level 0
No limitation of activity 5
Statement 26: We recommend using the Pediatric Crohn’s Disease Activity Index (PDCAI)
to assess the disease severity and to monitor treatment in children with CD.
The PCDAI focuses on: (1) Subjective reporting of the degree of abdominal pain,
stool pattern, and general well-being; (2) Extra-intestinal manifestations, such as fever,
arthritis, rash, and uveitis; (3) Physical examination findings including abdominal pain,
perirectal disease, extraintestinal manifestations, weight and height; and (4) Laboratory data,
including hematocrit, erythrocyte sedimentation rate (ESR), and serum albumin (66).
This index has high inter-rater reliability, and good construct validity with physician
global assessments of disease activity. Validity has been further demonstrated in several
20
Treatment Goals
Statement 27: In order to evaluate the response to therapy in active UC, a combination of
The ultimate target of medical therapy is variable among countries because there is no
fully agreed on or validated definition of remission, although many parameters have been
implications for clinical practice, with the need for more endoscopic assessment and likely
There is lack of clear evidence about the importance of histological remission as well
as endoscopic remission (deep remission) (73, 74). Recent studies suggest that the presence
There is a growing consensus among specialists that the target for UC should be
clinical and/or patient-reported remission (defined as absence of rectal bleeding and return to
normal bowel habit) combined with endoscopic remission (Mayo endoscopic subscore of ≤1)
(77).
normalization of CRP (to values under the upper limit of normal), and fecal calprotectinFC
(to 100–250 μg/g), and the change of treatment plan if the target has not been achieved (78).
21
a) CD: A reduction in the PCDAI score of at least 12.5 points.
Hyams et al., aimed to evaluate the responsiveness of the PCDAI to changes in the
status of patients after therapeutic interventions (79). Clinical response was best reflected by
a decrease in PCDAI of >12.5 points, and subgroup analysis for patients with severe disease
at diagnosis showed a higher mean PCDAI decrease (79). In another study, a change of 12.5
points in the PCDAI was shown to clearly represent a change in physician-assessed severity
(80).
As for PUCAI, a score reduction of at least 20 points was the standard target in
a) CD: Minimum 50% decrease in the PRO2 score (stool frequency and abdominal pain).
b) UC: Minimum 50% decrease in the PRO2 score (stool frequency and rectal bleeding).
Due to the strong correlation of PROs with patient well-being, this target should be
assessed early and frequently throughout the disease course. The STRIDE II study reinforces
a drop of minimum 50% in the PRO2 score for both UC and CD, as a treatment target (78).
22
a) CD: an alleviation in in the PCDAI score to a score of <7.5 or <10 points excluding
The same IOIBD consensus stated that an alleviation in the PCDAI score to a score of
<7.5 or <10 points excluding the height item for CD, and a reduction in the PUCAI score to a
score of less than 10 points for UC, represent definitions for clinical remission (78).
a) CD: PRO2 (stool frequency ≤3 and abdominal pain ≤1 and) or HBI <5.
b) UC: PRO2 (stool frequency=0 and rectal bleeding=0) or a partial Mayo score of <3
We agree with the IOIBD consensus regarding the definition of clinical remission for
Statement 32: Fecal calprotectin obtained within 12 weeks of starting medication in IBD
after initiating medical treatment (84). A meta-analysis indicated that patients with elevated
fecal calprotectinFC had 53% to 83% probability of relapse during the subsequent 2 to 3
months (85).
Other studies support that the level of fecal calprotectinFC at week 12 to 14 following
23
Statement 33: Cross-sectional imaging obtained six to nine months from starting the
In a prospective multicentric longitudinal study of patients with active CD, all patients
treatment initiation, and after 1 year of treatment, and the authors concluded that sonographic
Another multicentric trial evaluated the role of IUS SBUS for monitoring treatment
response, and the authors found out that almost all sonographic parameters determined during
response and improved clinical symptoms or endoscopic appearance, and reduction of CRP
(90). The authors also concluded that only the presence of the ‘comb sign’ on the index CT
should not usually be used for monitoring disease activity if MRI or IUS is available due to
radiation concerns.
A prospective single-center trial which evaluated patients with CD treated with anti-
TNF (infliximab or adalimumab) indicated that the Magnetic Resonance Index Of Activity
(MaRIA) score significantly changed at Week 26, and that the overall MaRIA score
correlated well with endoscopic score both at baseline and at Week 26 (91). The authors
24
concluded that the MaRIA has a high accuracy for prediction of endoscopic mucosal healing,
and is a reliable indicator to monitor the use of TNF antagonists in patients with CD (91).
with relapse, prolonged disease activity, new unexplained symptoms, and before switching of
treatment.
For follow-up of active disease in UC and CD, endoscopy remains the reference
standard, and several studies determined the benefit of mucosal healing (MH) outlined
In a recent meta-analysis, patients with MH had a pooled odds ratio (OR) of 4.50 for
achieving long-term (after at least 52 weeks) clinical remission, 4.15 for remaining free of
colectomy, 8.40 for achieving long-term MH, and 9.70 for achieving long-term
In a prospective multicentric cohort study, the authors showed that endoscopy was the
most sensitive method to detect the earliest mucosal changes, and that severe endoscopic
(a) CD: no ulceration or an SES-CD score less than 3 points (e.g., SES-CD ulceration sub
(b) UC: UCEIS score up to one point or Mayo endoscopic subscore equal of zero.
The Selecting Therapeutic Targets in Inflammatory Bowel Disease (STRIDE) initiative of the
International Organization for the Study of Inflammatory Bowel Diseases (IOIBD) has
25
recommended treatment targets in 2015 for adult patients with IBD. STRIDE II
recommendation for endoscopic healing that it is associated with long term outcome and it
reduce risk of bowl damage. EH was the main treatment procedure in STRIDE II initiative
healing (78).
Statement 37: Histologic remission and transmural healing are not recommended treatment
histologic index of severity (RHI) or the Nancy index (NI) can be used as an addition to
endoscopic remission to document a deeper degree of healing. In CD, transmural healing (as
healing.
The Nancy Index (NI) and Robarts Histopathological Index (RHI) are the two scores
that vary in complexities and features they evaluate (94). However, recent evidence suggests
that their ability to classify UC patients accurately and consistently could be improved (95).
that histologic remission and transmural healing are not recommended treatment goals in CD
or UC (78).
Statement 38: In UC and CD, the normalized quality of life related to health and absence of
26
Vote: 100% strongly agreed; moderate-quality evidence
We agree with the STRIDE II recommendation regarding the quality of life for
Statement 39: Prior to starting any biologic therapy, including anti-TNF treatment, patients
with IBD must be screened for latent tuberculosis (TB) using chest radiography and a
purified protein derivative (PPD) skin test and/or an interferon-gamma release assay (IGRA).
why it must be excluded before the treatment’s initiation using a standard diagnosis protocol,
which that includes chest radiography and a purified protein derivative (PPD) skin test and/or
Statement 40: Biological therapies should be used in conjunction with preventive anti-
tuberculosis therapy, with at least isoniazid for the first six months, in IBD patients with
Treatment Algorithms
considered, and the preferred treatment strategy should be suggested according to the risk
profile. A “step-up” approach is recommended for patients who do not have high-risk
27
The term 'step-up' refers to a sequential treatment strategy that often begins with a less
budesonide, with escalation to the highly effective, but potentially more toxic treatment
In this strategy, one would avoid overtreating and unnecessary exposure to the risk of
developing adverse events, especially in a subgroup of patients who may do well with the
standard paradigm. For the same reason of toxicity, physicians are often reluctant to advance
therapy resulting in patients not being adequately treated and developing tissue damage with
The iIdeas of using highly effective, but potentially more toxic treatment strategies
early in the course of a chronic illness to prevent disease progression and disability, has
gained popularity for the treatment of patients with CD. Moreover, the “top-down” strategy
Statement 42: The conventional “step-up” approach is the core approach for the treatment of
UC, except for patients who present with acute severe ulcerative colitis (ASUC) that require
hospitalization.
and requires patient’s hospitalization. Recent data favors the “topstep down approach” using
rescue therapy as an initial medical treatment, but its failure mandates surgical intervention
(100-102).
Crohn’s disease
28
Statement 43: We recommend AGAINST using 5-ASA for the maintenance or even
The ECCO team performed a meta-analysis of seven eligible RCTs that compared the
use of oral 5-ASA or sulfphasalazine with placebo in patients with active CD (103). Overall,
there was no significant effect for induction of clinical remission, and among the five trials of
5-ASA alone, there was also no benefit over placebo for inducing clinical remission (103).
Statement 44: Oral Budesonide should only be used to induce clinical remission in
individuals with active mild-to-moderate CD confined to the terminal ileum and/or ascending
colon/cecum.
dose of 9 mg/day with placebo indicated that budesonide was superior to placebo for
inducing clinical response, and clinical remission in patients with mildly active CD in the
at a dose of 9 mg/day with mesalazine up to 4.5 g/day, budesonide was not superior to
mesalazine for inducing clinical remission in patients with mildly active CD in the small
and/or large intestine, but clinical response was more frequently seen in patients receiving
Statement 45: Systemic corticosteroids can be used for the induction of remission in active,
moderate-to-severe CD.
A Cochrane systematic review evaluated data from two2 RCTs regarding the efficacy
29
placebo for the treatment of moderately-to-severely active CD. The results indicated that the
with placebo, and corticosteroids were reported to be twice as effective in inducing clinical
Statement 46: We recommend AGAINST using thiopurines monotherapy for the remission
are corticosteroid-dependent.
The pooled analysis of several studies has shown no differences for induction of
remission between thiopurines and placebo (107). Since the quality of evidence is low
regarding the use of thiopurines therapy for the induction of remission and induction of
Statement 47: We recommend biologic therapy for induction and maintenance and induction
Monoclonal antibodies directed against TNF-α are fast-actingfast acting and potent
administered intravenously at a dose of 5 mg/kg at 0-, 2-, and 6-weeks during induction, and
every 8 weeks thereafter. Adalimumab is a fully humanized IgG1 monoclonal antibody given
subcutaneously (SC) at a dose of 160 mg, and then 80 mg 2 weeks after induction, followed
30
α, self-administered SC at a dose of 400 mg at Weeks 0, 2, and 4, followed by 400 mg every
4 weeks thereafter.
pegol) from several meta-analyses of RCTs support their efficacy for induction of clinical
The choice of anti-TNF agent depends on patient preference, availability, cost, and
accessibility. However, a recent study revealed that infliximab with AZA and adalimumab
with an immunosuppressant for induction of clinical remission and response in biologic naïve
CD patients.
One study evaluated the use of combination therapy of adalimumab with thiopurine as
compared with adalimumab monotherapy for the induction of clinical remission in patients
naïve to both therapies. The results showed that combination therapy was not superior to
therapy.
Disease) study compared the efficacy of infliximab combined with AZA over infliximab
monotherapy in patients naïve to both therapies, who failed to respond to steroids or 5-ASA.
with infliximab monotherapy, and was also more likely to result in mucosal healing (113).
31
Statement 50: For moderate to severe CD patients who failed both anti-TNF therapy and/or
Ustekinumab is an IgG1 monoclonal antibody that binds to the p40 subunit shared by
One systematic review and meta-analysis pooled the results from RCTs in which
ustekinumab was compared with placebo for induction of remission in patients with
moderate-to-severe active luminal CD, and the results showed a significant clinical response
Statement 51: For moderate to severe CD patients who failed both anti-TNF therapy and/or
Vedolizumab is a monoclonal IgG1 antibody that acts by blocking the α4β7 integrin
a fixed dose of 300 mg at 0, 2, and 6 weeks for induction, and every 8 weeks thereafter (118).
Several RCTs evaluated the treatment with vedolizumab or placebo, and reported on
induction of clinical response and clinical remission in adult patients with moderate-to-severe
active CD (117, 119, 120). In all these studies, patients treated with vedolizumab had
Statement 52: For moderate to severe CD patients who failed anti-TNF therapy, we
32
active luminal CD who were non-responsive or intolerant to previous anti-TNF agents (121).
The authors reported no significantly different clinical response and clinical remission rates,
Statement 53: Infliximab is recommended as the first choice of biologic to induce and
Infliximab was the first agent shown to be effective in an RCT for inducing closure of
perianal fistulae and for maintaining this response over 1 year (122).
A meta-analysis of the existing data revealed that infliximab was found to be effective
in inducing fistula healing, and in maintaining clinical fistula healing with no significant risk
Statement 54: Adalimumab can be used to induce and maintain remission in complex
A meta-analysis of the current data showed that adalimumab was superior when
compared to placebo for fistula healing after 56 weeks (107). Moreover, the open-label
CHOICE trial demonstrated that complete fistula healing could be achieved in patients who
Statement 55: A combined medical and surgical approach is recommended for patients with
33
There is insufficient evidence to support a decision for or against the use of
Statement 56: We recommend AGAINST using antibiotics for the closure of fistulae in CD
Antibiotics are widely used in the treatment of perianal CD, but most published
studies are uncontrolled (125). Despite the lack of evidence to support their role as
Ulcerative Colitis
Statement 57: Oral and/or topical mesalazine derivatives are recommended as first-line
treatment for the induction and maintenance of remission in mild to moderate UC.
Oral 5-ASA (5-aminosalicylic acid) is the standard therapy for mild to moderately
active UC. Meta-analyses support the efficacy of oral 5-ASA for induction therapy for mild
to moderately active UC (110, 126). Once daily dosing is as effective as divided doses (127).
Doses ≥2 g/day are more effective than dosages <2 g/day for remission (110). The majority of
patients with mild to moderate UC will respond to 2–3 g 5-ASA (depending on formulation
used) and higher doses can be used in those with more severe symptoms or those not
responding initially.
Statement 58: Budesonide MMX or topical and/or oral corticosteroids are recommended for
34
Vote: 100% strongly agreed; high-quality evidence
Randomized controlled trials have shown that oral budesonide MMX 9 mg daily is
significantly more effective than placebo and can induce remission in mild to moderate UC,
corticosteroids to induce remission in UC. If conventional oral corticosteroids are used, the
patient should be advised about common and serious side effects of corticosteroids.
Oral corticosteroids are very effective when used as induction agents, mainly to
concerns. On the short term, side effects such as increased risk of infection, weight gain,
should be considered and relayed to the patient. Furthermore, corticosteroids should never be
used as maintenance agents as its prolonged use is associated with metabolic bone disease,
(132). B
corticosteroids (33% vs 55%), and is not associated with adrenal suppression or a significant
35
Vote: 100% strongly agreed; high-quality evidence
Numerous studies confirm a benefit of thiopurines over placebo for the maintenance
patients from four maintenance studies of azathioprine versus placebo and showed a benefit
The VARSITY trial evaluated patients with moderately to severely active UC who
had failed conventional therapies and were randomized to intravenous vedolizumab 300 mg
at weeks 0, 2 and 6 and then every 8 weeks, versus adalimumab subcutaneously 160 mg at
week 0, 80 mg at week 2, and then 40 mg fortnightly (137). At 52 weeks, the primary end-
point of clinical remission (a complete Mayo score ≤2 with no subscore >1), and mucosal
healing (Mayo endoscopic subscore ≤1) were significantly higher for the vedolizumab group.
These data provide support for vedolizumab as a first-line biologic option for UC
Statement 63: In patients with moderately active UC who have failed conventional therapy,
All of the above-mentioned agents could be used as a treatment for patients with
moderately active UC who have failed conventional therapy, but the choice of drug should be
determined by clinical factors, patient choice, cost, likely adherence and local infusion
capacity (138).
36
Statement 64: We recommend using ustekinumab for inductionnitiation and maintenance of
adults with moderate to severely active UC in adults who had failed to respond or were
vedolizumab (139). Patients were randomized 1:1:1 to receive a single IV dose of placebo,
had a significant clinical remission at week 8, endoscopic healing, and clinical response.
to severely active ulcerative colitisUC among various biologic agents, showed superior
Statement: We recommend AGAINST using Tofacitinib for patients who have a history of
thromboembolic disease, cardiovascular disease, or those ≥50 years old with at least one
Recent data from an open-label study of rheumatoid arthritis patients (over 50 years
with at least one cardiovascular risk factor), comparing tofacitinib 5 mg or 10 mg twice daily
with TNF-inhibitor therapy, have shown a five-fold increase in pulmonary embolus for the
group on 10 mg twice daily tofacitinib compared with TNF inhibitor therapy (141).
It is advisable that the high dose should not be used in patients at increased risk of
pulmonary embolus.
37
Statement 66: We recommend AGAINST methotrexate use to initiate or maintain remission
sulfasalazine and mercaptopurine does not support the role of Methotrexate in the
evaluated patients who were allocated to 25 mg/week parenteral methotrexate versus placebo
alongside prednisolone for a flare of UC, and the results showed that Methotrexate was not
superior to placebo for the primary end-point of steroid-free remission at week 16 (Mayo
score ≤2 with no item >1 and complete withdrawal of steroids and no use of another
In the UC SUCCESS study, patients in whom corticosteroid therapy had failed and
who were receiving infliximab and azathioprine combination therapy had significantly higher
remission rates at week 16, compared with infliximab alone (144). A recent technical review
from AGA supports the association between infliximab and thiopurines for the treatment of
in adult ambulatory patients with moderate to severe UC who have attained remission with
38
There is current no strong evidence that supports the use of 5-ASA continuation for
maintenance of remission in adult ambulatory patients with moderate to severe UC who have
attained remission with use of immunomodulators, and/or biologic agents or tofacitinib (146,
147).
39
Biologics
The use of biologics in moderate to severe UC
availability, cost, risk of infection, presence of extra intestinal manifestations of IBD, and the
Several studies have outlined the following factors as selection criteria for a biological
agent selection: patient preferences, availability, cost, risk of infection, presence of extra
refractory condition.
analyzed. The results showed that all active interventions were superior to placebo for
induction of remission, and for maintenance of remission. Moreover, it was concluded that all
medications were well-toleratedwell tolerated with low rates of serious adverse events (145).
infliximab), ustekinumab or vedolizumab, for adult patients with moderate to severely active
40
We agree with the current recommendations regarding the possible use of the
following biological agents for induce and maintenance of remission in adult patients with
certolizumab pegol), vedolizumab, or ustekinumab for patients with severely active CD who
immunosuppressants or corticosteroids.
moderate to severely active UC in adults who had failed to respond or were intolerant to
Patients were randomized 1:1:1 to receive a single IV dose of placebo, 130 mg ustekinumab,
The VARSITY trial evaluated patients with moderately to severely active UC who had
weeks 0, 2 and 6 and then every 8 weeks, versus adalimumab subcutaneously 160 mg at week
clinical remission, and mucosal healing were significantly higher for the vedolizumab group.
The series of PRECISE studies have shown that Certolizumab pegol offers a rapid
response and sustained response and remission for patients with moderate to severe CD,
regardless of their prior exposure to anti-TNF therapy and concomitant medication use (151-
154).
41
Statement 73: We recommend an early start of biological therapy for patients with CD who
complications, such as colon cancer, hospitalizations, and surgery (155). The AGA Institute
Ulcerative Colitis Clinical Care Pathway (156), suggested that early therapy with a biologic
agent should be considered in patients who have factors associated with high colectomy risk
or worse prognosis. These factors include extensive colitis, deep ulcers, age <40, elevated C-
reactive protein (CRP) and erythrocyte sedimentation rate (ESR), steroid-requiring disease,
infection (156). However, more recent guidelines primarily used disease severity to guide
when biologic therapy is used, which was largely defined by the traditional Truelove-Witts
patients.
evaluated patients with moderate-to-severe CD, naïve to both immunomodulators and anti-
mucosal healing, and an overall better outcome (113). In another study by D’Haens et al., the
42
early combined therapy was superior to conventional therapy for the induction of clinical
remission (158).
and the combined methotrexate-infliximab therapy as an option for inducing and maintaining
remission in active CD and UC patients (159). The results did not support the use of
combined therapy for induction and maintaining remission in CD and UC patients, although
remission in CD (159).
Statement 75: We recommend starting vedolizumab for patients ≥65 years old, patients with
history of a recent infection, and for individuals at higher risk of infection or malignancy. We
recommend using vedolizumab for 2 to 30 weeks for patients with moderate to severe
fistulizing CD.
Several studies have demonstrated significant risks associated with the use of anti-
tumor necrosis factor (anti-TNF) therapies, corticosteroids, and thiopurines for the treatment
of IBD patients such as higher risks of malignancy and opportunistic infections in elderly
patients (161-163). Although the safety profile of vedolizumab is proven by several papers,
limited data exists regarding the safety and efficacy of this drug in older populations (118,
164). However, the patient’s age ≥65 years should not be considered as a contraindication for
vedolizumab administration.
43
A meta-analysis by Bonovas et al., evaluated the risk of infection and malignancy in
adults with IBD treated with various biological agents (165). The authors concluded that
biologic agents increase the risk of opportunistic infections in patients with IBD, but not the
risk of serious infections. Therefore, it is reasonable to accept the use of vedolizumab for
individuals at higher risk of infection or malignancy who are under careful monitorization.
treatment for patients with moderately to severely active CD, who had a history of fistulizing
disease or an active draining fistula (166). After 6 weeks of induction treatment with
vedolizumab (intravenous doses of 300 mg at Weeks 0 and 2), the patients were randomized
to receive either placebo or vedolizumab every 8 weeks or every 4 weeks, and were entered
into a 46-week maintenance phase. The authors found out higher rates of fistula closure and
Sequencing of medications
Statement 76: If disease relapse occurs with vedolizumab therapy, dose-escalation (typically
by shortening dosing interval to every four weeks) should be considered while evaluating for
escalation in a group of patients with UC. Amongst their cohort of 22 patients treated with
vedolizumab with a partial response to standard 8-weekly dosing, almost half were observed
effects pooled efficacy rate of 53.8% (114), and with a small cohort study of 36 dose-
escalated patients with CD or UC, in which a 50% response rate was observed (168).
44
Statement 77: If disease relapse occurs with ustekinumab therapy, dose-escalation (typically
by decreasing the dosing interval to every four weeks) should be considered while evaluating
interval to 4 weeks for patients with CD who did not respond to doses every 8 weeks
improved clinical and biological indices of disease activity, without severe adverse effects
(169).
These results are in accordance with another retrospective study whichstudy, which
evaluated the ustekinumab dose-escalation strategy for selected CD patients who failed to
achieve remission on standard Q8 week regimen. The authors outlined that the dose-
escalation strategy improved clinical outcomes, prevented worsening disease severity, and
Interventions based on therapeutic drug monitoring for patients with IBD and loss of
response to anti-TNF agents
Statement 78: In patients failing anti-TNF therapy, we recommend optimizing the dose,
or vedolizumab, based on serum drug level (trough) and the presence of anti-drug antibodies
(ADAs).
45
The majority of patients treated with anti-tumor necrosis factor (TNF) therapy
develop anti-drug antibodies (ADAs), which might result in loss of treatment efficacy.,
Thiswhich usually occurs within 12 months after the onset of treatment (172). Therefore, the
measurement of anti-TNF antibody trough levels (TL), and the determination of ADA
presence are frequently performed to optimize the management of patients with IBD (173).
The current guidelines recommend optimizing the dose or switching to another anti-
Ustekinumab and vedolizumab are an option for patients who have not achieved
adequate response with anti-TNF agents despite adequate drug concentrations, and can also
In the GEMINI 1 trial of vedolizumab, over 40% of patients with UC were prior TNF
failures. In this study, the response rates at week 6 for vedolizumab vs placebo were 47% vs
25% (118). However, a post-hoc analysis revealed that the rates of response at week 6 were
53% for patients naive to anti-TNF therapy and 39% for patients with prior anti-TNF failure
(175).
In the GEMINI 2 study of vedolizumab in patients with CD, almost half of the cohort
consisted of patients who had previously failed anti-TNF therapy. Week 6 clinical remission
for vedolizumab vs placebo was 14.5% vs 6.8% (117). However, CD patients who had failed
anti-TNF therapy had a rate of remission at week 6 of 15% compared to 12% of patients who
The UNITI-1 trial, which evaluated patients with CD and included a large number of
patients with prior anti-TNF failure, had a week 6 response of 34.3% and 33.7% for patients
treated with 130 mg or 6 mg/kg of ustekinumab, respectively, vs 21.5% for the placebo group
(41). In UNITI-2, in which the majority of patients were naive to treatment, response to
46
treatment was 52.7% and 55.0% for ustekinumab dosing of 130 mg or 6 mg/kg, respectively,
Statement 79: In patients with low serum drug levels and positive ADAs, we recommend
switching to an alternative anti-TNF agent, especially in the presence of high ADA titers.
In patients with low titers of ADAs, drug concentrations may remain high enough to
be effective, while in patients who develop high titers of ADAs, a substantial portion of the
drug will be neutralized, and is likely to produce a clinical non-response over time (176).
Several studied support patients the switch to a different anti-TNF agent for patients
A recent meta-analysis evaluated the efficacy and safety of a second anti-TNF agent
intolerance to a first drug. The efficacy of a second anti-TNF in CD patients largely depends
on the cause for switching. The authors concluded that the remission rate is higher when the
reason to withdraw the first anti-TNF is intolerance (61%), compared with secondary (45%)
Statement 80: Patients with low serum drug levels and negative ADAs require dose
Studies suggest that a low level of drug antibodies, can be overcome by dose-
series of twelve IBD patients who were on infliximab or adalimumab therapy, and were
found to have detectable but low-level antidrug antibodies, dose-escalation of the drug
47
In a recent observational study, the authors evaluated different predictive external
authors identified two models with the highest classification accuracy which indicated dose-
escalations (for trough concentrations < 5 µg/mL) in 88% of cases, thus questioning
Statement 81: Patients who do not respond to anti TNF therapy while having with adequate
serum drug levels and negative ADAs (primary non response (PNR)) require switching
For patients with primary non-response PNR to one anti-TNF, the likelihood that they
will respond to a second is small, and switching to a different class of drugs appears to be
more appropriate. Recent data suggests that drug levels in primary non-respondersPNRs are
often lower than in responders, and antibody formation can be a significant factor within a
48
Chapter 2. Special Patient population
Using of biologics in pregnancy
Statement 82: We recommend that individuals females with active disease or who are high-
risk of disease recurrence to continue their medications during pregnancy. In contrast, those
with inactive disease who choose to cease medication can do so at the beginning of the 3rd
trimester.
Women with an active IBD prior to conception have increased likelihood of adverse
pregnancy outcomes such as premature birth, intrauterine growth restriction, and spontaneous
the fetus, is accepted if there is no significant increase in the risk of disease flare. Several
49
studies on pregnant women with quiescent IBD did not show any increase in risk of flare if
Statement 83: For infants who have been exposed to biologic treatments in utero, we
recommend delaying BCG immunization until at least six months after birth and not giving
Several studies support the use of inactivated vaccines for the immunization of
newborns who were exposed to anti-TNF drugs, vedolizumab and ustekinumab in utero (188,
189).
On the other hand, current data suggests that the BCG vaccine should be deferred to 6
months of age, and rotavirus vaccine should not be given at all (as there is no value in giving
thiopurines, and anti-TNF to maintain remission. Corticosteroids should be reserved for the
treatment of flares.
Over the last two decades, both topical 5-ASAs and non-enteric coated formulations
preparations based on 5-ASA have remained a standard of IBD therapy (193, 194). In a
cohort study, Bell et al., (195) evaluated pregnant patients with distal colitis on maintenance
with topical 5-ASA therapies at the time of conception, and found that 5-ASA was safe and
effective for managing distal colitis during pregnancy. Marteau et al., also conducted a study
in which pregnant IBD patients were monitored while taking between 1-4 g/d of mesalamine
microgranules, and found no serious complications during the course of pregnancy, nor did
50
AZA and 6-MP are pregnancy category “D” drugs, and because of their cytotoxicity,
and potential risk of birth defects, they should be used with great care during pregnancy
(197).
TNF-α inhibitors are currently the most commonly used drugs for the treatment of
IBD in pregnancy, and are considered pregnancy category “B” drugs (188). Biologics like
infliximab and adalimumab cross the placenta, especially during the third trimester (188).
Mahadevan et al., evaluated pregnant patients with IBD being treated with infliximab,
and cord blood with concentrations in the mother’s circulation (198). The levels of infliximab
and adalimumab were elevated in infant and cord blood compared to their respective
maternal levels, with the median level of infliximab in cord blood being 60% higher than that
of the mother.
Statement 85: We recommend using mainly MRI or ultrasound for imaging when required
The main advantage of MRI is the ability to image deep soft tissue structures in a
manner that is less operator- dependent and does not use utilize ionizing radiation, thus
Endoscopy is the most definitive method of monitoring and evaluating IBD’s activity.
However, endoscopic procedures have been theorized to pose a threat to the fetus through the
possibility of intra-procedural maternal hypoxia and hypotension, which can cause fetal
hypoxia and potential demise, thus being preferred in the second trimester if necessary (199).
51
Vote: 100% strongly agreed; high-quality evidence
pregnant patients with reduced mobility, with Fondaparinux being the most utilized
Statement 87: Engaging the multidisciplinary team and the patient in your decision-making
process during pregnancy is recommended, and should include an obstetrician with relevant
experience.
of patients diagnosed with IBD. During pregnancy, the presence of aAn experienced
obstetrician in the MDT is helpful in monitoring the mother’s and fetal wellbeing, and can
Statement 88: Except for active perianal disease as well as an ileocecal anastomosis or
ileoanal pouch (where a CS is usually favored), the delivery mode must be determined by
Perianal disease and ileo-cecal anastomosis are important factors whichfactors, which
can obstruct the mechanism of labourlabor. Therefore,, in these circumstances are impose
delivery through cesarean section rather than vaginally is preferred. Otherwise, the mode of
delivery is dictated by obstetrical factors such as acute fetal distress, fetal dystocia, placental
52
Although not without risk of adverse effects, 5-ASA derivaivatives, thiopurines, and anti-
TNF agents can be used for the treatment of IBD during pregnancy and breastfeeding, as long
with IBD.
therapy have similar risks of infection, and similar milestone achievement at 12 months to
Statement 91: We recommend that pregnant women diagnosed with IBD on oral and/or
Over the last two decades, both topical 5-ASAs and non-enteric coated formulations
preparations based on 5-ASA have remained a standard of IBD therapy (193, 194), and
phthalate-free 5-ASA drugs should be used during pregnancy and breastfeeding (203).
Statement 92: We recommend that pregnant women diagnosed with IBD on thiopurine as a
During pregnancy, the active metabolite 6-thioguanine (6-TG) crosses the placenta, but
the prodrugs AZA and 6-MP do not (204). Recent studies showed no increased risk of
adverse pregnancy outcome in the case of thiopurine use during pregnancy, accordinglyso
53
Statement 93: We recommend continuous usage of anti-TNF maintenance treatment in
A systematic review showed that anti-TNF therapy does not increase the risk of
unfavorable pregnancy outcomes among women with IBD (207). The long-term effects of in
utero exposure to anti-TNF are not extensively explored. A recent study shows a normal
health outcome and first year development in children exposed to anti-TNF, comparable to
Statement 94: We recommend that pregnant women with UC suffering from a mild-to-
moderate flare while on 5-ASA maintenance therapy must modify their combination oral and
remission for pregnant patients suffering from a mild-to-moderate flare while on 5-ASA
symptomatic remission in pregnant women diagnosed with IBD who experience a disease
We agree with general guidelines and support the addition of systemic corticosteroids
IBD who experience a disease flare while on optimum 5-ASA or thiopurine maintenance
therapy (209).
54
Statement 96: We recommend that methotrexate should be stopped at least three months
before pregnancy and until breastfeeding is stopped to avoid detrimental effects on the infant.
abortifacient and has teratogenic effects, such as causing the development of craniofacial
metabolites have a long half-life, methotrexate must be discontinued at least 3 months before
conception.
with suspected IBD before endoscopy. Bacterial infections, such as Clostridium difficile,
Clostridium difficile is more frequently associated with IBD in both adult and pediatric
population with IBD, so it is reasonable to rule out this infection by a microbiological stool
Statement 98: Complete blood count, at least two inflammatory markers (CRP, fecal
calprotectinFC or fecal lactoferrin), albumin, transaminases, and GGT, should all be included
in the initial blood tests. Fecal calprotectinFC correlates with detection of intestinal
55
Multiple blood tests may appear to be abnormal in Ipatient with IBD. Examples
include: complete blood cell count (decreased hemoglobin or elevated total white cell count
and platelet count), serum albumin (decreased), and inflammatory markers such as CRP and
Data from pediatric IBD registries indicate that at the time of diagnosis 54% of
children with mild UC and 21% of children with mild CD have normal results for the
The most important fecal surrogate markers for detection of inflammation at diagnosis
include FC and lactoferrin, both being important tools for identifying the presence of
pediatric patients with CD, whereas only 86% of the patients had an increased CRP and 83%
an elevated ESR (67). The combination of any 2 of these 3 markers appears to possess a
marker for intestinal inflammation, and discriminate IBD from other extraintestinal
case-control study of FC, area under the receiver operating characteristic curve of FC to
diagnose IBD was 0.93, considerably higher than the AUC of blood inflammatory markers
(218).
Statement 99: All children with suspected IBD should have an ileo-colonoscopy and an
56
Ileo-colonoscopy (and biopsies) is the most essential part of the diagnostic workup in
that ‘‘multiple’’ biopsies from 5 sites around the colon (including the rectum), and the ileum
should be taken, and a minimum of 2 samples from each of these sites should be obtained for
Thus, an EGD is recommended as part of the initial evaluation of children with suspected
IBD, regardless of upper GI symptoms (220). Upper endoscopy is also useful in evaluation
for celiac disease which can have a similar presentation to IBD in both the adult and pediatric
populations (221).
Statement 100: Even if there are no macroscopic abnormalities, multiple biopsies (2 or more
per section) should be taken from all parts of the accessible gastrointestinal tract.
importance of minimum 2 samples obtained through biopsy from 5 sites around the colon,
and the ileum, even though no macroscopic abnormalities are identified on endoscopic
examination (185).
Statement 101: At the time of diagnosis, we recommend using MRE over CT scan and
fluoroscopy as the imaging technique of choice in pediatric IBD because of its excellent
MRI is the preferred test for imaging the small bowel at diagnosis because it can
detect changes that are characteristic of IBD, and estimate both the extent of intestinal
57
inflammation and the degree of damage (strictures or penetrating disease). It has the
IBD has confirmed that MRE is sensitive and specific for diagnosis of PIBD and that it
should supersede conventional fluoroscopy as the small bowel imaging technique in centers
with appropriate expertise (222). The pooled sensitivity and specificity in this study for MRE
Pelvic MRI is recommended for the evaluation of patients with CD with suspected or
proven perianal involvement, allowing evaluation of extent and location of perianal fistulas
and abscesses, thus providing critical information for both surgical management and for
Statement 102: VCE is an alternative option for identifying small intestinal mucosal lesions
Wireless VCE is the best alternative to MRE for investigating the SB, and it detects
mucosal abnormalities. The main advantages of WCE are the ability to visualize the entire
SB with minimal discomfort, and to detect mucosal lesions with a higher sensitivity than
MRE (224). In a meta-analysis in PIBD, the diagnostic yield for WCE ranged from 58% to
72% (225).
severe disease with systemic features, and children <1 year (226, 227).
Statement 103: SBUS is a useful screening technique in the initial diagnostic workup of
pediatric patients with suspected IBD, but because of its low sensitivity, it should be
58
Vote: 100% strongly agreed; moderate-quality evidence
SBUS accurately detects, locates, and characterizes inflammation of the bowel wall
and assesses peri-intestinal abnormalities, with a good negative predictive value for IBD,
detecting CD lesions at the terminal ileum have shown an overall sensitivity and specificity
Statement 104: All patients with infantile IBD presenting in the first two years of life should
It appears that patients with very early onset of IBD, until the first 2 years of life, may
have an underlying genetic basis (231). A large proportion of monogenic etiologies reflect
The evaluation of primary immune deficiencies in patients with IBD is complex, and
of IBD in children, genetic testing, analysis of immunoglobulin classes (IgA, IgG, IgM, IgE),
Statement 105: We recommend using the PUCAI in children with UC to monitor disease
activity at each visit, and to consider reviewing therapy whenever the PUCAI ≥ 10 points.
59
We agree with the Guideline from the European Crohn’s and Colitis Organization and
using the PUCAI in children with UC to monitor disease activity at each visit, and to consider
substantial treatment changes, for cancer surveillance, and when symptoms may not be
disease-related, and if fecal calprotectin is high; however, it is not usually indicated during
many studies. It allows initial and differential diagnosis, and, even though gastrointestinal
malignancies are rare in the pediatric group, could be used for cancer surveillance, especially
High fecal calprotectin levels correlate well with endoscopic disease activity, so it is
advisable to perform an ileo-colonoscopy with biopsy when this marker is increased (238).
Medical Management of UC
ASA and Enemas
Statement 108: For mild-to-moderate UC, oral 5-ASA is suggested as first-line approach to
induceitiate and maintain clinical remission. Rectal and oral 5-ASA combination treatment is
60
Current evidence supports the use of 5-ASA for induction and maintenance of
the PUCAI score (240, 241). In another pediatric RCT, low versus higher dose balsalazide
induced remission in 9%versus 12% of children, respectively (242). Combining oral and
corticosteroids.
suppositories (0.5 g daily) were associated with improved disease activity at 3 and 6 weeks in
Oral Corticosteroids
moderate UC with no response to 5-ASA treatments, and as a first-line treatment for patient
Several studies that evaluated the use of oral steroids for treating children with active
treated for 8 weeks with steroids or 5-ASA, the authors reported that 87% had clinical
61
remission, 40% of patients achieved endoscopic remission, and 15% of patients obtained
Statement 111: In children with mild disease not responding to 5-ASA, second-generation
oral steroids such as budesonide-MMX and beclomethasone dipropionate (BDP) may be tried
before oral prednisolone. The use of budesonide-MMX is preferable for left-sided colitis.
patients (112).
prednisolone and mesalamine (185, 249), but there is limited data regarding its efficacy in
pediatric patients.
An RCT that evaluated children with mild-to-moderate UC showed that oral BDP, 5
mg/day for 4 weeks, was more effective than 5- ASA in achieving both clinical and
relapsing disease.
Higher steroid dependency rates were reported in pediatric population when compared
ASA, adjuvant therapy with enemas, and a change of therapy to thiopurines or biologic
agents.
62
Immunosuppressants
yearly) while receiving optimum 5-ASA therapy. Thiopurines should be considered after
Few studied have evaluated the efficacy of thiopurines for both induction and
maintenance o
remission rates of 49% at 1 year (253) and 72% at 2 years (254) in thiopurine-treated
children, with no difference in either clinical or endoscopic end-points between early or late
initiation of treatment. A few retrospective studies (255, 256) in children supported the
benefit of thiopurines in maintaining remission and steroid sparing, with a median time to
Statement 114: Induction of remission with thiopurines is not recommended in children with
UC.
Limited data does not support the use of thiopurines as an induction of remission
Statement 115: Patients with an inadequate response to steady thiopurine dose, leucopenia or
63
Several studies supported the idea of testing for TMPT in order to prevent
dosing (259-261).
Biologics
thiopurines.
children with moderate-severe UC (262). The response rate to infliximab was 75% (45/ of 60
patients). Both clinical remission (PUCAI < 10 points) and complete mucosal healing (Mayo
Different studies in children have shown a pooled long-term success rate of IFX in
UC of 64% (263), and a corticosteroid-free remission of 38% and 21% at 12 and 24 months,
respectively (253).
Statement 116: Based on serum drug levels and anti-drug antibodyADA concentration,
infliximab (secondary non response) or are intolerant to infliximab. In patients who lack
64
A meta-analysis that evaluated the TNF inhibitors for moderate-to-severe adult UC
suggested that while infliximab is more effective than adalimumab in the induction of
remission, response and mucosal healing, both are comparable in efficacy (264).
switched to adalimumab after infliximab failure, achieved and maintained clinical remission
with moderate-severe UC (267). Among week 6 Mayo clinical responders (60%) who
week 14.
vedolizumab as second-line biologics in IBD patients concluded that the effectiveness and
safety of second-line anti-TNF and vedolizumab at 12 months appeared largely similar (268).
Nonetheless, drug and antibody levels should dictate the course of action in patients
with secondary loss of response. Ongoing symptoms despite adequate drug levels, mandates
switching therapy, while high antibodies titer predicts failure of dose intensification (269).
Statement 117
Statement 119: Patients on anti- TNF therapy (infliximab and adalimumab) with a high anti-
drug antibodyADA level should be switched to another biologic therapy within the same
treatment class when available. In the absence of alternatives from the same class, switching
65
Vote: 100% strongly agreed; high-quality evidence
and CD in patients who have failed at least 1 other agent. The GEMINI 3 study of
vedolizumab in patients with CD who had previously failed at least 1 other anti-TNF α agent
found that at week 10 of treatment, a higher proportion of patients given vedolizumab were in
Afif et al., reported that among patients who tested positive for antibodies to
infliximab, 92% (11/12) had a complete or partial response after changing to another anti-
Several studies support the idea of switching to a different biologic class if another
anti- TNF agent is unavailable, and the patients have high anti-drug antibodyADA levels
(272, 273).
Statement 120: During biological therapy, patients should be monitored for TB contact
history, suggestive manifestations, and indications of active TB. Chest x-ray and IGRA may
be performed yearly.
therapy (96), as suchso it must be excluded before the treatment’s initiation using standard
diagnosis protocol, which includes chest radiography and a purified protein derivative (PPD)
66
Pediatric patients in clinical, biochemical, and endoscopic remission are more likely
Reintroduction of the same treatment is usually, but not always, successful and close clinical
with subclinical disease activity are at much higher risk of relapse when any treatment is
Statement 122
Statement 123: IBD patients should be tested for hepatitis B virus, hepatitis C virus, and
varicella-zoster virus (without any history of varicella immunization, chicken pox or shingles
biological therapy.
only after screening of hepatitis B, hepatitis C, and varicella-zoster viruses, in order to avoid
67
Vote: 100% strongly agreed; high-quality evidence
Several studies provided data on the use of 5-ASA in mild to moderate active CD
(278-280). These analyses included studies using various formulations and doses of non-
sulfasalazine 5-ASAs (i.e., mesalamine and olsalazine), and generally reported no benefit
The data did not assess mild and moderate disease separately, and no RCTs in
pediatric patients were found, so it is reasonable not to use 5-ASA agents to induce clinical
The data is scarce regarding the efficacy of sulfasalazine in CD. Some studies have
indicated that sulfasalazine has a marginal benefit over placebo from a clinical remission
No RCTs were found in pediatric patients, and while mild disease was analyzed
remission of CD (278, 281). Sulfasalazine was not effective in preventing relapse of CD, but
there was a non-significant trend toward improvement over placebo with mesalamine.
68
Corticosteroids
children, but approximately half of the patients will become dependent on corticosteroids or
remission in children with mild-to-moderate active CD who failed 5-ASA, sulfasalazine, oral
Corticosteroids continue to be the basic treatment to control acute disease that has not
responded to first line therapy (i.e., 5-ASA) (283). Conventional corticosteroid therapy is
commonly used for the short-term treatment of moderate to severe symptoms, and is typically
used for achieving a quick relief of symptoms. It is important to minimize the use of
As for the failure of exclusive enteral nutrition, the data is scarce, but it seems that
Data from several small studies comparing treatment with prednisone to budesonide
prednisone may be more effective for inducing remission in patients who failed budesonide
therapy.
69
Statement 129: We suggest AGAINST use of corticosteroids to maintain clinical remission
corticosteroid therapy compared to placebo (288). Due to the lack of demonstrated efficacy in
preventing relapse, and concerns around the adverse events associated with long-term use,
particularly in children, we agreed that corticosteroids should not be used to maintain clinical
Statement 130: We suggest inducing clinical remission in pediatric patients with CD using
Statement 131: Partial enteral nutrition is not allowed to trigger clinical remission in
pediatric patients with CD. It should only be as an adjunctive to medications that maintain
clinical remission.
In one RCT that evaluated children with active CD, partial enteral nutrition was less
effective than total enteral nutrition for the induction of clinical remission (289). Similarly, in
a recent multicenter North American study, patients allowed 20% of total calories as regular
food actually consumed 50% of calories as such, and were less likely to achieve either
clinical remission or reduction in fecal calprotectin compared with those receiving exclusive
132
Immunosuppressants
70
Statement 133: We recommend AGAINST using thiopurine alone to induce clinical
remission in children with CD of any severity. In female patients with CD, we suggest
292).
maintaining remission over 6–18 months (134). One additional small RCT withdrawal trial,
published after the meta-analyses, also reported a reduction in risk of relapse with ongoing
A small RCT found that, in children receiving corticosteroid therapy, the addition of
6-mercaptopurine was associated with a lower rate of relapse compared to adjunctive placebo
at 18 months (294).
using genotyping (295, 296) or enzymatic activity (297), compared to no testing before
initiating thiopurine therapy to individualize dosing. Among the 1145 patients included, only
2 (0.17%) patients were homozygous, and 150 (13.1%) were heterozygous for variant alleles
While most patients with leukopenia in the largest study did not have reduced
enzymatic activity, individuals with TPMT mutations and low or intermediate enzymatic
71
activity had a significant reduction in the risk of hematologic adverse events with TPMT
remission using thiopurines or methotrexate within the first year to judge the need for
treatment modification.
observational studies, long-term remission rates were 37% to 62% at 6 months, and 25% to
higher rates of long-term remission for up to 3 years compared to ongoing active endoscopic
disease (300). Rates of mucosal healing with anti-TNF therapy (27%‒31%) were higher than
For induction therapy, a meta-analysis found that anti-TNF therapy alone or with
concomitant therapies was significantly more effective than placebo for the outcome of
failure to achieve symptomatic remission (278). Results were significant for infliximab and
adalimumab, but not certolizumab pegol. For maintenance therapy, another meta-analysis
72
showed that anti-TNF therapy significantly reduced the risk of relapse in patients with CD in
clinical remission compared to placebo. Results were significant for infliximab and
to thiopurine or methotrexate.
Statement 138: We suggest anti-TNF therapy as first-line treatment to induce and maintain
clinical remission in children with severe inflammatory CD at higher risk for progressive and
complicated disease.
Additional support for the early use of anti-TNF therapy comes from two prospective
treatment naïve patients (158, 305). In these studies, the “top-down” treatment was associated
with significantly higher rates of symptomatic remission at earlier time points compared to
Statement 139: We recommend combining Infliximab with immunosuppressants for the first
4 to 6 months of therapy.
We agree with the recent European guidelines for treatment of pediatric UC, which
73
Statement 140: We suggest AGAINST combining adalimumab with immunosuppressants in
The DIAMOND RCT evaluated adult patients who were immunosuppressant- and
biologic-naïve, and found no difference in 26-week clinical remission rates between the
(71.8%) (306).
Similarly, post-hoc analyses of cohort data from RCTs in adults did not show a
therapy in male children with CD. We suggest using parenteral methotrexate instead.
The COMMIT study compared the efficacy of combination therapy with infliximab
the combination treatment group (309). Overall combination therapy with infliximab plus an
immunosuppressant was not associated with a benefit over infliximab alone in preventing
(TDM) in children with CD with poor clinical response to anti-TNF induction treatment or
74
Several studies have demonstrated that antibodies to anti-TNFs were associated with
greater likelihood of loss of response, and higher serum anti-TNF levels were associated with
In a retrospective case series of pediatric patients with IBD, those with very low
infliximab drug levels had high rates of infliximab antibodies, non-response, or loss of
response (313).
Two RCTs assessed the use of ustekinumab as maintenance therapy in patients who
significantly increased rates of clinical remission at 22 weeks compared with placebo (41.7%
In the combined population in the UNITI-IM trial, significantly more patients were in
Conclusions:
75
References:
76
11. Chen P, Zhou G, Lin J, Li L, Zeng Z, Chen M, et al. Serum Biomarkers for Inflammatory
Bowel Disease. Front Med (Lausanne). 2020;7:123.
12. Mirkov MU, Verstockt B, Cleynen I. Genetics of inflammatory bowel disease: beyond
NOD2. The lancet Gastroenterology & hepatology. 2017;2(3):224-34.
13. Gisbert JP, Bermejo F, Pérez-Calle J-L, Taxonera C, Vera I, McNicholl AG, et al. Fecal
calprotectin and lactoferrin for the prediction of inflammatory bowel disease relapse.
Inflammatory bowel diseases. 2009;15(8):1190-8.
14. Von Roon AC, Karamountzos L, Purkayastha S, Reese GE, Darzi AW, Teare JP, et al.
Diagnostic precision of fecal calprotectin for inflammatory bowel disease and colorectal
malignancy. Official journal of the American College of Gastroenterology| ACG.
2007;102(4):803-13.
15. Schoepfer AM, Beglinger C, Straumann A, Trummler M, Renzulli P, Seibold F.
Ulcerative colitis: correlation of the Rachmilewitz endoscopic activity index with fecal
calprotectin, clinical activity, C-reactive protein, and blood leukocytes. Inflammatory bowel
diseases. 2009;15(12):1851-8.
16. Vinding KK, Elsberg H, Thorkilgaard T, Belard E, Pedersen N, Elkjaer M, et al. Fecal
calprotectin measured by patients at home using smartphones—a new clinical tool in
monitoring patients with inflammatory bowel disease. Inflammatory bowel diseases.
2016;22(2):336-44.
17. Langner C, Magro F, Driessen A, Ensari A, Mantzaris GJ, Villanacci V, et al. The
histopathological approach to inflammatory bowel disease: a practice guide. Virchows
Archiv. 2014;464(5):511-27.
18. Lin WC, Chang CW, Chen MJ, Hsu TC, Wang HY. Effectiveness of sigmoidoscopy for
assessing ulcerative colitis disease activity and therapeutic response. Medicine (Baltimore).
2019;98(21):e15748.
19. Spiceland CM, Lodhia N. Endoscopy in inflammatory bowel disease: Role in
diagnosis, management, and treatment. World J Gastroenterol. 2018;24(35):4014-20.
20. Passos MAT, Chaves FC, Chaves-Junior N. THE IMPORTANCE OF COLONOSCOPY IN
INFLAMMATORY BOWEL DISEASES. Arq Bras Cir Dig. 2018;31(2):e1374-e.
21. Magro F, Langner C, Driessen A, Ensari A, Geboes K, Mantzaris GJ, et al. European
consensus on the histopathology of inflammatory bowel disease☆. Journal of Crohn's and
Colitis. 2013;7(10):827-51.
22. Bitton A, Peppercorn MA, Antonioli DA, Niles JL, Shah S, Bousvaros A, et al. Clinical,
biological, and histologic parameters as predictors of relapse in ulcerative colitis.
Gastroenterology. 2001;120(1):13-20.
23. Flynn S, Eisenstein S. Inflammatory Bowel Disease Presentation and Diagnosis. Surg
Clin North Am. 2019;99(6):1051-62.
24. Liu W, Liu J, Xiao W, Luo G. A Diagnostic Accuracy Meta-analysis of CT and MRI for
the Evaluation of Small Bowel Crohn Disease. Academic Radiology. 2017;24(10):1216-25.
25. Gallego JC, Echarri A. Role of magnetic resonance imaging in the management of
perianal Crohn's disease. Insights Imaging. 2018;9(1):47-58.
26. Sahni VA, Ahmad R, Burling D. Which method is best for imaging of perianal fistula?
Abdom Imaging. 2008;33(1):26-30.
27. Raman SP, Horton KM, Fishman EK. Computed tomography of Crohn's disease: The
role of three dimensional technique. World J Radiol. 2013;5(5):193-201.
28. Calabrese E, Maaser C, Zorzi F, Kannengiesser K, Hanauer SB, Bruining DH, et al.
Bowel Ultrasonography in the Management of Crohn's Disease. A Review with
77
Recommendations of an International Panel of Experts. Inflamm Bowel Dis.
2016;22(5):1168-83.
29. Magro F, Gionchetti P, Eliakim R, Ardizzone S, Armuzzi A, Barreiro-de Acosta M, et al.
Third European Evidence-based Consensus on Diagnosis and Management of Ulcerative
Colitis. Part 1: Definitions, Diagnosis, Extra-intestinal Manifestations, Pregnancy, Cancer
Surveillance, Surgery, and Ileo-anal Pouch Disorders. Journal of Crohn's and Colitis.
2017;11(6):649-70.
30. Fine KD, Schiller LR. AGA technical review on the evaluation and management of
chronic diarrhea. Gastroenterology. 1999;116(6):1464-86.
31. D'Aoust J, Battat R, Bessissow T. Management of inflammatory bowel disease with
Clostridium difficile infection. World J Gastroenterol. 2017;23(27):4986-5003.
32. Mylonaki M, Langmead L, Pantes A, Johnson F, Rampton DS. Enteric infection in
relapse of inflammatory bowel disease: importance of microbiological examination of stool.
Eur J Gastroenterol Hepatol. 2004;16(8):775-8.
33. Masclee GM, Penders J, Jonkers DM, Wolffs PF, Pierik MJ. Is clostridium difficile
associated with relapse of inflammatory bowel disease? results from a retrospective and
prospective cohort study in the Netherlands. Inflamm Bowel Dis. 2013;19(10):2125-31.
34. Gryboski JD. Clostridium difficile in inflammatory bowel disease relapse. J Pediatr
Gastroenterol Nutr. 1991;13(1):39-41.
35. Berg AM, Kelly CP, Farraye FA. Clostridium difficile infection in the inflammatory
bowel disease patient. Inflamm Bowel Dis. 2013;19(1):194-204.
36. Heidari H, Sedigh Ebrahim-Saraie H, Amanati A, Motamedifar M, Hadi N, Bazargani A.
Toxin profiles and antimicrobial resistance patterns among toxigenic clinical isolates of
Clostridioides (Clostridium) difficile. Iran J Basic Med Sci. 2019;22(7):813-9.
37. Leighton JA, Shen B, Baron TH, Adler DG, Davila R, Egan JV, et al. ASGE guideline:
endoscopy in the diagnosis and treatment of inflammatory bowel disease. Gastrointestinal
endoscopy. 2006;63(4):558-65.
38. Kedia S, Das P, Madhusudhan KS, Dattagupta S, Sharma R, Sahni P, et al.
Differentiating Crohn's disease from intestinal tuberculosis. World J Gastroenterol.
2019;25(4):418-32.
39. Liu Y-Y, Chen M-K, Cao Z, Liu S-Z, Ding B-J. Differential diagnosis of intestinal
tuberculosis from Crohn's disease and primary intestinal lymphoma in China. Saudi J
Gastroenterol. 2014;20(4):241-7.
40. Du J, Ma Y-Y, Xiang H, Li Y-M. Confluent granulomas and ulcers lined by epithelioid
histiocytes: new ideal method for differentiation of ITB and CD? A meta analysis. PLoS One.
2014;9(10):e103303-e.
41. Feagan BG, Sandborn WJ, Gasink C, Jacobstein D, Lang Y, Friedman JR, et al.
Ustekinumab as Induction and Maintenance Therapy for Crohn's Disease. N Engl J Med.
2016;375(20):1946-60.
42. Bae J, Park sh, Ye B, Kim S, Cho Y, Youn E, et al. Development and Validation of a
Novel Prediction Model for Differential Diagnosis Between Crohn's Disease and Intestinal
Tuberculosis. Inflammatory bowel diseases. 2017;23.
43. Jin XJ, Kim JM, Kim HK, Kim L, Choi SJ, Park IS, et al. Histopathology and TB-PCR kit
analysis in differentiating the diagnosis of intestinal tuberculosis and Crohn's disease. World
J Gastroenterol. 2010;16(20):2496-503.
78
44. Annunziata ML, Caviglia R, Papparella LG, Cicala M. Upper gastrointestinal
involvement of Crohn’s disease: a prospective study on the role of upper endoscopy in the
diagnostic work-up. Digestive diseases and sciences. 2012;57(6):1618-23.
45. Rutgeerts P, Onette E, Vantrappen G, Geboes K, Broeckaert L, Talloen L. Crohn's
disease of the stomach and duodenum: a clinical study with emphasis on the value of
endoscopy and endoscopic biopsies. Endoscopy. 1980;12(06):288-94.
46. Kopylov U, Yung DE, Engel T, Vijayan S, Har-Noy O, Katz L, et al. Diagnostic yield of
capsule endoscopy versus magnetic resonance enterography and small bowel contrast
ultrasound in the evaluation of small bowel Crohn’s disease: systematic review and meta-
analysis. Digestive and Liver Disease. 2017;49(8):854-63.
47. Triester SL, Leighton JA, Leontiadis GI, Gurudu SR, Fleischer DE, Hara AK, et al. A
meta-analysis of the yield of capsule endoscopy compared to other diagnostic modalities in
patients with non-stricturing small bowel Crohn's disease. Official journal of the American
College of Gastroenterology| ACG. 2006;101(5):954-64.
48. Van Weyenberg SJ, Bouman K, Jacobs MA, Halloran BP, Van der Peet DL, Mulder CJ,
et al. Comparison of MR enteroclysis with video capsule endoscopy in the investigation of
small-intestinal disease. Abdominal imaging. 2013;38(1):42-51.
49. Nemeth A, Kopylov U, Koulaouzidis A, Johansson GW, Thorlacius H, Amre D, et al.
Use of patency capsule in patients with established Crohn’s disease. Endoscopy.
2016;48(04):373-9.
50. Mow WS, Lo SK, Targan SR, Dubinsky MC, Treyzon L, Abreu-Martin MT, et al. Initial
experience with wireless capsule enteroscopy in the diagnosis and management of
inflammatory bowel disease. Clinical Gastroenterology and Hepatology. 2004;2(1):31-40.
51. Monteiro S, de Castro FD, Carvalho PB, Rosa B, Moreira MJ, Pinho R, et al. Essential
role of small bowel capsule endoscopy in reclassification of colonic inflammatory bowel
disease type unclassified. World journal of gastrointestinal endoscopy. 2017;9(1):34.
52. Hellers G, Bergstrand O, Ewerth S, Holmström B. Occurrence and outcome after
primary treatment of anal fistulae in Crohn's disease. Gut. 1980;21(6):525-7.
53. Sandborn WJ, Fazio VW, Feagan BG, Hanauer SB. AGA technical review on perianal
Crohn’s disease. Gastroenterology. 2003;125(5):1508-30.
54. Regueiro M. The role of endoscopy in the evaluation of fistulizing Crohn's disease.
Gastrointestinal Endoscopy Clinics. 2002;12(3):621-33.
55. Silverberg MS, Satsangi J, Ahmad T, Arnott ID, Bernstein CN, Brant SR, et al. Toward
an integrated clinical, molecular and serological classification of inflammatory bowel
disease: report of a Working Party of the 2005 Montreal World Congress of
Gastroenterology. Can J Gastroenterol. 2005;19 Suppl A:5a-36a.
56. Spekhorst LM, Visschedijk MC, Alberts R, Festen EA, van der Wouden E-J, Dijkstra G,
et al. Performance of the Montreal classification for inflammatory bowel diseases. World J
Gastroenterol. 2014;20(41):15374-81.
57. Levine A, Griffiths A, Markowitz J, Wilson DC, Turner D, Russell RK, et al. Pediatric
modification of the Montreal classification for inflammatory bowel disease: the Paris
classification. Inflamm Bowel Dis. 2011;17(6):1314-21.
58. Dotson JL, Crandall WV, Zhang P, Forrest CB, Bailey LC, Colletti RB, et al. Feasibility
and validity of the pediatric ulcerative colitis activity index in routine clinical practice. J
Pediatr Gastroenterol Nutr. 2015;60(2):200-4.
79
59. Zittan E, Kabakchiev B, Kelly OB, Milgrom R, Nguyen GC, Croitoru K, et al.
Development of the Harvey-Bradshaw Index-pro (HBI-PRO) Score to Assess Endoscopic
Disease Activity in Crohn's Disease. J Crohns Colitis. 2017;11(5):543-8.
60. Harvey RF, Bradshaw JM. A simple index of Crohn's-disease activity. Lancet.
1980;1(8167):514.
61. Daperno M, D'Haens G, Van Assche G, Baert F, Bulois P, Maunoury V, et al.
Development and validation of a new, simplified endoscopic activity score for Crohn's
disease: the SES-CD. Gastrointest Endosc. 2004;60(4):505-12.
62. Lewis JD, Chuai S, Nessel L, Lichtenstein GR, Aberra FN, Ellenberg JH. Use of the
noninvasive components of the Mayo score to assess clinical response in ulcerative colitis.
Inflamm Bowel Dis. 2008;14(12):1660-6.
63. Turner D, Otley AR, Mack D, Hyams J, de Bruijne J, Uusoue K, et al. Development,
validation, and evaluation of a pediatric ulcerative colitis activity index: a prospective
multicenter study. Gastroenterology. 2007;133(2):423-32.
64. Turner D, Seow CH, Greenberg GR, Griffiths AM, Silverberg MS, Steinhart AH. A
systematic prospective comparison of noninvasive disease activity indices in ulcerative
colitis. Clin Gastroenterol Hepatol. 2009;7(10):1081-8.
65. Turner D, Mack D, Leleiko N, Walters TD, Uusoue K, Leach ST, et al. Severe pediatric
ulcerative colitis: a prospective multicenter study of outcomes and predictors of response.
Gastroenterology. 2010;138(7):2282-91.
66. Hyams JS, Ferry GD, Mandel FS, Gryboski JD, Kibort PM, Kirschner BS, et al.
Development and validation of a pediatric Crohn's disease activity index. J Pediatr
Gastroenterol Nutr. 1991;12(4):439-47.
67. Shaoul R, Sladek M, Turner D, Paeregaard A, Veres G, Wauters GV, et al. Limitations
of fecal calprotectin at diagnosis in untreated pediatric Crohn's disease. Inflamm Bowel Dis.
2012;18(8):1493-7.
68. Otley A, Loonen H, Parekh N, Corey M, Sherman PM, Griffiths AM. Assessing activity
of pediatric Crohn's disease: which index to use? Gastroenterology. 1999;116(3):527-31.
69. Grant A, Lerer T, Griffiths AM, Hyams JS, Otley A. Assessing disease activity using the
pediatric Crohn's disease activity index: Can we use subjective or objective parameters
alone? World J Gastroenterol. 2021;27(30):5100-11.
70. Higgins P, Schwartz M, Mapili J, Krokos I, Leung J, Zimmermann E. Patient defined
dichotomous end points for remission and clinical improvement in ulcerative colitis. Gut.
2005;54(6):782-8.
71. Samaan MA, Mosli MH, Sandborn WJ, Feagan BG, D'Haens GR, Dubcenco E, et al. A
systematic review of the measurement of endoscopic healing in ulcerative colitis clinical
trials: recommendations and implications for future research. Inflammatory bowel diseases.
2014;20(8):1465-71.
72. Neurath MF, Travis SP. Mucosal healing in inflammatory bowel diseases: a
systematic review. Gut. 2012;61(11):1619-35.
73. Bryant RV, Costello SP, Schoeman S, Sathananthan D, Knight E, Lau SY, et al. Limited
uptake of ulcerative colitis “treat‐to‐target” recommendations in real‐world practice.
Journal of gastroenterology and hepatology. 2018;33(3):599-607.
74. Bryant R, Winer S, SPL T, Riddell R. Systematic review: histological remission in
inflammatory bowel disease. Is ‘complete’remission the new treatment paradigm? An IOIBD
initiative. Journal of Crohn's and Colitis. 2014;8(12):1582-97.
80
75. Ardizzone S, Cassinotti A, Duca P, Mazzali C, Penati C, Manes G, et al. Mucosal
healing predicts late outcomes after the first course of corticosteroids for newly diagnosed
ulcerative colitis. Clinical Gastroenterology and Hepatology. 2011;9(6):483-9. e3.
76. Meucci G, Fasoli R, Saibeni S, Valpiani D, Gullotta R, Colombo E, et al. Prognostic
significance of endoscopic remission in patients with active ulcerative colitis treated with
oral and topical mesalazine: a prospective, multicenter study. Inflammatory bowel diseases.
2012;18(6):1006-10.
77. Peyrin-Biroulet L, Sandborn W, Sands B, Reinisch W, Bemelman W, Bryant R, et al.
Selecting therapeutic targets in inflammatory bowel disease (STRIDE): determining
therapeutic goals for treat-to-target. Official journal of the American College of
Gastroenterology| ACG. 2015;110(9):1324-38.
78. Turner D, Ricciuto A, Lewis A, D'Amico F, Dhaliwal J, Griffiths AM, et al. STRIDE-II: An
Update on the Selecting Therapeutic Targets in Inflammatory Bowel Disease (STRIDE)
Initiative of the International Organization for the Study of IBD (IOIBD): Determining
Therapeutic Goals for Treat-to-Target strategies in IBD. Gastroenterology.
2021;160(5):1570-83.
79. Hyams J, Markowitz J, Otley A, Rosh J, Mack D, Bousvaros A, et al. Evaluation of the
pediatric crohn disease activity index: a prospective multicenter experience. Journal of
pediatric gastroenterology and nutrition. 2005;41(4):416-21.
80. Kundhal P, Critch J, Zachos M, Otley A, Stephens D, Griffiths A. Pediatric Crohn
Disease Activity Index: responsive to short-term change. Journal of pediatric
gastroenterology and nutrition. 2003;36(1):83-9.
81. Fabiszewska S, Derda E, Szymanska E, Osiecki M, Kierkus J. Safety and Effectiveness
of Vedolizumab for the Treatment of Pediatric Patients with Very Early Onset Inflammatory
Bowel Diseases. J Clin Med. 2021;10(13).
82. Aloi M, Di Nardo G, Conte F, Mazzeo L, Cavallari N, Nuti F, et al. Methotrexate in
paediatric ulcerative colitis: a retrospective survey at a single tertiary referral centre.
Alimentary Pharmacology & Therapeutics. 2010;32(8):1017-22.
83. Tajiri H, Arai K, Kagimoto S, Kunisaki R, Hida N, Sato N, et al. Infliximab for pediatric
patients with ulcerative colitis: a phase 3, open-label, uncontrolled, multicenter trial in
Japan. BMC Pediatr. 2019;19(1):351.
84. Haisma S-M, Verkade HJ, Scheenstra R, van der Doef HPJ, Bodewes FAJA, van
Rheenen PF. Time-to-reach Target Calprotectin Level in Newly Diagnosed Patients With
Inflammatory Bowel Disease. Journal of Pediatric Gastroenterology and Nutrition.
2019;69(4):466-73.
85. Heida A, Park KT, van Rheenen PF. Clinical Utility of Fecal Calprotectin Monitoring in
Asymptomatic Patients with Inflammatory Bowel Disease: A Systematic Review and Practical
Guide. Inflamm Bowel Dis. 2017;23(6):894-902.
86. Boschetti G, Garnero P, Moussata D, Cuerq C, Préaudat C, Duclaux-Loras R, et al.
Accuracies of serum and fecal S100 proteins (calprotectin and calgranulin C) to predict the
response to TNF antagonists in patients with Crohn's disease. Inflamm Bowel Dis.
2015;21(2):331-6.
87. Guidi L, Marzo M, Andrisani G, Felice C, Pugliese D, Mocci G, et al. Faecal calprotectin
assay after induction with anti-Tumour Necrosis Factor α agents in inflammatory bowel
disease: Prediction of clinical response and mucosal healing at one year. Dig Liver Dis.
2014;46(11):974-9.
81
88. Ripollés T, Paredes JM, Martínez-Pérez MJ, Rimola J, Jauregui-Amezaga A, Bouzas R,
et al. Ultrasonographic changes at 12 weeks of anti-TNF drugs predict 1-year sonographic
response and clinical outcome in Crohn's disease: a multicenter study. Inflammatory bowel
diseases. 2016;22(10):2465-73.
89. Kucharzik T, Wittig BM, Helwig U, Börner N, Rössler A, Rath S, et al. Use of intestinal
ultrasound to monitor Crohn’s disease activity. Clinical Gastroenterology and Hepatology.
2017;15(4):535-42. e2.
90. Bruining DH, Loftus Jr EV, Ehman EC, Siddiki HA, Nguyen DL, Fidler JL, et al.
Computed tomography enterography detects intestinal wall changes and effects of
treatment in patients with Crohn's disease. Clinical Gastroenterology and Hepatology.
2011;9(8):679-83. e1.
91. Stoppino LP, Della Valle N, Rizzi S, Cleopazzo E, Centola A, Iamele D, et al. Magnetic
resonance enterography changes after antibody to tumor necrosis factor (anti-TNF) alpha
therapy in Crohn’s disease: correlation with SES-CD and clinical-biological markers. BMC
medical imaging. 2016;16(1):1-9.
92. Shah SC, Colombel J-F, Sands BE, Narula N. Mucosal healing is associated with
improved long-term outcomes of patients with ulcerative colitis: a systematic review and
meta-analysis. Clinical gastroenterology and hepatology. 2016;14(9):1245-55. e8.
93. Orlando A, Mocciaro F, Renna S, Scimeca D, Rispo A, Scribano ML, et al. Early post-
operative endoscopic recurrence in Crohn's disease patients: Data from an Italian Group for
the study of inflammatory bowel disease (IG-IBD) study on a large prospective multicenter
cohort. Journal of Crohn's and Colitis. 2014;8(10):1217-21.
94. Lobatón T, Bessissow T, Ruiz-Cerulla A, De Hertogh G, Bisschops R, Guardiola J, et al.
Prognostic value of histological activity in patients with ulcerative colitis in deep remission: A
prospective multicenter study. United European gastroenterology journal. 2018;6(5):765-72.
95. Arkteg CB, Wergeland Sørbye S, Buhl Riis L, Dalen SM, Florholmen J, Goll R. Real-life
evaluation of histologic scores for Ulcerative Colitis in remission. PLoS One.
2021;16(3):e0248224.
96. Beaugerie L, Rahier JF, Kirchgesner J. Predicting, Preventing, and Managing
Treatment-Related Complications in Patients With Inflammatory Bowel Diseases. Clin
Gastroenterol Hepatol. 2020;18(6):1324-35.e2.
97. Piotrowska M, Krajewska J, Fichna J, Majchrzak K. [Strategies in Crohn's disease
treatment - "step-up" vs. "top-down"]. Postepy Biochem. 2020;65(4):313-7.
98. Rogler G. Top-down or step-up treatment in Crohn's disease? Dig Dis. 2013;31(1):83-
90.
99. Tsui JJ, Huynh HQ. Is top-down therapy a more effective alternative to conventional
step-up therapy for Crohn's disease? Ann Gastroenterol. 2018;31(4):413-24.
100. Holvoet T, Lobaton T, Hindryckx P. Optimal Management of Acute Severe Ulcerative
Colitis (ASUC): Challenges and Solutions. Clin Exp Gastroenterol. 2021;14:71-81.
101. Verdon C, Bessissow T, Lakatos PL. Management of Acute Severe Colitis in the Era of
Biologicals and Small Molecules. J Clin Med. 2019;8(12):2169.
102. Seah D, De Cruz P. Review article: the practical management of acute severe
ulcerative colitis. Alimentary Pharmacology & Therapeutics. 2016;43(4):482-513.
103. Torres J, Bonovas S, Doherty G, Kucharzik T, Gisbert JP, Raine T, et al. ECCO
Guidelines on Therapeutics in Crohn's Disease: Medical Treatment. Journal of Crohn's and
Colitis. 2019;14(1):4-22.
82
104. Rezaie A, Kuenzig ME, Benchimol EI, Griffiths AM, Otley AR, Steinhart AH, et al.
Budesonide for induction of remission in Crohn's disease. Cochrane Database of Systematic
Reviews. 2015(6).
105. Moja L, Danese S, Fiorino G, Del Giovane C, Bonovas S. Systematic review with
network meta-analysis: comparative efficacy and safety of budesonide and mesalazine
(mesalamine) for Crohn's disease. Aliment Pharmacol Ther. 2015;41(11):1055-65.
106. Benchimol EI, Seow CH, Steinhart AH, Griffiths AM. Traditional corticosteroids for
induction of remission in Crohn's disease. Cochrane Database of Systematic Reviews.
2008(2).
107. Torres J, Bonovas S, Doherty G, Kucharzik T, Gisbert JP, Raine T, et al. ECCO
Guidelines on Therapeutics in Crohn's Disease: Medical Treatment. Journal of Crohn's and
Colitis. 2020;14(1):4-22.
108. Stidham R, Lee T, Higgins P, Deshpande A, Sussman D, Singal A, et al. Systematic
review with network meta‐analysis: the efficacy of anti‐TNF agents for the treatment of
Crohn's disease. Alimentary pharmacology & therapeutics. 2014;39(12):1349-62.
109. Cholapranee A, Hazlewood GS, Kaplan GG, Peyrin‐Biroulet L, Ananthakrishnan AN.
Systematic review with meta‐analysis: comparative efficacy of biologics for induction and
maintenance of mucosal healing in Crohn's disease and ulcerative colitis controlled trials.
Alimentary pharmacology & therapeutics. 2017;45(10):1291-302.
110. Ford AC, Achkar J-P, Khan KJ, Kane SV, Talley NJ, Marshall JK, et al. Efficacy of 5-
aminosalicylates in ulcerative colitis: systematic review and meta-analysis. Official journal of
the American College of Gastroenterology| ACG. 2011;106(4):601-16.
111. Hazlewood GS, Rezaie A, Borman M, Panaccione R, Ghosh S, Seow CH, et al.
Comparative effectiveness of immunosuppressants and biologics for inducing and
maintaining remission in Crohn's disease: a network meta-analysis. Gastroenterology.
2015;148(2):344-54. e5.
112. Matsumoto T, Motoya S, Watanabe K, Hisamatsu T, Nakase H, Yoshimura N, et al.
Adalimumab monotherapy and a combination with azathioprine for Crohn’s disease: a
prospective, randomized trial. Journal of Crohn's and Colitis. 2016;10(11):1259-66.
113. Colombel JF, Sandborn WJ, Reinisch W, Mantzaris GJ, Kornbluth A, Rachmilewitz D,
et al. Infliximab, azathioprine, or combination therapy for Crohn's disease. New England
journal of medicine. 2010;362(15):1383-95.
114. Sands BE, Sandborn WJ, Panaccione R, O'Brien CD, Zhang H, Johanns J, et al.
Ustekinumab as Induction and Maintenance Therapy for Ulcerative Colitis. N Engl J Med.
2019;381(13):1201-14.
115. Sandborn WJ, Gasink C, Gao L-L, Blank MA, Johanns J, Guzzo C, et al. Ustekinumab
induction and maintenance therapy in refractory Crohn's disease. New England Journal of
Medicine. 2012;367(16):1519-28.
116. MacDonald JK, Nguyen TM, Khanna R, Timmer A. Anti‐IL‐12/23p40 antibodies for
induction of remission in Crohn's disease. Cochrane Database of Systematic Reviews.
2016(11).
117. Sandborn WJ, Feagan BG, Rutgeerts P, Hanauer S, Colombel J-F, Sands BE, et al.
Vedolizumab as induction and maintenance therapy for Crohn's disease. New England
Journal of Medicine. 2013;369(8):711-21.
118. Feagan BG, Rutgeerts P, Sands BE, Hanauer S, Colombel JF, Sandborn WJ, et al.
Vedolizumab as induction and maintenance therapy for ulcerative colitis. N Engl J Med.
2013;369(8):699-710.
83
119. Feagan BG, Greenberg GR, Wild G, Fedorak RN, Paré P, McDonald JW, et al.
Treatment of active Crohn's disease with MLN0002, a humanized antibody to the α4β7
integrin. Clinical Gastroenterology and Hepatology. 2008;6(12):1370-7.
120. Sands BE, Feagan BG, Rutgeerts P, Colombel J-F, Sandborn WJ, Sy R, et al. Effects of
vedolizumab induction therapy for patients with Crohn’s disease in whom tumor necrosis
factor antagonist treatment failed. Gastroenterology. 2014;147(3):618-27. e3.
121. Kawalec P, Moćko P. An indirect comparison of ustekinumab and vedolizumab in the
therapy of TNF-failure Crohn's disease patients. Journal of comparative effectiveness
research. 2018;7(2):101-11.
122. Present DH, Rutgeerts P, Targan S, Hanauer SB, Mayer L, Van Hogezand R, et al.
Infliximab for the treatment of fistulas in patients with Crohn's disease. New England Journal
of Medicine. 1999;340(18):1398-405.
123. Feroz SH, Ahmed A, Muralidharan A, Thirunavukarasu P. Comparison of the Efficacy
of the Various Treatment Modalities in the Management of Perianal Crohn's Fistula: A
Review. Cureus. 2020;12(12):e11882.
124. Lichtiger S, Binion D, Wolf D, Present D, Bensimon A, Wu E, et al. The CHOICE trial:
adalimumab demonstrates safety, fistula healing, improved quality of life and increased
work productivity in patients with Crohn’s disease who failed prior infliximab therapy.
Alimentary pharmacology & therapeutics. 2010;32(10):1228-39.
125. Panés J, Rimola J. Perianal fistulizing Crohn's disease: pathogenesis, diagnosis and
therapy. Nature reviews Gastroenterology & hepatology. 2017;14(11):652-64.
126. Feagan BG, MacDonald JK. Oral 5‐aminosalicylic acid for induction of remission in
ulcerative colitis. Cochrane database of systematic reviews. 2012(10).
127. Wang Y, Parker CE, Bhanji T, Feagan BG, MacDonald JK. Oral 5‐aminosalicylic acid for
induction of remission in ulcerative colitis. Cochrane Database of Systematic Reviews.
2016(4).
128. D'Haens G, Kovacs A, Vergauwe P, Nagy F, Molnar T, Bouhnik Y, et al. Clinical trial:
Preliminary efficacy and safety study of a new Budesonide-MMX® 9 mg extended-release
tablets in patients with active left-sided ulcerative colitis. Journal of Crohn's and Colitis.
2010;4(2):153-60.
129. Sandborn WJ, Travis S, Moro L, Jones R, Gautille T, Bagin R, et al. Once-daily
budesonide MMX® extended-release tablets induce remission in patients with mild to
moderate ulcerative colitis: results from the CORE I study. Gastroenterology.
2012;143(5):1218-26. e2.
130. Travis SP, Danese S, Kupcinskas L, Alexeeva O, D'Haens G, Gibson PR, et al. Once-
daily budesonide MMX in active, mild-to-moderate ulcerative colitis: results from the
randomised CORE II study. Gut. 2014;63(3):433-41.
131. Rubin D, Cohen R, Sandborn W, Lichtenstein G, Axler J, Riddell R, et al. Budesonide
MMX® 9 mg for inducing remission in patients with mild-to-moderate ulcerative colitis not
adequately controlled with oral 5-ASAs. J Crohns Colitis. 2015;9(Suppl 1):S7.
132. Danese S, Siegel C, Peyrin‐Biroulet L. integrating budesonide‐MMX into treatment
algorithms for mild‐to‐moderate ulcerative colitis. Alimentary pharmacology & therapeutics.
2014;39(10):1095-103.
133. Löfberg R, Danielsson Å, Suhr O, Nilsson Å, Schiöler R, Nyberg A, et al. Oral
budesonide versus prednisolone in patients with extensive and left sided ulcerative colitis.
Gastroenterology. 1996;110(6):1713-8.
84
134. Khan KJ, Dubinsky MC, Ford AC, Ullman TA, Talley NJ, Moayyedi P. Efficacy of
immunosuppressive therapy for inflammatory bowel disease: a systematic review and meta-
analysis. Official journal of the American College of Gastroenterology| ACG.
2011;106(4):630-42.
135. Gisbert JP, Linares PM, McNicholl AG, Maté J, Gomollón F. Meta-analysis: the
efficacy of azathioprine and mercaptopurine in ulcerative colitis. Aliment Pharmacol Ther.
2009;30(2):126-37.
136. Timmer A, Patton PH, Chande N, McDonald JW, MacDonald JK. Azathioprine and 6-
mercaptopurine for maintenance of remission in ulcerative colitis. Cochrane Database Syst
Rev. 2016;2016(5):Cd000478.
137. Sands B, Peyrin-Biroulet L, Loftus E, Danese S, Colombel J, Abhyankar B, et al. 416a –
Vedolizumab Shows Superior Efficacy Versus Adalimumab: Results of Varsity—The First
Head-To-Head Study of Biologic Therapy for Moderate-To-Severe Ulcerative Colitis.
Gastroenterology. 2019;156:S-81.
138. Sardesai A, Dignass A, Quon P, Milev S, Cappelleri JC, Kisser A, et al. Cost-
effectiveness of tofacitinib compared with infliximab, adalimumab, golimumab, vedolizumab
and ustekinumab for the treatment of moderate to severe ulcerative colitis in Germany. J
Med Econ. 2021;24(1):279-90.
139. Sandborn W, Sands B, Panaccione R, O’Brien C, Zhang H, Johanns J, et al. OP37
Efficacy and safety of ustekinumab as maintenance therapy in ulcerative colitis: Week 44
results from UNIFI. Journal of Crohn's and Colitis. 2019;13(Supplement_1):S025-S6.
140. Singh S, Murad MH, Fumery M, Dulai PS, Sandborn WJ. First- and Second-Line
Pharmacotherapies for Patients With Moderate to Severely Active Ulcerative Colitis: An
Updated Network Meta-Analysis. Clinical gastroenterology and hepatology : the official
clinical practice journal of the American Gastroenterological Association. 2020;18(10):2179-
91.e6.
141. gov C. Safety study of tofacitinib versus tumor necrosis factor (TNF) inhibitor in
subjects with rheumatoid arthritis. 2014.
142. Wang Y, MacDonald JK, Vandermeer B, Griffiths AM, El‐Matary W. Methotrexate for
maintenance of remission in ulcerative colitis. Cochrane Database of Systematic Reviews.
2015(8).
143. Carbonnel F, Colombel JF, Filippi J, Katsanos KH, Peyrin-Biroulet L, Allez M, et al.
Methotrexate is not superior to placebo for inducing steroid-free remission, but induces
steroid-free clinical remission in a larger proportion of patients with ulcerative colitis.
Gastroenterology. 2016;150(2):380-8. e4.
144. Panaccione R, Ghosh S, Middleton S, Márquez JR, Scott BB, Flint L, et al. Combination
therapy with infliximab and azathioprine is superior to monotherapy with either agent in
ulcerative colitis. Gastroenterology. 2014;146(2):392-400. e3.
145. Singh S, Allegretti JR, Siddique SM, Terdiman JP. AGA Technical Review on the
Management of Moderate to Severe Ulcerative Colitis. Gastroenterology. 2020;158(5):1465-
96.e17.
146. Chapman TP, Frias Gomes C, Louis E, Colombel JF, Satsangi J. Review article:
withdrawal of 5-aminosalicylates in inflammatory bowel disease. Aliment Pharmacol Ther.
2020;52(1):73-84.
147. Doherty G, Katsanos KH, Burisch J, Allez M, Papamichael K, Stallmach A, et al.
European Crohn's and Colitis Organisation Topical Review on Treatment Withdrawal ['Exit
Strategies'] in Inflammatory Bowel Disease. J Crohns Colitis. 2018;12(1):17-31.
85
148. Na SY, Moon W. Perspectives on Current and Novel Treatments for Inflammatory
Bowel Disease. Gut Liver. 2019;13(6):604-16.
149. Shen B, Kochhar G, Navaneethan U, Liu X, Farraye FA, Gonzalez-Lama Y, et al. Role of
interventional inflammatory bowel disease in the era of biologic therapy: a position
statement from the Global Interventional IBD Group. Gastrointest Endosc. 2019;89(2):215-
37.
150. Bhattacharya A, Osterman MT. Biologic Therapy for Ulcerative Colitis. Gastroenterol
Clin North Am. 2020;49(4):717-29.
151. Sandborn WJ, Schreiber S, Hanauer SB, Colombel JF, Bloomfield R, Lichtenstein GR.
Reinduction with certolizumab pegol in patients with relapsed Crohn's disease: results from
the PRECiSE 4 Study. Clin Gastroenterol Hepatol. 2010;8(8):696-702.e1.
152. Lichtenstein G, Thomsen OO, Schreiber S, Lawrance IC, Hanauer SB, Bloomfield R, et
al. S1040 Long-Term Remission With Certolizumab Pegol in Crohn's Disease: Efficacy Over 4
Years in Patients With NO Prior TNF-α Inhibitor Exposure (PRECiSE 3 Study).
Gastroenterology. 2010;5(138):S-165.
153. Schreiber S, Colombel JF, Bloomfield R, Nikolaus S, Schölmerich J, Panés J, et al.
Increased response and remission rates in short-duration Crohn's disease with
subcutaneous certolizumab pegol: an analysis of PRECiSE 2 randomized maintenance trial
data. Am J Gastroenterol. 2010;105(7):1574-82.
154. Sandborn WJ, Feagan BG, Stoinov S, Honiball PJ, Rutgeerts P, Mason D, et al.
Certolizumab pegol for the treatment of Crohn's disease. N Engl J Med. 2007;357(3):228-38.
155. Berg DR, Colombel JF, Ungaro R. The Role of Early Biologic Therapy in Inflammatory
Bowel Disease. Inflamm Bowel Dis. 2019;25(12):1896-905.
156. Feuerstein JD, Isaacs KL, Schneider Y, Siddique SM, Falck-Ytter Y, Singh S. AGA Clinical
Practice Guidelines on the Management of Moderate to Severe Ulcerative Colitis.
Gastroenterology. 2020;158(5):1450-61.
157. Pabla BS, Schwartz DA. Assessing Severity of Disease in Patients with Ulcerative
Colitis. Gastroenterol Clin North Am. 2020;49(4):671-88.
158. D'Haens G, Baert F, van Assche G, Caenepeel P, Vergauwe P, Tuynman H, et al. Early
combined immunosuppression or conventional management in patients with newly
diagnosed Crohn's disease: an open randomised trial. Lancet. 2008;371(9613):660-7.
159. Nielsen OH, Steenholdt C, Juhl CB, Rogler G. Efficacy and safety of methotrexate in
the management of inflammatory bowel disease: A systematic review and meta-analysis of
randomized, controlled trials. EClinicalMedicine. 2020;20.
160. Lichtenstein GR, Loftus EV, Isaacs KL, Regueiro MD, Gerson LB, Sands BE. ACG Clinical
Guideline: Management of Crohn's Disease in Adults. Am J Gastroenterol. 2018;113(4):481-
517.
161. Cottone M, Kohn A, Daperno M, Armuzzi A, Guidi L, D'Inca R, et al. Advanced age is
an independent risk factor for severe infections and mortality in patients given anti-tumor
necrosis factor therapy for inflammatory bowel disease. Clin Gastroenterol Hepatol.
2011;9(1):30-5.
162. Toruner M, Loftus EV, Jr., Harmsen WS, Zinsmeister AR, Orenstein R, Sandborn WJ,
et al. Risk factors for opportunistic infections in patients with inflammatory bowel disease.
Gastroenterology. 2008;134(4):929-36.
163. Peyrin-Biroulet L, Khosrotehrani K, Carrat F, Bouvier AM, Chevaux JB, Simon T, et al.
Increased risk for nonmelanoma skin cancers in patients who receive thiopurines for
inflammatory bowel disease. Gastroenterology. 2011;141(5):1621-28.e1-5.
86
164. Yajnik V, Khan N, Dubinsky M, Axler J, James A, Abhyankar B, et al. Efficacy and
Safety of Vedolizumab in Ulcerative Colitis and Crohn's Disease Patients Stratified by Age.
Adv Ther. 2017;34(2):542-59.
165. Bonovas S, Fiorino G, Allocca M, Lytras T, Nikolopoulos GK, Peyrin-Biroulet L, et al.
Biologic Therapies and Risk of Infection and Malignancy in Patients With Inflammatory
Bowel Disease: A Systematic Review and Network Meta-analysis. Clin Gastroenterol
Hepatol. 2016;14(10):1385-97.e10.
166. Feagan BG, Schwartz D, Danese S, Rubin DT, Lissoos TW, Xu J, et al. Efficacy of
Vedolizumab in Fistulising Crohn's Disease: Exploratory Analyses of Data from GEMINI 2. J
Crohns Colitis. 2018;12(5):621-6.
167. Perry C, Fischer K, Elmoursi A, Kern C, Currier A, Kudaravalli P, et al. Vedolizumab
Dose Escalation Improves Therapeutic Response in a Subset of Patients with Ulcerative
Colitis. Dig Dis Sci. 2021;66(6):2051-8.
168. Samaan MA, Birdi S, Morales MS, Honap S, Tamilarasan AG, Cunningham G, et al.
Effectiveness of vedolizumab dose intensification to achieve inflammatory bowel disease
control in cases of suboptimal response. Frontline Gastroenterol. 2020;11(3):188-93.
169. Ollech JE, Normatov I, Peleg N, Wang J, Patel SA, Rai V, et al. Effectiveness of
Ustekinumab Dose Escalation in Patients With Crohn's Disease. Clin Gastroenterol Hepatol.
2021;19(1):104-10.
170. Haider SA, Yadav A, Perry C, Su L, Akanbi O, Kudaravalli P, et al. Ustekinumab dose
escalation improves clinical responses in refractory Crohn's disease. Therap Adv
Gastroenterol. 2020;13:1756284820959245.
171. Kopylov U, Hanzel J, Liefferinckx C, De Marco D, Imperatore N, Plevris N, et al.
Effectiveness of ustekinumab dose escalation in Crohn's disease patients with insufficient
response to standard-dose subcutaneous maintenance therapy. Aliment Pharmacol Ther.
2020;52(1):135-42.
172. Mitrev N, Vande Casteele N, Seow CH, Andrews JM, Connor SJ, Moore GT, et al.
Review article: consensus statements on therapeutic drug monitoring of anti-tumour
necrosis factor therapy in inflammatory bowel diseases. Aliment Pharmacol Ther.
2017;46(11-12):1037-53.
173. Ben-Horin S, Chowers Y. Review article: loss of response to anti-TNF treatments in
Crohn's disease. Aliment Pharmacol Ther. 2011;33(9):987-95.
174. Fine S, Papamichael K, Cheifetz AS. Etiology and Management of Lack or Loss of
Response to Anti-Tumor Necrosis Factor Therapy in Patients With Inflammatory Bowel
Disease. Gastroenterol Hepatol (N Y). 2019;15(12):656-65.
175. Feagan BG, Rubin DT, Danese S, Vermeire S, Abhyankar B, Sankoh S, et al. Efficacy of
Vedolizumab Induction and Maintenance Therapy in Patients With Ulcerative Colitis,
Regardless of Prior Exposure to Tumor Necrosis Factor Antagonists. Clin Gastroenterol
Hepatol. 2017;15(2):229-39.e5.
176. Carrascosa JM. Immunogenicity in biologic therapy: implications for dermatology.
Actas Dermosifiliogr. 2013;104(6):471-9.
177. Grossi V, Gulli F, Infantino M, Stefanile A, Napodano C, Benucci M, et al. The
Laboratory Role in anti-TNF Biological Therapy Era. Immunol Invest. 2020;49(3):317-32.
178. Plasencia C, Pascual-Salcedo D, García-Carazo S, Lojo L, Nuño L, Villalba A, et al. The
immunogenicity to the first anti-TNF therapy determines the outcome of switching to a
second anti-TNF therapy in spondyloarthritis patients. Arthritis Res Ther. 2013;15(4):R79.
87
179. Gisbert JP, Marín AC, McNicholl AG, Chaparro M. Systematic review with meta-
analysis: the efficacy of a second anti-TNF in patients with inflammatory bowel disease
whose previous anti-TNF treatment has failed. Aliment Pharmacol Ther. 2015;41(7):613-23.
180. Kothari MM, Nguyen DL, Parekh NK. Strategies for overcoming anti-tumor necrosis
factor drug antibodies in inflammatory bowel disease: Case series and review of literature.
World J Gastrointest Pharmacol Ther. 2017;8(3):155-61.
181. Schräpel C, Kovar L, Selzer D, Hofmann U, Tran F, Reinisch W, et al. External Model
Performance Evaluation of Twelve Infliximab Population Pharmacokinetic Models in Patients
with Inflammatory Bowel Disease. Pharmaceutics. 2021;13(9):1368.
182. Roblin X, Marotte H, Rinaudo M, Del Tedesco E, Moreau A, Phelip JM, et al.
Association between pharmacokinetics of adalimumab and mucosal healing in patients with
inflammatory bowel diseases. Clin Gastroenterol Hepatol. 2014;12(1):80-4.e2.
183. Bush MC, Patel S, Lapinski RH, Stone JL. Perinatal outcomes in inflammatory bowel
disease. J Matern Fetal Neonatal Med. 2004;15(4):237-41.
184. Morales M, Berney T, Jenny A, Morel P, Extermann P. Crohn's disease as a risk factor
for the outcome of pregnancy. Hepatogastroenterology. 2000;47(36):1595-8.
185. Magro F, Gionchetti P, Eliakim R, Ardizzone S, Armuzzi A, Barreiro-de Acosta M, et al.
Third European Evidence-based Consensus on Diagnosis and Management of Ulcerative
Colitis. Part 1: Definitions, Diagnosis, Extra-intestinal Manifestations, Pregnancy, Cancer
Surveillance, Surgery, and Ileo-anal Pouch Disorders. J Crohns Colitis. 2017;11(6):649-70.
186. Zelinkova Z, van der Ent C, Bruin KF, van Baalen O, Vermeulen HG, Smalbraak HJ, et
al. Effects of discontinuing anti-tumor necrosis factor therapy during pregnancy on the
course of inflammatory bowel disease and neonatal exposure. Clin Gastroenterol Hepatol.
2013;11(3):318-21.
187. de Lima A, Zelinkova Z, van der Ent C, Steegers EA, van der Woude CJ. Tailored anti-
TNF therapy during pregnancy in patients with IBD: maternal and fetal safety. Gut.
2016;65(8):1261-8.
188. Beaulieu DB, Ananthakrishnan AN, Martin C, Cohen RD, Kane SV, Mahadevan U. Use
of Biologic Therapy by Pregnant Women With Inflammatory Bowel Disease Does Not Affect
Infant Response to Vaccines. Clin Gastroenterol Hepatol. 2018;16(1):99-105.
189. Papp KA, Haraoui B, Kumar D, Marshall JK, Bissonnette R, Bitton A, et al. Vaccination
Guidelines for Patients With Immune-Mediated Disorders on Immunosuppressive Therapies.
J Cutan Med Surg. 2019;23(1):50-74.
190. Park SH, Kim HJ, Lee CK, Song EM, Kang S-B, Jang BI, et al. Safety and Optimal Timing
of BCG Vaccination in Infants Born to Mothers Receiving Anti-TNF Therapy for Inflammatory
Bowel Disease. Journal of Crohn's and Colitis. 2020;14(12):1780-4.
191. Heller MM, Wu JJ, Murase JE. Fatal case of disseminated BCG infection after
vaccination of an infant with in utero exposure to infliximab. Journal of the American
Academy of Dermatology. 2011;65(4):870.
192. Bendaoud S, Nahon S, Gornet J-M, Pariente B, Beaugerie L, Abitbol V, et al. P817
Live-vaccines and lactation in newborn exposed in utero to anti-TNF: A multi-centre French
experience in inflammatory bowel disease. Journal of Crohn's and Colitis.
2018;12(supplement_1):S527-S.
193. Trallori G, d'Albasio G, Bardazzi G, Bonanomi AG, Amorosi A, Del Carlo P, et al. 5-
Aminosalicylic acid in pregnancy: clinical report. Ital J Gastroenterol. 1994;26(2):75-8.
88
194. De Broe ME, Stolear JC, Nouwen EJ, Elseviers MM. 5-Aminosalicylic acid (5-ASA) and
chronic tubulointerstitial nephritis in patients with chronic inflammatory bowel disease: is
there a link? Nephrol Dial Transplant. 1997;12(9):1839-41.
195. Bell CM, Habal FM. Safety of topical 5-aminosalicylic acid in pregnancy. Am J
Gastroenterol. 1997;92(12):2201-2.
196. Marteau P, Tennenbaum R, Elefant E, Lémann M, Cosnes J. Foetal outcome in
women with inflammatory bowel disease treated during pregnancy with oral mesalazine
microgranules. Aliment Pharmacol Ther. 1998;12(11):1101-8.
197. Goldstein LH, Dolinsky G, Greenberg R, Schaefer C, Cohen-Kerem R, Diav-Citrin O, et
al. Pregnancy outcome of women exposed to azathioprine during pregnancy. Birth Defects
Res A Clin Mol Teratol. 2007;79(10):696-701.
198. Mahadevan U, Wolf DC, Dubinsky M, Cortot A, Lee SD, Siegel CA, et al. Placental
transfer of anti-tumor necrosis factor agents in pregnant patients with inflammatory bowel
disease. Clin Gastroenterol Hepatol. 2013;11(3):286-92; quiz e24.
199. Nguyen GC, Seow CH, Maxwell C, Huang V, Leung Y, Jones J, et al. The Toronto
Consensus Statements for the Management of Inflammatory Bowel Disease in Pregnancy.
Gastroenterology. 2016;150(3):734-57.e1.
200. Kawaguchi R, Haruta S, Kobayashi H. Efficacy and safety of venous thromboembolism
prophylaxis with fondaparinux in women at risk after cesarean section. Obstet Gynecol Sci.
2017;60(6):535-41.
201. Bar-Gil Shitrit A, Grisaru-Granovsky S, Ben Ya'acov A, Goldin E. Management of
Inflammatory Bowel Disease During Pregnancy. Dig Dis Sci. 2016;61(8):2194-204.
202. Matro R, Martin CF, Wolf D, Shah SA, Mahadevan U. Exposure Concentrations of
Infants Breastfed by Women Receiving Biologic Therapies for Inflammatory Bowel Diseases
and Effects of Breastfeeding on Infections and Development. Gastroenterology.
2018;155(3):696-704.
203. Kanis SL, van der Woude CJ. Proper Use of Inflammatory Bowel Disease Drugs during
Pregnancy. Digestive Diseases. 2016;34(suppl 1)(Suppl. 1):61-6.
204. Saarikoski S, Seppälä M. Immunosuppression during pregnancy: transmission of
azathioprine and its metabolites from the mother to the fetus. Am J Obstet Gynecol.
1973;115(8):1100-6.
205. Casanova MJ, Chaparro M, Domènech E, Barreiro-de Acosta M, Bermejo F, Iglesias E,
et al. Safety of thiopurines and anti-TNF-α drugs during pregnancy in patients with
inflammatory bowel disease. Am J Gastroenterol. 2013;108(3):433-40.
206. Coelho J, Beaugerie L, Colombel JF, Hébuterne X, Lerebours E, Lémann M, et al.
Pregnancy outcome in patients with inflammatory bowel disease treated with thiopurines:
cohort from the CESAME Study. Gut. 2011;60(2):198-203.
207. Zelinkova Z, de Haar C, de Ridder L, Pierik MJ, Kuipers EJ, Peppelenbosch MP, et al.
High intra-uterine exposure to infliximab following maternal anti-TNF treatment during
pregnancy. Aliment Pharmacol Ther. 2011;33(9):1053-8.
208. Narula N, Al-Dabbagh R, Dhillon A, Sands BE, Marshall JK. Anti-TNFα therapies are
safe during pregnancy in women with inflammatory bowel disease: a systematic review and
meta-analysis. Inflamm Bowel Dis. 2014;20(10):1862-9.
209. Lamb CA, Kennedy NA, Raine T, Hendy PA, Smith PJ, Limdi JK, et al. British Society of
Gastroenterology consensus guidelines on the management of inflammatory bowel disease
in adults. Gut. 2019;68(Suppl 3):s1-s106.
89
210. Temprano KK, Bandlamudi R, Moore TL. Antirheumatic drugs in pregnancy and
lactation. Semin Arthritis Rheum. 2005;35(2):112-21.
211. Banaszkiewicz A, Kądzielska J, Gawrońska A, Pituch H, Obuch-Woszczatyński P,
Albrecht P, et al. Enterotoxigenic Clostridium perfringens infection and pediatric patients
with inflammatory bowel disease. J Crohns Colitis. 2014;8(4):276-81.
212. Hourigan SK, Sears CL, Oliva-Hemker M. Clostridium difficile Infection in Pediatric
Inflammatory Bowel Disease. Inflamm Bowel Dis. 2016;22(4):1020-5.
213. Mack DR, Langton C, Markowitz J, LeLeiko N, Griffiths A, Bousvaros A, et al.
Laboratory values for children with newly diagnosed inflammatory bowel disease.
Pediatrics. 2007;119(6):1113-9.
214. Trivedi PJ, Chapman RW. PSC, AIH and overlap syndrome in inflammatory bowel
disease. Clin Res Hepatol Gastroenterol. 2012;36(5):420-36.
215. Sidler MA, Leach ST, Day AS. Fecal S100A12 and fecal calprotectin as noninvasive
markers for inflammatory bowel disease in children. Inflamm Bowel Dis. 2008;14(3):359-66.
216. Sipponen T, Savilahti E, Kolho KL, Nuutinen H, Turunen U, Färkkilä M. Crohn's disease
activity assessed by fecal calprotectin and lactoferrin: correlation with Crohn's disease
activity index and endoscopic findings. Inflamm Bowel Dis. 2008;14(1):40-6.
217. Cabrera-Abreu JC, Davies P, Matek Z, Murphy MS. Performance of blood tests in
diagnosis of inflammatory bowel disease in a specialist clinic. Arch Dis Child. 2004;89(1):69-
71.
218. Henderson P, Casey A, Lawrence SJ, Kennedy NA, Kingstone K, Rogers P, et al. The
diagnostic accuracy of fecal calprotectin during the investigation of suspected pediatric
inflammatory bowel disease. Am J Gastroenterol. 2012;107(6):941-9.
219. de Bie CI, Buderus S, Sandhu BK, de Ridder L, Paerregaard A, Veres G, et al.
Diagnostic workup of paediatric patients with inflammatory bowel disease in Europe: results
of a 5-year audit of the EUROKIDS registry. J Pediatr Gastroenterol Nutr. 2012;54(3):374-80.
220. Levine A, Koletzko S, Turner D, Escher JC, Cucchiara S, de Ridder L, et al. ESPGHAN
revised porto criteria for the diagnosis of inflammatory bowel disease in children and
adolescents. J Pediatr Gastroenterol Nutr. 2014;58(6):795-806.
221. Tully MA. Pediatric celiac disease. Gastroenterol Nurs. 2008;31(2):132-40; quiz 41-2.
222. Giles E, Barclay AR, Chippington S, Wilson DC. Systematic review: MRI enterography
for assessment of small bowel involvement in paediatric Crohn's disease. Aliment Pharmacol
Ther. 2013;37(12):1121-31.
223. Essary B, Kim J, Anupindi S, Katz JA, Nimkin K. Pelvic MRI in children with Crohn
disease and suspected perianal involvement. Pediatr Radiol. 2007;37(2):201-8.
224. Liao Z, Gao R, Xu C, Li ZS. Indications and detection, completion, and retention rates
of small-bowel capsule endoscopy: a systematic review. Gastrointest Endosc.
2010;71(2):280-6.
225. Cohen SA, Klevens AI. Use of capsule endoscopy in diagnosis and management of
pediatric patients, based on meta-analysis. Clin Gastroenterol Hepatol. 2011;9(6):490-6.
226. Cheifetz AS, Kornbluth AA, Legnani P, Schmelkin I, Brown A, Lichtiger S, et al. The risk
of retention of the capsule endoscope in patients with known or suspected Crohn's disease.
Am J Gastroenterol. 2006;101(10):2218-22.
227. Fritscher-Ravens A, Scherbakov P, Bufler P, Torroni F, Ruuska T, Nuutinen H, et al.
The feasibility of wireless capsule endoscopy in detecting small intestinal pathology in
children under the age of 8 years: a multicentre European study. Gut. 2009;58(11):1467-72.
90
228. Chiorean L, Schreiber-Dietrich D, Braden B, Cui X-W, Buchhorn R, Chang J-M, et al.
Ultrasonographic imaging of inflammatory bowel disease in pediatric patients. World J
Gastroenterol. 2015;21(17):5231-41.
229. van Wassenaer EA, Benninga MA, van Limbergen JL, D’Haens GR, Griffiths AM, Koot
BGP. Intestinal Ultrasound in Pediatric Inflammatory Bowel Disease: Promising, but Work in
Progress. Inflammatory Bowel Diseases. 2021.
230. Bremner AR, Griffiths M, Argent JD, Fairhurst JJ, Beattie RM. Sonographic evaluation
of inflammatory bowel disease: a prospective, blinded, comparative study. Pediatr Radiol.
2006;36(9):947-53.
231. Uhlig HH, Schwerd T, Koletzko S, Shah N, Kammermeier J, Elkadri A, et al. The
diagnostic approach to monogenic very early onset inflammatory bowel disease.
Gastroenterology. 2014;147(5):990-1007.e3.
232. Kelsen JR, Baldassano RN, Artis D, Sonnenberg GF. Maintaining intestinal health: the
genetics and immunology of very early onset inflammatory bowel disease. Cell Mol
Gastroenterol Hepatol. 2015;1(5):462-76.
233. Ouahed J, Spencer E, Kotlarz D, Shouval DS, Kowalik M, Peng K, et al. Very Early
Onset Inflammatory Bowel Disease: A Clinical Approach With a Focus on the Role of
Genetics and Underlying Immune Deficiencies. Inflamm Bowel Dis. 2020;26(6):820-42.
234. Turner D, Ruemmele FM, Orlanski-Meyer E, Griffiths AM, de Carpi JM, Bronsky J, et
al. Management of Paediatric Ulcerative Colitis, Part 1: Ambulatory Care-An Evidence-based
Guideline From European Crohn's and Colitis Organization and European Society of
Paediatric Gastroenterology, Hepatology and Nutrition. J Pediatr Gastroenterol Nutr.
2018;67(2):257-91.
235. Annese V, Daperno M, Rutter MD, Amiot A, Bossuyt P, East J, et al. European
evidence based consensus for endoscopy in inflammatory bowel disease. Journal of Crohn's
and Colitis. 2013;7(12):982-1018.
236. Thakkar K, Lucia CJ, Ferry GD, McDuffie A, Watson K, Tsou M, et al. Repeat
endoscopy affects patient management in pediatric inflammatory bowel disease. Am J
Gastroenterol. 2009;104(3):722-7.
237. Kayton ML. Cancer and pediatric inflammatory bowel disease. Semin Pediatr Surg.
2007;16(3):205-13.
238. Waugh N, Cummins E, Royle P, Kandala NB, Shyangdan D, Arasaradnam R, et al.
Faecal calprotectin testing for differentiating amongst inflammatory and non-inflammatory
bowel diseases: systematic review and economic evaluation. Health Technol Assess.
2013;17(55):xv-xix, 1-211.
239. Murray A, Nguyen TM, Parker CE, Feagan BG, MacDonald JK. Oral 5-aminosalicylic
acid for induction of remission in ulcerative colitis. Cochrane Database Syst Rev.
2020;8(8):Cd000543.
240. Winter HS, Krzeski P, Heyman MB, Ibarguen-Secchia E, Iwanczak B, Kaczmarski M, et
al. High- and low-dose oral delayed-release mesalamine in children with mild-to-moderately
active ulcerative colitis. J Pediatr Gastroenterol Nutr. 2014;59(6):767-72.
241. Turner D, Yerushalmi B, Kori M, Broide E, Mozer-Glassberg Y, Shaoul R, et al. Once-
Versus Twice-daily Mesalazine to Induce Remission in Paediatric Ulcerative Colitis: A
Randomised Controlled Trial. J Crohns Colitis. 2017;11(5):527-33.
242. Quiros JA, Heyman MB, Pohl JF, Attard TM, Pieniaszek HJ, Bortey E, et al. Safety,
efficacy, and pharmacokinetics of balsalazide in pediatric patients with mild-to-moderate
91
active ulcerative colitis: results of a randomized, double-blind study. J Pediatr Gastroenterol
Nutr. 2009;49(5):571-9.
243. Probert CS, Dignass AU, Lindgren S, Oudkerk Pool M, Marteau P. Combined oral and
rectal mesalazine for the treatment of mild-to-moderately active ulcerative colitis: rapid
symptom resolution and improvements in quality of life. J Crohns Colitis. 2014;8(3):200-7.
244. Marteau P, Probert CS, Lindgren S, Gassul M, Tan TG, Dignass A, et al. Combined oral
and enema treatment with Pentasa (mesalazine) is superior to oral therapy alone in patients
with extensive mild/moderate active ulcerative colitis: a randomised, double blind, placebo
controlled study. Gut. 2005;54(7):960-5.
245. Heyman MB, Kierkus J, Spénard J, Shbaklo H, Giguere M. Efficacy and safety of
mesalamine suppositories for treatment of ulcerative proctitis in children and adolescents.
Inflamm Bowel Dis. 2010;16(11):1931-9.
246. Tung J, Loftus EV, Jr., Freese DK, El-Youssef M, Zinsmeister AR, Melton LJ, 3rd, et al. A
population-based study of the frequency of corticosteroid resistance and dependence in
pediatric patients with Crohn's disease and ulcerative colitis. Inflamm Bowel Dis.
2006;12(12):1093-100.
247. Cakir M, Ozgenc F, Yusekkaya HA, Ecevit CO, Yagci RV. Steroid response in moderate
to severe pediatric ulcerative colitis: a single center's experience. World J Pediatr.
2011;7(1):50-3.
248. Beattie RM, Nicholls SW, Domizio P, Williams CB, Walker-Smith JA. Endoscopic
assessment of the colonic response to corticosteroids in children with ulcerative colitis. J
Pediatr Gastroenterol Nutr. 1996;22(4):373-9.
249. Campieri M, Adamo S, Valpiani D, D'Arienzo A, D'Albasio G, Pitzalis M, et al. Oral
beclometasone dipropionate in the treatment of extensive and left-sided active ulcerative
colitis: a multicentre randomised study. Aliment Pharmacol Ther. 2003;17(12):1471-80.
250. Romano C, Famiani A, Comito D, Rossi P, Raffa V, Fries W. Oral beclomethasone
dipropionate in pediatric active ulcerative colitis: a comparison trial with mesalazine. J
Pediatr Gastroenterol Nutr. 2010;50(4):385-9.
251. Karolewska-Bochenek K, Dziekiewicz M, Banaszkiewicz A. Budesonide MMX in
Paediatric Patients With Ulcerative Colitis. J Crohns Colitis. 2017;11(11):1402.
252. Jakobsen C, Bartek J, Jr., Wewer V, Vind I, Munkholm P, Groen R, et al. Differences in
phenotype and disease course in adult and paediatric inflammatory bowel disease--a
population-based study. Aliment Pharmacol Ther. 2011;34(10):1217-24.
253. Hyams JS, Lerer T, Mack D, Bousvaros A, Griffiths A, Rosh J, et al. Outcome following
thiopurine use in children with ulcerative colitis: a prospective multicenter registry study.
Am J Gastroenterol. 2011;106(5):981-7.
254. Aloi M, DʼArcangelo G, Bramuzzo M, Gasparetto M, Martinelli M, Alvisi P, et al. Effect
of Early Versus Late Azathioprine Therapy in Pediatric Ulcerative Colitis. Inflamm Bowel Dis.
2016;22(7):1647-54.
255. Wang Y, Parker CE, Feagan BG, MacDonald JK. Oral 5-aminosalicylic acid for
maintenance of remission in ulcerative colitis. Cochrane Database Syst Rev.
2016;2016(5):Cd000544.
256. Tajiri H, Tomomasa T, Yoden A, Konno M, Sasaki M, Maisawa S, et al. Efficacy and
safety of azathioprine and 6-mercaptopurine in Japanese pediatric patients with ulcerative
colitis: a survey of the Japanese Society for Pediatric Inflammatory Bowel Disease. Digestion.
2008;77(3-4):150-4.
92
257. Pozler O, Chládek J, Malý J, Hroch M, Dědek P, Beránek M, et al. Steady-state of
azathioprine during initiation treatment of pediatric inflammatory bowel disease. J Crohns
Colitis. 2010;4(6):623-8.
258. Timmer A, McDonald JW, Macdonald JK. Azathioprine and 6-mercaptopurine for
maintenance of remission in ulcerative colitis. Cochrane Database Syst Rev.
2007(1):Cd000478.
259. Gilissen LPL, Wong DR, Engels LGJB, Bierau J, Bakker JA, Paulussen ADC, et al.
Therapeutic drug monitoring of thiopurine metabolites in adult thiopurine tolerant IBD
patients on maintenance therapy. Journal of Crohn's and Colitis. 2012;6(6):698-707.
260. Lee JH, Kim TJ, Kim ER, Hong SN, Chang DK, Choi L-H, et al. Measurements of 6-
thioguanine nucleotide levels with TPMT and NUDT15 genotyping in patients with Crohn's
disease. PLoS One. 2017;12(12):e0188925-e.
261. Sparrow MP. Use of allopurinol to optimize thiopurine immunomodulator efficacy in
inflammatory bowel disease. Gastroenterol Hepatol (N Y). 2008;4(7):505-11.
262. Hyams J, Damaraju L, Blank M, Johanns J, Guzzo C, Winter HS, et al. Induction and
maintenance therapy with infliximab for children with moderate to severe ulcerative colitis.
Clin Gastroenterol Hepatol. 2012;10(4):391-9.e1.
263. Turner D, Griffiths AM. Acute severe ulcerative colitis in children: a systematic
review. Inflamm Bowel Dis. 2011;17(1):440-9.
264. Thorlund K, Druyts E, Mills EJ, Fedorak RN, Marshall JK. Adalimumab versus
infliximab for the treatment of moderate to severe ulcerative colitis in adult patients naïve
to anti-TNF therapy: an indirect treatment comparison meta-analysis. J Crohns Colitis.
2014;8(7):571-81.
265. Vahabnezhad E, Rabizadeh S, Dubinsky MC. A 10-year, single tertiary care center
experience on the durability of infliximab in pediatric inflammatory bowel disease. Inflamm
Bowel Dis. 2014;20(4):606-13.
266. Volonaki E, Mutalib M, Kiparissi F, Shah N, Lindley KJ, Elawad M. Adalimumab as a
second-line biological therapy in children with refractory ulcerative colitis. Eur J
Gastroenterol Hepatol. 2015;27(12):1425-8.
267. Hyams J, Griffiths A, Veereman G, Turner D, Chan D, Adedokun O, et al. P-097 A
Multicenter Open-Label Study Assessing Pharmacokinetics, Efficacy, and Safety of
Subcutaneous Golimumab in Pediatric Subjects with Moderately-Severely Active Ulcerative
Colitis. Inflammatory Bowel Diseases. 2016;22:S39-S40.
268. Rundquist S, Sachs MC, Eriksson C, Olén O, Montgomery S, Halfvarson J, et al. Drug
survival of anti-TNF agents compared with vedolizumab as a second-line biological
treatment in inflammatory bowel disease: results from nationwide Swedish registers.
Alimentary Pharmacology & Therapeutics. 2021;53(4):471-83.
269. Yanai H, Lichtenstein L, Assa A, Mazor Y, Weiss B, Levine A, et al. Levels of drug and
antidrug antibodies are associated with outcome of interventions after loss of response to
infliximab or adalimumab. Clin Gastroenterol Hepatol. 2015;13(3):522-30.e2.
270. Sands BE, Feagan BG, Rutgeerts P, Colombel JF, Sandborn WJ, Sy R, et al. Effects of
vedolizumab induction therapy for patients with Crohn's disease in whom tumor necrosis
factor antagonist treatment failed. Gastroenterology. 2014;147(3):618-27.e3.
271. Afif W, Loftus EV, Jr., Faubion WA, Kane SV, Bruining DH, Hanson KA, et al. Clinical
utility of measuring infliximab and human anti-chimeric antibody concentrations in patients
with inflammatory bowel disease. Am J Gastroenterol. 2010;105(5):1133-9.
93
272. Dalal SR, Cohen RD. What to Do When Biologic Agents Are Not Working in
Inflammatory Bowel Disease Patients. Gastroenterol Hepatol (N Y). 2015;11(10):657-65.
273. Aardoom MA, Veereman G, de Ridder L. A Review on the Use of Anti-TNF in Children
and Adolescents with Inflammatory Bowel Disease. Int J Mol Sci. 2019;20(10):2529.
274. Dohos D, Hanák L, Szakács Z, Kiss S, Párniczky A, Erőss B, et al. Systematic review
with meta-analysis: the effects of immunomodulator or biological withdrawal from mono-
or combination therapy in inflammatory bowel disease. Aliment Pharmacol Ther.
2021;53(2):220-33.
275. Tarnok A, Kiss Z, Kadenczki O, Veres G. Characteristics of biological therapy in
pediatric patients with Crohn's disease. Expert Opin Biol Ther. 2019;19(3):181-96.
276. Cheon JH. Understanding the complications of anti-tumor necrosis factor therapy in
East Asian patients with inflammatory bowel disease. J Gastroenterol Hepatol.
2017;32(4):769-77.
277. Rahier JF, Magro F, Abreu C, Armuzzi A, Ben-Horin S, Chowers Y, et al. Second
European evidence-based consensus on the prevention, diagnosis and management of
opportunistic infections in inflammatory bowel disease. J Crohns Colitis. 2014;8(6):443-68.
278. Ford AC, Kane SV, Khan KJ, Achkar J-P, Talley NJ, Marshall JK, et al. Efficacy of 5-
aminosalicylates in Crohn's disease: systematic review and meta-analysis. Official journal of
the American College of Gastroenterology| ACG. 2011;106(4):617-29.
279. Lim WC, Wang Y, MacDonald JK, Hanauer S. Aminosalicylates for induction of
remission or response in Crohn's disease. Cochrane Database Syst Rev. 2016;7(7):Cd008870.
280. Coward S, Kuenzig ME, Hazlewood G, Clement F, McBrien K, Holmes R, et al.
Comparative Effectiveness of Mesalamine, Sulfasalazine, Corticosteroids, and Budesonide
for the Induction of Remission in Crohn's Disease: A Bayesian Network Meta-analysis.
Inflamm Bowel Dis. 2017;23(3):461-72.
281. Akobeng AK, Zhang D, Gordon M, MacDonald JK. Oral 5-aminosalicylic acid for
maintenance of medically-induced remission in Crohn's disease. Cochrane Database Syst
Rev. 2016;9(9):Cd003715.
282. Cezard JP, Munck A, Mouterde O, Morali A, Lenaerts C, Lachaux A, et al. Prevention
of relapse by mesalazine (Pentasa) in pediatric Crohn's disease: a multicenter, double-blind,
randomized, placebo-controlled trial. Gastroenterol Clin Biol. 2009;33(1 Pt 1):31-40.
283. Faubion WA, Jr., Loftus EV, Jr., Harmsen WS, Zinsmeister AR, Sandborn WJ. The
natural history of corticosteroid therapy for inflammatory bowel disease: a population-
based study. Gastroenterology. 2001;121(2):255-60.
284. O'Sullivan M. Symposium on 'The challenge of translating nutrition research into
public health nutrition'. Session 3: Joint Nutrition Society and Irish Nutrition and Dietetic
Institute Symposium on 'Nutrition and autoimmune disease'. Nutrition in Crohn's disease.
Proc Nutr Soc. 2009;68(2):127-34.
285. Levine A, Weizman Z, Broide E, Shamir R, Shaoul R, Pacht A, et al. A comparison of
budesonide and prednisone for the treatment of active pediatric Crohn disease. J Pediatr
Gastroenterol Nutr. 2003;36(2):248-52.
286. Levine A, Broide E, Stein M, Bujanover Y, Weizman Z, Dinari G, et al. Evaluation of
oral budesonide for treatment of mild and moderate exacerbations of Crohn's disease in
children. J Pediatr. 2002;140(1):75-80.
287. Kuenzig ME, Rezaie A, Seow CH, Otley AR, Steinhart AH, Griffiths AM, et al.
Budesonide for maintenance of remission in Crohn's disease. Cochrane Database Syst Rev.
2014;2014(8):Cd002913.
94
288. Steinhart AH, Ewe K, Griffiths AM, Modigliani R, Thomsen OO. Corticosteroids for
maintenance of remission in Crohn's disease. Cochrane Database Syst Rev.
2003(4):Cd000301.
289. Johnson T, Macdonald S, Hill SM, Thomas A, Murphy MS. Treatment of active
Crohn's disease in children using partial enteral nutrition with liquid formula: a randomised
controlled trial. Gut. 2006;55(3):356-61.
290. Lee D, Baldassano RN, Otley AR, Albenberg L, Griffiths AM, Compher C, et al.
Comparative Effectiveness of Nutritional and Biological Therapy in North American Children
with Active Crohn's Disease. Inflamm Bowel Dis. 2015;21(8):1786-93.
291. Chande N, Tsoulis DJ, MacDonald JK. Azathioprine or 6-mercaptopurine for induction
of remission in Crohn's disease. Cochrane Database Syst Rev. 2013(4):Cd000545.
292. Khan KJ, Dubinsky MC, Ford AC, Ullman TA, Talley NJ, Moayyedi P. Efficacy of
immunosuppressive therapy for inflammatory bowel disease: a systematic review and meta-
analysis. Am J Gastroenterol. 2011;106(4):630-42.
293. Wenzl HH, Primas C, Novacek G, Teml A, Öfferlbauer-Ernst A, Högenauer C, et al.
Withdrawal of long-term maintenance treatment with azathioprine tends to increase
relapse risk in patients with Crohn's disease. Dig Dis Sci. 2015;60(5):1414-23.
294. Markowitz J, Grancher K, Kohn N, Lesser M, Daum F. A multicenter trial of 6-
mercaptopurine and prednisone in children with newly diagnosed Crohn's disease.
Gastroenterology. 2000;119(4):895-902.
295. Coenen MJ, de Jong DJ, van Marrewijk CJ, Derijks LJ, Vermeulen SH, Wong DR, et al.
Identification of Patients With Variants in TPMT and Dose Reduction Reduces Hematologic
Events During Thiopurine Treatment of Inflammatory Bowel Disease. Gastroenterology.
2015;149(4):907-17.e7.
296. Newman WG, Payne K, Tricker K, Roberts SA, Fargher E, Pushpakom S, et al. A
pragmatic randomized controlled trial of thiopurine methyltransferase genotyping prior to
azathioprine treatment: the TARGET study. Pharmacogenomics. 2011;12(6):815-26.
297. Sayani FA, Prosser C, Bailey RJ, Jacobs P, Fedorak RN. Thiopurine methyltransferase
enzyme activity determination before treatment of inflammatory bowel disease with
azathioprine: effect on cost and adverse events. Can J Gastroenterol. 2005;19(3):147-51.
298. Patel V, Wang Y, MacDonald JK, McDonald JW, Chande N. Methotrexate for
maintenance of remission in Crohn's disease. Cochrane Database Syst Rev.
2014;2014(8):Cd006884.
299. Scherkenbach LA, Stumpf JL. Methotrexate for the Management of Crohn's Disease
in Children. Ann Pharmacother. 2016;50(1):60-9.
300. Grover Z, Burgess C, Muir R, Reilly C, Lewindon PJ. Early Mucosal Healing with
Exclusive Enteral Nutrition is Associated with Improved Outcomes in Newly Diagnosed
Children with Luminal Crohn's disease. J Crohns Colitis. 2016;10(10):1159-64.
301. Rutgeerts P, Van Assche G, Sandborn WJ, Wolf DC, Geboes K, Colombel JF, et al.
Adalimumab induces and maintains mucosal healing in patients with Crohn's disease: data
from the EXTEND trial. Gastroenterology. 2012;142(5):1102-11.e2.
302. Rutgeerts P, Diamond RH, Bala M, Olson A, Lichtenstein GR, Bao W, et al. Scheduled
maintenance treatment with infliximab is superior to episodic treatment for the healing of
mucosal ulceration associated with Crohn's disease. Gastrointest Endosc. 2006;63(3):433-
42; quiz 64.
95
303. Colombel JF, Sandborn WJ, Reinisch W, Mantzaris GJ, Kornbluth A, Rachmilewitz D,
et al. Infliximab, azathioprine, or combination therapy for Crohn's disease. N Engl J Med.
2010;362(15):1383-95.
304. Hazlewood GS, Rezaie A, Borman M, Panaccione R, Ghosh S, Seow CH, et al.
Comparative effectiveness of immunosuppressants and biologics for inducing and
maintaining remission in Crohn's disease: a network meta-analysis. Gastroenterology.
2015;148(2):344-54.e5; quiz e14-5.
305. Fan R, Zhong J, Wang ZT, Li SY, Zhou J, Tang YH. Evaluation of "top-down" treatment
of early Crohn's disease by double balloon enteroscopy. World J Gastroenterol.
2014;20(39):14479-87.
306. Matsumoto T, Motoya S, Watanabe K, Hisamatsu T, Nakase H, Yoshimura N, et al.
Adalimumab Monotherapy and a Combination with Azathioprine for Crohn's Disease: A
Prospective, Randomized Trial. J Crohns Colitis. 2016;10(11):1259-66.
307. Jones JL, Kaplan GG, Peyrin-Biroulet L, Baidoo L, Devlin S, Melmed GY, et al. Effects of
Concomitant Immunomodulator Therapy on Efficacy and Safety of Anti-Tumor Necrosis
Factor Therapy for Crohn's Disease: A Meta-analysis of Placebo-controlled Trials. Clin
Gastroenterol Hepatol. 2015;13(13):2233-40.e1-2; quiz e177-8.
308. Feagan BG, McDonald JW, Panaccione R, Enns RA, Bernstein CN, Ponich TP, et al.
Methotrexate in combination with infliximab is no more effective than infliximab alone in
patients with Crohn's disease. Gastroenterology. 2014;146(3):681-8.e1.
309. Kierkuś J, Iwańczak B, Wegner A, Dadalski M, Grzybowska-Chlebowczyk U, Łazowska
I, et al. Monotherapy with infliximab versus combination therapy in the maintenance of
clinical remission in children with moderate to severe Crohn disease. J Pediatr Gastroenterol
Nutr. 2015;60(5):580-5.
310. Moore C, Corbett G, Moss AC. Systematic Review and Meta-Analysis: Serum
Infliximab Levels During Maintenance Therapy and Outcomes in Inflammatory Bowel
Disease. J Crohns Colitis. 2016;10(5):619-25.
311. Nanda KS, Cheifetz AS, Moss AC. Impact of antibodies to infliximab on clinical
outcomes and serum infliximab levels in patients with inflammatory bowel disease (IBD): a
meta-analysis. Am J Gastroenterol. 2013;108(1):40-7; quiz 8.
312. Paul S, Moreau AC, Del Tedesco E, Rinaudo M, Phelip JM, Genin C, et al.
Pharmacokinetics of adalimumab in inflammatory bowel diseases: a systematic review and
meta-analysis. Inflamm Bowel Dis. 2014;20(7):1288-95.
313. Merras-Salmio L, Kolho KL. Clinical Use of Infliximab Trough Levels and Antibodies to
Infliximab in Pediatric Patients With Inflammatory Bowel Disease. J Pediatr Gastroenterol
Nutr. 2017;64(2):272-8.
314. Sandborn WJ, Gasink C, Gao LL, Blank MA, Johanns J, Guzzo C, et al. Ustekinumab
induction and maintenance therapy in refractory Crohn's disease. N Engl J Med.
2012;367(16):1519-28.
96