Mucosal need to evaluate mucosal healing; clinicians hear

Mucosal
barrier dysfunction is central to the pathogenesis of Crohn’s disease and leads
to loss of intestinal immune homeostasis. An intact mucosal barrier prevents
the translocation of bacteria into the mucosa and submucosa, thereby
downregulating the pathologic immune response. Once this barrier is impaired,
pathogenic bacteria are able permeate the gut, activating proinflammatory
signaling pathways associated with Crohn’s disease.

Patients
with Crohn’s disease experience phases of active disease and remission;
however, those in remission may still be affected by mucosal damage. While
patients experience variable disease courses, with disease activity fluctuating
over time, structural damage to the luminal GI tract may continue to progress in
asymptomatic patients during a phase of low disease activity.NR3 
2
Several
studies have demonstrated that a patient’s current symptoms do not always correlate
with mucosal statusNR4 .3 Notably, an evaluation of Crohn’s
symptoms, assessed by the Crohn’s disease activity index (CDAI) vs endoscopy,
assessed by Crohn’s disease endoscopic findings (CDEIS) showed no correlation
between the 2 measures (rAS5 =0.13;
not significant NS) (Figure 2).NR6 
4 Therefore, in order to fully
assess disease severity and risk of complications associated with disease
progression in patients with Crohn’s disease, clinicians need to be able to
evaluate the patients’s mucosal
status so that they can manage the disease appropriatelyNR7 .5

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“More people are becoming aware of the need to evaluate
mucosal healing; clinicians hear about the need to ‘treat-to-target’ and the lack
of correlation between symptoms and mucosal status. The FDA now requires
endoscopic response and remission to be included as primary end points in
clinical trials for new Crohn’s disease therapies, a decision that has placed
further emphasis on the importance of mucosal healing.” – Dr Dubinsky

 

While
endoscopy is the current “gold standard” for assessing mucosal statusNR9 ,
several limitations
exist that hamper the widespread use of endoscopy for assessment and ongoing
monitoring of mucosal status.5-7 The procedure is invasiveNR10 , causes
discomfort to patients resulting in low compliance, and comes with risks of
perforation and bleeding, as well as cardiovascular risks associated with
sedation.NR11 8,9
AS12 In Crohn’s disease, endoscopy is particularly
problematic, as it cannot be used to visualize transmural inflammation that
patients with Crohn’s disease experience.NR13 6 Endoscopy
results are qualitative and open to interpretation by the readerNR14 AS15 , and are therefore susceptible
to considerable variability from one endoscopist to anotherNR16 AS17 .8,9
As
recently demonstrated in Laharie et al, the CDEIS and Simple Endoscopic Score
for Crohn’s Disease (SES-CD) scores, which are considered to be the “endoscopic
gold standard” end points, are in agreement only 59% of the time.NR18 7 Additionally,
there are significant costs associated with endoscopy because of the expense of
both the imaging equipment and the procedure. NR19 5,6,8,9AS20 

 

“We really need an objective way to view snapshots of the
mucosa without having to keep scoping people.” – Dr Dubinsky

 

Various mucosal healing surrogates have been evaluated for
their sensitivity and specificity to assess mucosal damage in patients with
Crohn’s disease; however, each has notable shortcomings. Mucosal healing
surrogates can be categorized as standard
of care biomarkersNR21 AS22 , disease activity indicesNR23 , imaging methods, magnetic resonance imaging grading
indices, NR24 and experimental
biomarkersNR25 AS26 .10-14
Standard
of care biomarkers include fecal calprotectin (FC), C-reactive protein (CRP),
and leukocytesNR27 . FC is the only noninvasive biomarker capable
of discriminating between inactive and active Crohn’s disease; however, correlation of FC to endoscopy varies
based on disease anatomy and location. FC is also limited by its ability to
distinguish inflammatory bowel disease (IBD) symptoms from other inflammatory
responses, such as bacterial infection and drug-induced enterocolitis. Finally,
FC levels are prone to analytic variability and sample stability issues. NR28 13

 

“The more noninvasive biomarkers we have to objectively
evaluate the mucosa, the better off patients will be.” – Dr Dubinsky

 

Serology may offer a viable complementary approach to
endoscopy for assessing and monitoring mucosal status. Serologic markers of inflammation
correlate with the degree of mucosal damage. Several signaling molecules are
involved in mucosal injury and the repair of pathways, including inflammation,
angiogenesis, matrix remodeling, growth factors, immune recruitment modulation,
and cell adhesion. These molecules can be assayed via serologic testing, which
is noninvasiveNR29 .15 Therefore, serologic markers
can be used in conjunction with an initial endoscopy and can subsequently be
used alone for ongoing monitoring of disease progression between endoscopies as
a more practical approach to monitoring mucosal status.

Mucosal
healing, defined as the absence of ulceration and erosions, is an accepted
treat-to-target goal for patients with Crohn’s disease that is supported by
clinical evidence. The Selecting Therapeutic Targets in Inflammatory Bowel
Disease (STRIDE) initiative assembled a global committee of 33 specialists with
expertise in treating IBD to determine an appropriate evidence-based treat-to-target
regimen for patients with IBD. After a thorough review of the literature, this
group identified mucosal healing as a therapeutic goal for patients with
Crohn’s disease. Mucosal healing is an attainable goal with the implementation
of a comprehensive patient management plan, including ongoing evaluation of the
treatment goal and appropriate modification of the management approach designed
to reach that goal.NR30 5

The availability of a serology-based
mucosal healing test has the potential to improve patient outcomes by providing
the means to regularly evaluate mucosal status and to determine how
aggressively a patient should be treated, regardless of whether the patient is experiencing
a flare or an asymptomatic period, to ultimately achieve the treat-to-target
goal of mucosal healing.NR31 2,5,8AS32 

 

Development and Validation of a
Multimarker Serum Test for the Assessment of Mucosal Healing in Patients With Crohn’s
Disease

 

Vermeire
and colleagues have recently developed a serum-based, multianalyte, mucosal healing
algorithm, incorporating a panel of biomarkers associated with biological
pathways that are important for mucosal homeostasis in patients with Crohn’s
disease.NR33 15

In
order to identify a set of biomarkers to be included in the panel, retrospective
serum samples were taken from adult patients with Crohn’s disease at or within
30 days of ileocolonoscopy. Based on this training cohort, a panel of serum
proteomic biomarkers was selected from an initial set of 48 markers correlating
with endoscopic activity and was used to train a logistic regression model
against visualized endoscopic disease severity determined by either CDEIS or
SES-CD scores. The model was independently validated in a prospectively
collected, centrally read, longitudinal cohort of 118 patients from the
TAILORIX clinical trial (Table 1).

A
total of 748 samples from 396 patients—of which the mean age was 34 years, 49% were
male, 26% had ileal disease, 52% had ileocolonic disease, and 22% had colonic
disease—were used for the training and validation of a Mucosal Healing Index
(MHI). Patients were included regardless of therapeutic treatment.NR37 15,16

The
final model utilized 13 biomarkers representing multiple biological pathways
involved in the mucosal healing process, including angiogenesis (angiopoietin Ang1,
Ang2), cell adhesion (carcinoembryonic antigen-related cell adhesion molecule CEACAM1AS38 , vascular cell adhesion molecule  VCAM1), growth factor signaling (transforming
growth factor ? TGF?), inflammation (CRP, serum amyloid A SAA1), matrix
remodeling (matrix metalloproteinase MMP-1, -2, -3, -9 and extracellular matrix
metalloproteinase inducer EMMPRIN), and immune modulation (interleukin IL-7).

The
MHI was developed as a scale ranging from 0–100. The overall accuracy of the test was 90%, with a negative predictive value
(NPV) of 92% for identifying patients in remission (CDEIS