Mucosal need to evaluate mucosal healing; clinicians hear

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.

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 
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


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
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
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.

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


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

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).

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

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).

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 <3) or with mild (CDEIS 3-8) endoscopic disease (MHI range 0–40) and a positive predictive value (PPV) of 87% for identifying patients with endoscopic evidence of active disease (CDEIS ?3; MHI range 50–100) (Table 2). NR41 An additional 14% of the specimens fell within an intermediate zone (MHI 41–49), with an observed 78% probability of active disease. This peripheral blood-based test can be used as a noninvasive surrogate for mucosal endoscopic activity, as assessed by ileocolonoscopy. Integration of this mucosal healing test in current clinical practice could aid in the management and monitoring of patients with Crohn's disease to help determine therapeutic efficacy in a treat-to-target paradigm. NR46 16 A Novel Serum Test Describes the Mucosal Healing State by Disease Location in Patients With Crohn's Disease The utility of noninvasive serological tests in patients with Crohn's disease stems from its transmural nature and lack of optimal endoscopic accessibility to the small bowel, particularly in patients with ileal and ileocolonic disease. With a newly developed serologic test demonstrating efficacy as a tool for assessing the intestinal mucosal state in patients with Crohn's disease, a second study by Vermeire et al aimed to assess the diagnostic performance and clinical utility of a novel mucosal healing test in specific subtypes of patients with Crohn's disease who have been classified by the location of their disease.NR47 15 In addition to determining the PPV and NPV in the combined group, the utility of the MHI was also determined by each disease location. Test accuracy was 95%, 90%, and 87% for ileal, ileocolonic, and colonic disease, respectively. "We all need our patients to achieve mucosal healing, or significant improvements in mucosal health. If we could calibrate an objective measure of mucosal healing to actual colonoscopy scores in an individual patient, then we can follow that biomarker thereafter, limiting the need for ongoing colonoscopies." – Dr Dubinsky   This novel serum test for the noninvasive evaluation of mucosal health shows comparable performance across ileal, ileocolonic, and colonic anatomic disease locations in patients with Crohn's disease. These results further validate the clinical utility of the test as a beneficial aid in assessing the state of the intestinal mucosa regardless of disease location.NR56 15 The MHI Can Assess the Efficacy of Biologic and Nonbiologic Therapies on the Mucosal Health of Patients With Crohn's Disease Dulai et al further extended these findings to test the performance of biologic and nonbiologic therapies in patients with Crohn's disease. Approximately 50% of the cohort consisted of patients treated with biologic therapies (adalimumab: 18.3%, infliximab: 15%, anti-integrins: 10.9%, and ustekinumab: 6.5%) and the remainder on thiopurines or mesalamine. The MHI test was performed agnostic of therapy.NR57 17 Mean MHI values demonstrated positive correlation with increasing endoscopic disease severity (P<0.0001; Figure 5), and there was no significant change in accuracy when looking at biologic exposed vs nonexposed individualsNR58 , demonstrating that the test is able to accurately assess mucosal healing in patients with Crohn's disease across several different types of therapeutic classes. Therefore, this test has the potential to be utilized as a noninvasive tool to monitor and help manage the care of patients with Crohn's disease regardless of therapy. "You want a marker that is responsive to change and responsive to treatment. If we could use a marker to show a change in mucosal healing following escalation or optimization of therapy without needing to rescope a patient, that would be very nice for managing Crohn's disease." – Dr Dubinsky   The PROMETHEUS® Monitr™ Mucosal Healing Diagnostic Test Allows Clinicians to Monitor Mucosal Healing in Patients With Crohn's DiseaseNR61  The PROMETHEUS Mucosal Healing Diagnostic Test, PROMETHEUS® MonitrTM Crohn's Disease, is the first serum test for monitoring mucosal healing. MonitrTM allows clinicians to noninvasively measure mucosal healing and to monitor changes in mucosal status over time in patients with Crohn's disease, lending itself to several potential clinical applications (Figure 6). Monitr has demonstrated a 90% concordance rate with endoscopically visualized mucosal inflammationNR64 .NR65 16 AS66 By providing a history of mucosal healing index scores over time, Monitr can help clinicians assess whether treat-to-target goals have been achieved. Additionally, information included in the test report can be used to facilitate patient counseling about disease management goals and to reinforce the importance of patients continuing appropriate treatment, regardless of their current symptoms. NR67  The Monitr diagnostic test may improve the standard of care for patients with Crohn's disease and it is a useful tool for clinicians NR68 to get patients to the recommended treat-to-target goal of mucosal healingNR69 AS70 .5,8       "Patients are still concerned about symptoms more than endoscopy. We, as clinicians, need to convey the benefits of mucosal healing to patients, so they will understand the importance of adhering to therapies even in the absence of symptoms." – Dr Dubinsky   The Monitr test can be used in conjunction with other clinical signs and symptoms to optimize therapy and extend periods of disease remission in patients with moderate-to-severe Crohn's disease. With the availability of this test, mucosal healing can be used as a noninvasive, standardized clinical end point for use in clinical practice as well as in future GI clinical trials.    A serologic test for mucosal healing may also reduce health care costs associated with the management of patients with Crohn's disease by providing a cost-effective method of assessing the GI mucosa.NR71 8,9 AS72 The test also provides clinicians with information needed to appropriately modify treatment and achieve mucosal healing, in some cases leading to additional cost savings by reducing the need for unnecessary escalation of biologic medications. Furthermore, mucosal healing has been associated with decreased need for corticosteroids, decreased hospitalization rates, sustained clinical remission, decreased incidence of colectomy and bowel resection, and decreased risk of colorectal cancerNR73 , thus controlling health care costs by improving patient outcomes.


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