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19 Stricturing Crohn’s Disease: Strictureplasty
289
after adrenalectomy [69]. In addition, there is a growing body of evidence indicating that liver brosis is a potentially reversible and bidirectional process overcoming the former paradigm of liver cirrhosis being an irreversible process. Repetitive
histological evaluation via liver biopsies could prove reduction of the brosis grade
after removal of the liver injury-causing triggers in patients with hepatitis C, [70]
hepatitis B, [71] non-alcoholic steatohepatitis (NASH) [72] or autoimmune hepatitis [73].
Although the gut comprises unique features compared to other organ broses,
such as severity and chronicity of inammation in the context of IBD, the quality
and quantity of the commensal microbiota or environmental inuences on the
disease course, intestinal brosis shares essentially all core mechanistic features
with brotic disease of the above-mentioned organs [74–77]. Therefore, it appears
to be reasonable to consider these mechanisms and therapeutic approaches and
apply them as promising approaches for the reversal of stricturing CD.
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293
Chapter 20
Challenges ofTranslation ofAnti-Fibrotic
Therapies into Clinical Practice inIBD
GerhardRogler
Abstract Fibrosis is an important clinical problem and affects a high number of
patients with inammatory bowel diseases (IBD). Anti-inammatory therapies may
not be sufcient to prevent intestinal brosis in IBD patients. Several anti-brotic
treatment approaches have been developed. However, there are signicant challenges in translating these anti-brotic therapies into clinical practice in IBD.
Anti-brotic therapy approaches in IBD are complicated by the fact that an effective and intact wound healing response and effective repair mechanisms are essential in Crohn’s disease and ulcerative colitis patients. This implies that the
anti-brotic therapies must not interfere with repair and tissue regeneration.
Strategies interfering with transforming growth factor (TGF)β expression and activation are promising in other brotic diseases but may lead to more inammation in
IBD.The specic pathophysiology of IBD makes it difcult to extrapolate clinical
data obtained with anti-brotic agents in other diseases than the gut. Another challenge is the lack of clear-cut clinical endpoints and readout for clinical trials for
intestinal brosis. At present, the development of anti-brotic therapies takes place
in other diseases such as lung and liver brosis. It will be important to develop new
clinical endpoints for intestinal brosis trials to test new anti-brotic treatment
strategies in IBD to benet from progress in other brotic diseases.
Keywords Inammatory bowel disease · Imaging · Clinical end points · Fibrosis
markers · Translational medicine
G. Rogler
Division of Gastroenterology and Hepatology, University Hospital Zürich,
Zürich, Switzerland
e-mail: gerhard.rogler@usz.ch
F. Rieder (ed.), Fibrostenotic Inammatory Bowel Disease,
https://doi.org/10.1007/978-3-319-90578-5_20
295© Springer International Publishing AG, part of Springer Nature 2018
296
G. Rogler
Abbreviations
CD Crohn’s disease
IBD Inammatory bowel disease
IL Interleukin
UC Ulcerative colitis
20.1 Introduction
Up to two thirds of patients with CD may develop either a stricturing or penetrating
disease course within 10years after diagnosis [1]. Up to 80% of all CD patients
undergo surgery at least once during the course of their disease [2–4]. In half of
these patients intestinal obstructions and strictures are the indication for surgery.
Recent data by Pittet and coworkers from the Swiss IBD Cohort group indicate that
over a period of 40years still more than 75% of patients have to undergo surgery
[5]. The most frequent reason for surgery right after diagnosis of CD is brosis [5].
Over the rst 25years thereafter an almost a linear decrease in the proportion of
surgery-free patients can be observed.
Whereas we are able to control for inammation better and better, an effective
preventive therapy for brosis or a pharmacological approach that could even reduce
brosis is literally absent. Most gastroenterologists believe that surgery can be
avoided by preventing or reducing inammation. This concept also has been brought
forward by Pariente and colleagues [6]. In this concept, surgery is necessary due to
a chronic subclinical inammation and subsequent brosis caused by smoldering
inammation [6]. The evidence to support this concept is weak. To some extent,
brosis might be independent from the inammatory process. Recent epidemiologic data indicate that early treatment intervention may prevent a B1–B3 development of disease subtypes but not B1–B2in CD patients [7].
It is obvious, that brosis research and development of potential therapeutic avenues is much more advanced in other brotic diseases. Therefore, it is important to
“think out of the box” and to learn from those areas to improve the situation of
patients with CD and UC. Whereas there is some progress in basic research on
brosis in IBD, clinical research on the prevention and therapy of brosis in IBD is
still largely absent. Pathophysiological mechanisms leading to brosis in IBD have
recently been reviewed [8–10].
20.2 Which Therapeutic Targets Have Been Identied
inOther Fibrotic Diseases?
Basic research in liver brosis not only focuses on anti-inammatory strategies as is
presently the case in CD [11–16]. Several other interesting approaches have been
investigated for the treatment of liver brosis: Inhibitors of proliferation and
20 Challenges ofTranslation ofAnti-Fibrotic Therapies into Clinical Practice inIBD
297
angiogenesis were tested successfully for the prevention of liver brosis. An interesting target is the Hedgehog signaling pathway [17, 18]. This pathway transmits
information in embryonic cells and is required for proper development. An involvement of Hedgehog signaling has recently been discussed for idiopathic pulmonary
brosis [19, 20] and liver brosis [17, 18]. The Hedgehog pathway was found to be
activated in lungs of patients with idiopathic pulmonary brosis where it is contributing to progression of brosis by increasing the proliferation, migration, extracellular matrix production, and survival of pulmonary broblasts [19].
Direct brogenesis inhibitors have been tested in animal models of pulmonary
of liver brosis. Among those direct brogenesis inhibitors are TGFβ1 and TGFβ1
receptor antagonists [21–25], hepatocyte growth factor (HGF) agonist [26],
angiotensin- receptor antagonists [27, 28], ACE inhibitors [29], connective tissue
growth factor (CTGF) antagonists [30, 31], cannabinoid receptor 1 antagonist
[32–34] and lysophosphatidic acid receptor type 1 (LPA1) antagonists [35, 36].
Instead of inhibiting brosis a successful strategy may be the stimulation of
extracellular matrix degradation [37, 38]. In respective brosis models inhibitors of
tissue inhibitor of metalloproteinases (TIMP) [39], TGFβ antagonists and inhibitors
of lysyl oxidase like 2 (LOXL2) [40] were tested. The LOXL2 was targeted also
clinically by a specic antibody in clinical trials in idiopathic lung brosis and liver
brosis, however respective trials were negative or stopped [41–43].
20.3 Why Is Translation ofAnti-Fibrotic Therapies into
Clinical Practice inIBD SoDifcult?
The development of anti-brotic therapies in IBD is difcult for two major reasons.
First, there is a lack of suitable animal models that would allow to test a series of
different compounds and identify promising candidates for IBD.There are some
models of intestinal brosis available; however, they all have specic disadvantages. Animal models of brosis have been recently summarized and reviewed by
Theresa Pizarro [44, 45]. In these animal models of intestinal brosis the initiation
of brosis usually is either induced by chemicals such as dextrane sodium sulfate
(DSS) [46–48] or 2,4,6-trinitrobenzenesulfonic acid (TNBS) [49–56] or by bacterial cell wall products such as peptidoglycan (PG-PS) [57, 58]. Of course, this way
of induction of brosis is quite articial. A spontaneous model, the SAMP1/YitFc
mouse strain was studied by Pizarro etal. [45, 59]. This mouse model has the great
advantage that intestinal brosis develops without chemical induction. Unfortunately,
this model seems to depend on local factors in the animal facilities and most
likely the local microbiota [60].
A recent heterotopic transplant model adapted from a bronchial transplant model
[61, 62] has the advantage of a reliable and rapid induction of brosis in isolated
parts of the small intestine [63]. Small bowel resections are transplanted subcutaneously into the neck of recipient animals [63]. A rapid brosis occurs within
7–14 days associated with increased expression of brosis- mediators such as
beta6 integrin, interleukin (IL)-13, and TGFβ [63]. In this model of intestinal
alpha
v
298
brosis pirfenidone and antibodies against MMP-9 proved to be effective and prevented the development of strictures whereas antibodies against LOX-L2 were not
successful [64, 65]. This may indicate that indeed targets and compounds can be
screened with this model that could be promising for further clinical development.
The second important challenge in the translation of anti-brotic therapies into
clinical practice in IBD is the lack of clinical scores and objective endpoints for
such clinical trials.
G. Rogler
20.4 Why Do WeHave No Clinical Trials onthePrevention
ofIntestinal Fibrosis?
At present, there is no reliable biomarker that would fulll the criteria for a good
endpoint in a respective clinical study. There are no serum markers of intestinal
brosis that accurately correlate with the process of brosis or the degree of collagen deposition. YKL-40 has been reported to be a marker for liver brosis [66].
Increased levels have also been found in patients with intestinal strictures but the
correlation coefcient is only r=0.457 and serum levels are also increased during
active inammation [67] making this marker not a good candidate for clinical trials.
All further “marker-candidates” do not show a sufcient correlation with the degree
of intestinal brosis to be useful for monitoring of an anti-brotic therapy. Several
new markers for liver brosis [68–70] have not been investigated in sufcient detail
in intestinal brosis. Most likely the volume of the brotic area in the intestinal wall
is too small to be reliably represented by a serum marker. In general, this important
aspect discriminates intestinal brosis and stricture formation from liver brosis or
lung brosis. Both are large organs and even in cases where the brosis is not completely homogeneous it affects the whole organ. In intestinal brosis, the majority
of the organ remains unaffected.
Besides the lack of serum markers there is a lack of clinical scores or indices that
have been stablished to quantify the clinical complaints and signs caused by brosis. No patient reported endpoints have been validated and are available for respective clinical trials.
In addition, to date the current imaging techniques have not been developed to a
point to be useful as clinical endpoints. In CT scans or MRI as well as in ultrasound
the evaluation of brosis mostly relies on subjective parameters. Contrast enhancement usually is seen as a sign of inammation. However, active brosis could also
lead to a contrast enhancement because it is a biologically and metabolically highly
active process [71]. Only when brosis is already established and a full scar or sclerosis has developed there is no contrast enhancement. A recently developed technique developed for the detection of intestinal brosis in MRI is “magnetization
transfer” (MT) [57, 58]. MT generates contrast that is primarily determined by the
fraction of large macromolecules or immobilized phospholipids in cell membranes
in tissue [58]. Connective tissue such as bone, cartilage and muscle show an intense
20 Challenges ofTranslation ofAnti-Fibrotic Therapies into Clinical Practice inIBD
Table 20.1 Current trials on brosis, strictures and Crohn’s disease
Trial nr Title Target Sponsor
NCT01986127 A randomized,
double-blinded,
placebo-controlled
study on the effects of
adalimumab
intralesional intestinal
strictures of Crohn’s
disease patients
NCT02675153 Efcacy and safety of
sirolimus in the
treatment of Crohn’s
disease with stenosis
NCT02395354 Comparative
prospective multicenter
randomized study of
endoscopic treatment of
stenosis in Crohn’s
disease: metal
self-expanding
prosthesis balloon
dilatation
Administration of intralesional
adalimumab (directly injected in
the stricture) associated to
endoscopic dilatation. Success
rate at week 8 compared with
placebo in patients with Crohn’s
disease with conrmed intestinal
stenosis (3 stenosis as maximum)
Efcacy and safety of sirolimus
in the treatment of stricturing
Crohn’s disease
To evaluate the efcacy of
endoscopic treatment (prosthesis
vs dilation), determined by the
percentage of free patients of a
new therapeutic intervention
(dilatation, prosthesis or surgery)
for symptomatic recurrence at
1year follow-up
Investigator
initiated; Hospital
Clinic of
Barcelona
Investigator
initiated; the
second Hospital
of Nanjing
Medical
University
Investigator
initiated; Grupo
Espanol de
Trabajo en
Enfermedad de
Crohn y Colitis
Ulcerosa
299
signal in MT. Also brotic strictures in the mucosal wall show an intense MT signal:
In normal, non-brotic bowel wall segments, an intermediate MT ratio of 25.4±3.4%
was measured, whereas, to the contrary, the MT ratio was signicantly increased in
bowel wall segments with brotic areas (35.3±4.0%, p<0.0001) [72]. MT could
become an option to quantify brosis in intestinal segments. On the other hand, new
ultrasound techniques such as shear wave elastography may be promising [73–77].
The difculties of translation of anti-brotic therapies into clinical practice in
IBD are reected by the fact that only three studies are currently active for patients
with Crohn’s disease and brosis (see Table20.1). All of them are investigator initiated illustrating that the pharmaceutical industry has not understood the potential of
this indication or does not want to face the outlined challenges in dening endpoints
and scores.
20.5 Which Endpoints Are Used inClinical Trials
onFibrosis inOther Diseases?
The lack of an easily determined clinical endpoint is a major disadvantage for trials
on intestinal brosis. What reliable endpoints are used in other diseases?