Gastroenterology & Hepatology

May 2018 - Volume 14, Issue 5, Supplement 2

A Noninvasive Method to Assess Mucosal Healing in Patients With Crohn’s Disease

William J. Sandborn, MD, Maria T. Abreu, MD, and Marla C. Dubinsky, MD

Abstract:  Ongoing inflammation in the gastrointestinal tract and loss of the mucosal barrier are key components of Crohn’s disease. Current treatment paradigms, including treat-to-target, are based on improvement of both clinical and endoscopic symptoms. Endoscopy is an essential tool for the evaluation of mucosal healing, but patients may be reluctant to undergo repeated procedures. Surrogate markers of inflammation, such as C-reactive protein and fecal calprotectin, are being used, yet they have several limitations in the assessment of mucosal healing. A new strategy, known as the Monitr test, assesses mucosal healing status by evaluating serum levels of 13 biomarkers in patients with Crohn’s disease. The 13 biomarkers are associated with cell adhesion, inflammation, angiogenesis, extracellular matrix remodeling, cell proliferation and repair, and immune cell recruitment. Monitr testing yields a mucosal healing index score that reflects disease severity. Validation of the test showed an overall accuracy of 90%, with a negative predictive value of 92% and a positive predictive value of 87% for identifying patients with endoscopic evidence of Crohn’s disease. Use of this noninvasive test may aid in the monitoring and management of patients with Crohn’s disease, while potentially reducing the need for repeated endoscopy.

 

The Role of Mucosal Healing in Patients With Crohn’s Disease

Maria T. Abreu, MD

Director, Crohn’s and Colitis Center
Professor of Medicine, Microbiology, and Immunology
University of Miami
Miller School of Medicine
Miami, Florida

In Crohn’s disease, mucosal healing is linked to the most important patient outcomes, namely, avoidance of surgery and hospitalization, and maintenance of a high quality of life.1-3 Patients with Crohn’s disease (as well as their unaffected first-degree relatives) have increased permeability within the intestine.4-6 The origin of this increased permeability is uncertain.5 One contributing factor may be inflammatory cytokines, such as tumor necrosis factor (TNF), that are produced locally.7 In mouse models, TNF can disturb barrier function.8 Anti-TNF therapy is one of the main modalities used to treat Crohn’s disease.1,7,8 It is assumed that local production of TNF-alpha in the intestines of patients with Crohn’s disease contributes to a leaky mucosal barrier.5,6,9 Some of the genetic defects that have been described in patients with Crohn’s disease are closely linked to barrier function, particularly repair of the epithelium.5

One way to treat inflammatory bowel disease is to target the production of inflammatory cytokines, which can disrupt the barrier.1,10 Research is also exploring methods that improve epithelial integrity, such as enhancing local levels of interleukin-22.11 In patients with Crohn’s disease, the inflammation is transmural,8,12,13 which has repercussions for the structural damage that can occur in these patients, but is more rare in patients with ulcerative colitis.12,13 In patients with Crohn’s disease, even if the intestinal mucosa is eventually healed, there may be transmural structural damage that cannot be improved by medical therapy.1,13

Treatment Goals

There have been recent breakthroughs in the medical therapies available for patients with inflammatory bowel disease. Infliximab and other anti-TNF agents showed that it was possible to heal the intestinal lining.1,3 Until the advent of infliximab, healing of the intestine was not even part of management goals. Currently, any new treatment under investigation for Crohn’s disease or ulcerative colitis must be shown to improve ulcerations.14-16

Treatment goals have now evolved to consistently encompass mucosal healing. The strategy known as treat-to-target involves treating the target of inflammation until there is both symptomatic and endoscopic improvement.15-17 This approach was highlighted by the phase 3 CALM study (Efficacy and Safety of Two Treatment Algorithms in Adults With Moderate to Severe Crohn’s Disease).15 In the control arm, changes in a patient’s medication were based solely on clinical symptoms. In the treat-to-target arm, changes in medication were based on clinical symptoms, as well as biochemical markers of inflammation. These patients underwent testing for levels of fecal calprotectin and C-reactive protein. Therapy was escalated when patients showed objective evidence of inflammation. In both groups, treatment was escalated from no treatment, to adalimumab induction followed by adalimumab every other week, to adalimumab every week, to weekly adalimumab and daily azathioprine.

The study found that patients in the treat-to-target group had much better outcomes than the control patients.15 Therapy was optimized quickly for patients in the treat-to-target arm, which led to higher rates of mucosal healing, deep remission, and reduced prednisone use compared with patients in the clinical management group. Post hoc exploratory analyses showed that the decision to escalate treatment was based on increased fecal calprotectin concentration in 62% of patients at 11 weeks after randomization and in 56% of patients at 23 weeks after randomization. Escalation based on increased C-reactive protein concentration, which is a less sensitive marker of inflammation,18 was less common, occurring among 46% of patients at 11 weeks postrandomization and in 46% of patients at 23 weeks postrandomization. At week 35, fecal calprotectin and C-reactive protein concentrations contributed equally to the decision to escalate in 45% of patients. Overall, the CALM study proved that treat-to-target is an effective strategy. 

The Role of Mucosal Healing

Mucosal healing can be defined in various ways.3 One measure of mucosal healing is the absence of ulcerations or inflammation during colonoscopy or capsule endoscopy.1,2,16 With histologic assessment, a pathologist confirms the absence of inflammatory cells in an area of previous involvement.2 With the advances in medical therapy, the expectation is not only for patients to feel better, with fewer clinical symptoms, but also for endoscopy to show improvement.2,3,16

Endoscopy has been the primary method to evaluate mucosal healing.1 Endoscopy enables the gastroenterologist to examine the mucosa and to obtain biopsies that can be evaluated microscopically for inflammation. However, patients with inflammatory bowel disease undergo many endoscopies, which can be a source of dissatisfaction, particularly because of the bowel prep.19 Endoscopy is expensive, and, on rare occasions, it can be associated with perforation and bleeding. The risk of perforation is higher among patients with Crohn’s disease compared with the general population.20 

Data suggest that the severity of endoscopic lesions does not correspond to clinical symptoms. A multicenter, prospective study evaluated the connection between the Crohn’s Disease Activity Index (CDAI) and the Crohn’s Disease Endoscopic Index of Severity (CDEIS) among patients with active colonic or ileocolonic Crohn’s disease. Only 29% of patients in clinical remission were also in endoscopic remission.21

Ideally, use of endoscopy to assess mucosal healing should follow a standardized method to capture data.2 Various instruments are validated to assess the severity of inflammation endoscopically.2 The CDEIS and the short version of the CDEIS (simple endoscopic score for Crohn’s disease [SES-CD]) have both been validated.2,22,23 The intestine is rated in segments. The ratings describe how much of the segment is involved, how much of it is ulcerated, the size of the ulcerations, and whether there are strictures.2 This method highlights the importance of structural damage in Crohn’s disease, which is difficult to manage once it has occurred. 

The scoring systems are considered by many to be too complex for clinical use.2,24 Many (if not most) gastroenterologists do not use these validated instruments to rate the severity of inflammation.2,24 The lack of a standardized measurement has several implications. It can be difficult to measure changes without knowing the baseline levels. In many cases, there are no accurate assessments before or after an intervention. Endoscopy can be a sensitive method of detecting ulcerations, but the benefit is diminished if the gastroenterologist has not properly identified and quantified the severity of the disease. In addition, inter-observer variability in the interpretation of involvement can lead to inconsistency in scoring.24 

Markers of Inflammation

Researchers are trying to develop noninvasive ways to identify whether a patient has active inflammation or disease. One approach is the use of fecal calprotectin as a marker of inflammation.1,25 Fecal calprotectin is a reasonably sensitive marker of inflammation in the intestine. Calprotectin is more accurate in patients with colonic inflammation, and less accurate in patients with small-intestinal disease.26 A recent systematic review of 19 studies (N=2499) on the value of calprotectin for the detection of endoscopic activity in symptomatic IBD patients concluded that calprotectin was more sensitive than C-reactive protein.27 The study also showed that calprotectin was more sensitive in ulcerative colitis than in Crohn’s disease. Furthermore, in an earlier study, calprotectin levels showed a better association with disease activity in ulcerative colitis than in Crohn’s disease.28 

As a stool-based marker, fecal calprotectin is more accurate for assessing distal inflammation.25 Inflammation that is higher in the small intestine may not be reflected in the fecal calprotectin test. In patients with colonic inflammation, the fecal calprotectin level can be much higher, even if the inflammation is limited.29 In general, however, patients with a normal level of fecal calprotectin do not have active inflammation.30 A limitation to the fecal calprotectin test is that patients are reluctant to collect stool samples. Another potential limitation of fecal calprotectin is that, although it measures a neutrophil protein, it does not help to determine if the bowel is in the repair phase. It is best when used in the same patient over time to determine if the value is decreasing or increasing.

Conclusion

It is necessary to find other ways to measure healing of the intestinal lining. Some patients may show some existing inflammation that is close to healing. A noninvasive method of monitoring mucosal healing  would be a tremendous benefit to patients. It would be helpful to have a quantifiable measurement to provide a number that indicates the state of tissue injury and repair. Although stool testing is noninvasive, many patients are reluctant to collect stool samples.

Disclosure

Dr Abreu is a member of the scientific advisory boards of AbbVie Laboratories, Celgene Corporation, Shire Pharmaceuticals, Roche Pharmaceuticals, Boehringer Ingelheim Pharmaceuticals, AMGEN ABP 710 Biosimilar Infliximab, and MedStar Health. She is on the advisory boards of Allergan Brazikumab and SERES. She is a consultant for Prometheus Laboratories Inc; Takeda; UCB, Inc.; Pfizer; Janssen; Eli Lilly Pharmaceuticals; and Theravance Biopharma US, Inc. She has performed training/consulting for Focus Medical Communications. She has performed lecturing/teaching for Imedex, Inc. She has lectured for CME Outfitters.

References

1. Lichtenstein GR, Hanauer SB, Sandborn WJ, et al; Practice Parameters Committee of American College of Gastroenterology. Management of Crohn’s disease in adults. Am J Gastroenterol. 2009;104(2):465-483.

2. D’Incà R, Caccaro R. Measuring disease activity in Crohn’s disease: what is currently available to the clinician. Clin Exp Gastroenterol. 2014;7:151-161.

3. 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. Aliment Pharmacol Ther. 2017;45(10):1291-1302.

4. Cromer WE, Mathis JM, Granger DN, Chaitanya GV, Alexander JS. Role of the endothelium in inflammatory bowel diseases. World J Gastroenterol. 2011;17(5):578-593.

5. Teshima CW, Dieleman LA, Meddings JB. Abnormal intestinal permeability in Crohn’s disease pathogenesis. Ann N Y Acad Sci. 2012;1258:159-165.

6. Gibson PR. Increased gut permeability in Crohn’s disease: is TNF the link? Gut. 2004;53(12):1724-1725.

7. Zeissig S, Bojarski C, Buergel N, et al. Downregulation of epithelial apoptosis and barrier repair in active Crohn’s disease by tumour necrosis factor alpha antibody treatment. Gut. 2004;53(9):1295-1302.

8. Roulis M, Armaka M, Manoloukos M, Apostolaki M, Kollias G. Intestinal epithelial cells as producers but not targets of chronic TNF suffice to cause murine Crohn-like pathology. Proc Natl Acad Sci U S A. 2011;108(13):5396-5401.

9. Suenaert P, Bulteel V, Lemmens L, et al. Anti-tumor necrosis factor treatment restores the gut barrier in Crohn’s disease. Am J Gastroenterol. 2002;97(8):2000-2004.

10. Flamant M, Roblin X. Inflammatory bowel disease: towards a personalized medicine. Ther Adv Gastroenterol. 2018;11:1756283X17745029.

11. Mizuno S, Mikami Y, Kamada N, et al. Cross-talk between RORγt+ innate lymphoid cells and intestinal macrophages induces mucosal IL-22 production in Crohn’s disease. Inflamm Bowel Dis. 2014;20(8):1426-1434.

12. Qin X. Why is damage limited to the mucosa in ulcerative colitis but transmural in Crohn’s disease? World J Gastrointest Pathophysiol. 2013;4(3):63-64.

13. Curciarello R, Docena GH, MacDonald TT. The role of cytokines in the fibrotic responses in Crohn’s disease. Front Med (Lausanne). 2017;4:126.

14. Kotze PG, Ma C, Almutairdi A, Panaccione R. Clinical utility of ustekinumab in Crohn’s disease. J Inflamm Res. 2018;11:35-47.

15. Colombel JF, Panaccione R, Bossuyt P, et al. Effect of tight control management on Crohn’s disease (CALM): a multicentre, randomised, controlled phase 3 trial. Lancet. 2018;390(10114):2779-2789.

16. Peyrin-Biroulet L, Sandborn W, Sands BE, et al. Selecting therapeutic targets in inflammatory bowel disease (STRIDE): determining therapeutic goals for treat-to-target. Am J Gastroenterol. 2015;110(9):1324-1338.

17. Bouguen G, Levesque BG, Feagan BG, et al. Treat to target: a proposed new paradigm for the management of Crohn’s disease. Clin Gastroenterol Hepatol. 2015;13(6):1042-1050.e2.

18. Chang S, Malter L, Hudesman D. Disease monitoring in inflammatory bowel disease. World J Gastroenterol. 2015;21(40):11246-11259.

19. Dave M, Loftus EV Jr. Mucosal healing in inflammatory bowel disease—a true paradigm of success? Gastroenterol Hepatol (N Y). 2012;8(1):29-38.

20. Makkar R, Bo S. Colonoscopic perforation in inflammatory bowel disease. Gastroenterol Hepatol (N Y). 2013;9(9):573-583.

21. Modigliani R, Mary JY, Simon JF, et al. Clinical, biological, and endoscopic picture of attacks of Crohn’s disease. Evolution on prednisolone. Groupe d’Etude Thérapeutique des Affections Inflammatoires Digestives. Gastroenterology. 1990;98(4):811-818. 

22. Daperno M, D’Haens G, Van Assche G, et al. Development and validation of a new, simplified endoscopic activity score for Crohn’s disease: the SES-CD. Gastrointest Endosc. 2004;60(4):505-512.

23. Mary JY, Modigliani R. Development and validation of an endoscopic index of the severity for Crohn’s disease: a prospective multicentre study. Groupe d’Etudes Thérapeutiques des Affections Inflammatoires du Tube Digestif (GETAID). Gut. 1989;30(7):983-989.

24. Walsh AJ, Bryant RV, Travis SP. Current best practice for disease activity assessment in IBD. Nat Rev Gastroenterol Hepatol. 2016;13(10):567-579.

25. Moniuszko A, Głuszek S, Rydzewska G. Rapid fecal calprotectin test for prediction of mucosal inflammation in ulcerative colitis and Crohn disease: a prospective cohort study. Pol Arch Intern Med. 2017;127(5):312-318.

26. Abej E, El-Matary W, Singh H, Bernstein CN. The utility of fecal calprotectin in the real-world clinical care of patients with inflammatory bowel disease. Can J Gastroenterol Hepatol. 2016;2016:2483261.

27. Mosli MH, Zou G, Garg SK, et al. C-reactive protein, fecal calprotectin, and stool lactoferrin for detection of endoscopic activity in symptomatic inflammatory bowel disease patients: a systematic review and meta-analysis. Am J Gastroenterol. 2015;110(6):802-819.

28. D’Haens G, Ferrante M, Vermeire S, et al. Fecal calprotectin is a surrogate marker for endoscopic lesions in inflammatory bowel disease. Inflamm Bowel Dis. 2012;18(12):2218-2224.

29. Bjarnason I. The use of fecal calprotectin in inflammatory bowel disease. Gastroenterol Hepatol (N Y). 2017;13(1):53-56.

30. Schoepfer AM, Beglinger C, Straumann A, et al. Fecal calprotectin correlates more closely with the Simple Endoscopic Score for Crohn’s disease (SES-CD) than CRP, blood leukocytes, and the CDAI. Am J Gastroenterol. 2010;105(1):162-169.

 

Emerging Modalities to Assess Mucosal Healing in Crohn’s Disease

Marla C. Dubinsky, MD

Professor of Pediatrics
Chief, Pediatric Gastroenterology and Hepatology and Nutrition
Co-Director, Susan and Leonard Feinstein IBD Clinical Center
Icahn School of Medicine at Mount Sinai
New York, New York

As previously discussed, new modalities are needed to assess mucosal healing in Crohn’s disease. The Monitr test (Prometheus) analyzes biomarkers in a patient’s peripheral blood to assess mucosal healing.1,2 Mucosal alterations involve particular pathways that mediate cell adhesion, inflammation, angiogenesis, matrix remodeling, growth factors, and immune recruitment modulation.1-3 These pathways are associated with mucosal damage and/or repair in patients with Crohn’s disease, and they were used to identify 13 biomarkers that are analyzed by the Monitr test. These biomarkers are CEACAM and VCAM (cell adhesion); C-reactive protein and serum amyloid A (inflammation); angiopoietin-1 and -2 (angiogenesis); matrix metalloproteases (MMP)1, MMP2, MMP3, MMP9, and extracellular matrix metalloproteinase inducer (matrix remodeling); transforming growth factor alpha (growth factor); and interleukin-7 (immune recruitment modulation; Figure 1).1 

Matrix remodeling is most likely one of the more important pathways contributing to the formation of scar tissue or collagen.4 The development of damage to the bowel wall involves matrix remodeling in addition to ongoing inflammation.3,5 Therefore, in patients with Crohn’s disease, we would expect to see increasing expression of biomarkers associated with matrix remodeling and inflammation.1,4 The idea behind the Monitr test is that assessment of these biomarkers in the peripheral blood will reflect changes in the gut mucosa.1 Until now, it was necessary to rely mainly on ileocolonoscopy and cross-sectional imaging to assess the extent of a patient’s mucosal damage.6

The Mucosal Healing Index Score

The biomarkers that are assessed with the Monitr test are combined in an algorithm that results in the mucosal healing index (MHI) score, which ranges from 0 to 100.2 Serum samples were taken from adult patients with Crohn’s disease at or within 30 days of ileocolonoscopy.1,2 There were 748 samples taken from 396 patients in separate training and validation phases. The clinical parameters of patients in the training and validation sets are listed in Table 1. A panel of serum biomarkers was used to train a logistic regression model against visualized endoscopic disease severity, with the latter determined by either CDEIS or SES-CD scores.2 Expression of these serum protein markers was therefore compared with the endoscopic scoring of that subject at the time that was closest from the endoscopy to the collection of the serum. The training cohort included 278 patients and 335 samples from 4 sites, and the validation cohort included 118 patients and 413 samples from the TAILORIX trial (Study Investigating Tailored Treatment With Infliximab for Active Crohn’s Disease). The validation cohort showed a 90% accuracy with endoscopically visualized mucosal inflammation. An MHI score of 0 to 40 is consistent with remission or mildly active Crohn’s disease, and is similar to a CDEIS of less than 3 for patients in remission and a CDEIS of 3 to 8 for patients with mild disease activity (Figure 2). An MHI score of 41 to 49 is considered intermediate. In the validation study, 14% of the specimens fell within the intermediate zone, with an observed 78% probability of active disease.2 An MHI score of 50 to 100 is consistent with active disease and is similar to a CDEIS score of 3 or greater.

Predictive Value

The performance of the Monitr test was determined using the validation cohort (Table 2). For the entire cohort the sensitivity and specificity were 82% and 94% respectively, indicating that the test has a 18% false negative rate but only a 6% false positive rate. The low false positive rate indicates that the test is good at ruling in active endoscopic disease. The predictive values were also assessed. In the validation cohort, 78% of the population was in remission/mild disease and 22% had moderate/severe disease as defined by endoscopy. In this specific population, the probability that a positive Monitr test result identified true active endoscopic disease was 87% (positive predictive value = PPV) and the probability that a negative Monitr result identified a patient with true mild endoscopic activity or remission was 92% (negative predictive value = NPV) (Table 2). In order to determine if disease location influenced test performance, the validation cohort was subdivided by the presence of ileal only, ileocolonic and colonic only disease. As shown in Table 2, sensitivity and specificity for the individual locations were similar to that for the population overall, indicating that the test is not influenced by disease location.

MHI scores have been shown to correlate with endoscopic disease severity (Figure 3). In an analysis of the Monitr test that focused on the efficacy of biologic and nonbiologic therapies, the mean MHI values demonstrated a positive correlation with increasing endoscopic disease severity (P<.0001).7 The mean MHI values were 31.7 among patients in remission, 47.2 in those with mild disease, 57.4 in those with moderate disease, and 56.4 in those with severe disease, and there was no significant difference between biologic exposed or nonexposed individuals.7 

The study evaluating the predictive value of Monitr showed that the patients’ MHI score changed throughout the weeks after treatment (Figure 4). The test can therefore be used to monitor patients with Crohn’s disease over time.6 Changes in the MHI score can offer insight into the patient’s disease severity. 

Conclusion

Monitr offers a noninvasive, comprehensive evaluation of biomarkers measured in the serum. The test can be used to assess baseline disease activity and response to therapy over time by following a patient with repeated measurements. Monitr could potentially be an adjunct to endoscopy, with testing at the same time as endoscopy, to provide a benchmark, and as a monitoring method thereafter.8 Monitr test results are easily conveyed among physicians and to the patient.

Until now, the only biomarkers in inflammatory bowel disease were fecal calprotectin and C-reactive protein, both of which displayed limitations when used to assess mucosal healing.6,7 The test appears to be especially beneficial for small bowel disease because it can be difficult to access the ileum.9 In addition, Monitr minimizes the need for repeated endoscopic and radiologic procedures.9,10 This test is a welcome addition and merits further exploration in the clinical space to optimize use.

Disclosure

Dr Dubinsky is a consultant for Prometheus Laboratories Inc.

References

1. Vermeire S, D’Haens G, Hale M, et al. A novel serum test to describe the mucosal healing state by disease location in Crohn’s disease patients [WCOG abstract 74]. Paper presented at: the World Congress of Gastroenterology at ACG2017; October 13-18, 2017; Orlando, FL.

2. Kelly OB, Silverberg MS, Dulai PS, et al. Development and validation of a multi-marker serum test for the assessment of mucosal healing in Crohn’s disease patients [WCOG abstract P2184]. Paper presented at: the World Congress of Gastroenterology at ACG2017; October 13-18, 2017; Orlando, FL.

3. Cromer WE, Mathis JM, Granger DN, Chaitanya GV, Alexander JS. Role of the endothelium in inflammatory bowel diseases. World J Gastroenterol. 2011;17(5):578-593.

4. Mortensen JH, Manon-Jensen T, Jensen MD, et al. Ulcerative colitis, Crohn’s disease, and irritable bowel syndrome have different profiles of extracellular matrix turnover, which also reflects disease activity in Crohn’s disease. PLoS One. 2017;12(10):e0185855.

5. Li N, Shi RH. Updated review on immune factors in pathogenesis of Crohn’s disease. World J Gastroenterol. 2018;24(1):15-22.

6. Lichtenstein GR, Hanauer SB, Sandborn WJ, et al; Practice Parameters Committee of American College of Gastroenterology. Management of Crohn’s disease in adults. Am J Gastroenterol. 2009;104(2):465-483.

7. Dulai PS, Boland BS, Vermeire S, et al. A non-invasive serological test to assess the efficacy of biologic and non-biologic therapies on the mucosal health of patients with Crohn’s disease [WCOG abstract P2142]. Poster presented at: the World Congress of Gastroenterology at ACG2017; October 13-18, 2017; Orlando, FL.

8. Chang S, Malter L, Hudesman D. Disease monitoring in inflammatory bowel disease. World J Gastroenterol. 2015;21(40):11246-11259.

9. D’Incà R, Caccaro R. Measuring disease activity in Crohn’s disease: what is currently available to the clinician. Clin Exp Gastroenterol. 2014;7:151-161.

10. Dave M, Loftus EV Jr. Mucosal healing in inflammatory bowel disease—a true paradigm of success? Gastroenterol Hepatol (N Y). 2012;8(1):29-38.

 

Clinical Use of a Noninvasive Test to Assess Mucosal Healing in Crohn’s Disease

William J. Sandborn, MD

Professor of Medicine and Adjunct Professor of Surgery
Chief, Division of Gastroenterology
Director, UCSD IBD Center
University of California San Diego
University of California San Diego Health System
La Jolla, California

As a newly launched test, the best use of Monitr in clinical practice is still under investigation.1 However, the test will likely be ordered initially alongside an endoscopy, to see if results from both tests are confirmatory.1-3 The validation of this test showed a 90% concordance rate with endoscopy. Monitr can then be used to monitor the effect of therapy between endoscopic procedures.1 For example, a baseline value can be compared with results from 2 or 3 months later. The Monitr test can provide an indication of how the disease is changing. This monitoring could be used in the context of several types of therapies, such as corticosteroids, immunosuppressive agents, and biologic agents.2

Monitr is not meant to completely replace endoscopy.2,3 It will likely be ordered with colonoscopy, in patients about to undergo a change in therapy or another intervention.2 The test can be used for periodic monitoring, perhaps every 3 to 6 months at the discretion of the physician, or until another colonoscopy is performed 6 to 12 months later.1 Decreasing the amount of colonoscopy procedures is appealing to patients. 

The test offers a clear assessment for patients in mild remission and those with active disease.1,4 Test results in the intermediate zone—with an MHI score between 40 and 50—still have an observed 78% probability of active disease, as compared with an 87% probability of active disease among patients with an MHI score in the high zone (from 50 to 100).

Assessment of Mucosal Healing Over Time

An important question in the field is how to assess mucosal healing status over time, and how monitoring should impact the decision to continue anti-TNF alpha agents and other therapies.2,5 In addition, there is the question of when to withdraw anti-TNF therapy in patients who appear to be in remission.5 Patients who are in clinical remission may still have endoscopic disease.3,6 If the patient has endoscopic remission and clinical disease remission, some physicians believe that it is reasonable to withdraw anti-TNF therapy. Other physicians, however, believe that anti-TNF therapy should not be stopped, even in the case of a deep remission.5 

It appears that the Monitr test reflects endoscopic healing.1 If a patient receiving anti-TNF therapy achieves clinical remission, then the Monitr test should be used. If the test indicates that the patient likely has mucosal healing, then anti-TNF therapy may no longer be needed.5 This approach makes sense for physicians who believe it is reasonable to withdraw anti-TNF therapy in the context of endoscopic remission. In this setting, monitoring for relapse is important, and regular colonoscopies can be replaced with Monitr testing.

In contrast, some physicians continue anti-TNF therapy in patients who are responding well, unless toxicity occurs.7-9 In this setting, the Monitr test can verify that the treatment goal—endoscopic remission—was met.3,10 The patient would continue with anti-TNF therapy, in the absence of toxicity.7

Use of Therapeutic Drug Monitoring

Therapeutic drug monitoring and Monitr testing are complementary tests that could be ordered together to identify a need to change therapy and to inform other management decisions. Therapeutic drug monitoring shows the level of drug in a patient’s blood, and, in the case of biologics, it can also assess the levels of anti-drug antibodies.8 Therapeutic drug monitoring is used for patients treated with any immunosuppressive or biologic agent, such as azathioprine, mercaptopurine, anti-TNF therapy, vedolizumab, and ustekinumab.8,11-13 If the drug concentration is subtherapeutic, and there are antibodies present, a new therapy could be considered.8 If the drug concentration is therapeutic, it will then be necessary to switch the patient to a new class of medication. It will then be necessary to know whether the symptoms are caused by active inflammatory disease or other causes, a common scenario in patients with Crohn’s disease. The Monitr test can indicate whether the patient has active disease in the context of his or her symptoms.1

Conclusion 

Monitr will likely be used to evaluate patients at certain time points in between colonoscopy procedures. Patients appear to appreciate use of this test to decrease the number of colonoscopies they must undergo. Given the many possible uses for Monitr, it will be interesting to see how it will be employed across different clinical settings. 

Disclosure

Dr Sandborn has received consulting fees from or performed contracted research for Janssen, AbbVie, UCB Pharma, Takeda, Pfizer, Amgen, Genentech, Receptos, Actavis, Shire, Salix, and Prometheus Laboratories Inc.

References

1. Vermeire S, D’Haens G, Hale M, et al. A novel serum test to describe the mucosal healing state by disease location in Crohn’s disease patients [WCOG abstract 74]. Paper presented at: the World Congress of Gastroenterology at ACG2017; October 13-18, 2017; Orlando, FL.

2. Lichtenstein GR, Hanauer SB, Sandborn WJ, et al; Practice Parameters Committee of American College of Gastroenterology. Management of Crohn’s disease in adults. Am J Gastroenterol. 2009;104(2):465-483.

3. D’Incà R, Caccaro R. Measuring disease activity in Crohn’s disease: what is currently available to the clinician. Clin Exp Gastroenterol. 2014;7:151-161.

4. Kelly OB, Silverberg MS, Dulai PS, et al. Development and validation of a multi-marker serum test for the assessment of mucosal healing in Crohn’s disease patients [WCOG abstract P2184]. Paper presented at: the World Congress of Gastroenterology at ACG2017; October 13-18, 2017; Orlando, FL.

5. Papamichael K, Vermeire S. Withdrawal of anti-tumour necrosis factor α   therapy in inflammatory bowel disease. World J Gastroenterol. 2015;21(16):4773-4778.

6. Modigliani R, Mary JY, Simon JF, et al. Clinical, biological, and endoscopic picture of attacks of Crohn’s disease. Evolution on prednisolone. Groupe d’Etude Thérapeutique des Affections Inflammatoires Digestives. Gastroenterology. 1990;98(4):811-818.

7. Boyapati R, Torres J, Palmela C, et al. Withdrawal of drug therapy for patients with quiescent Crohn’s disease. Cochrane Database of Systematic Reviews. 2017(2):1-10. doi:10.1002/14651858.CD14012540.

8. Flamant M, Roblin X. Inflammatory bowel disease: towards a personalized medicine. Ther Adv Gastroenterol. 2018;11:1756283X17745029.

9. Shergill AK, Terdiman JP. Controversies in the treatment of Crohn’s disease: the case for an accelerated step-up treatment approach. World J Gastroenterol. 2008;14(17):2670-2677.

10. Peyrin-Biroulet L, Sandborn W, Sands BE, et al. Selecting therapeutic targets in inflammatory bowel disease (STRIDE): determining therapeutic goals for treat-to-target. Am J Gastroenterol. 2015;110(9):1324-1338.

11. Barlow NL, Mohammed P, Berg JD, et al. Serum trough infliximab and anti-infliximab antibodies in a cohort of gastroenterology and rheumatology patients’ infliximab therapeutic drug monitoring. Ann Clin Biochem. 2016;53(Pt 4):
477-484.

12. Battat R, Kopylov U, Bessissow T, et al. Association between ustekinumab trough concentrations and clinical, biomarker, and endoscopic outcomes in patients with Crohn’s disease. Clin Gastroenterol Hepatol. 2017;15(9):1427-1434.e2

13. Belaiche J, Desager JP, Horsmans Y, Louis E. Therapeutic drug monitoring of azathioprine and 6-mercaptopurine metabolites in Crohn disease. Scand J Gastroenterol. 2001;36(1):71-76.

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