Role of Biomarkers for the Management of Ulcerative Colitis

Publication Date: February 20, 2023
Last Updated: May 15, 2023

Summary of Recommendations

In patients with UC in symptomatic remission, the AGA suggests a monitoring strategy that combines biomarkers and symptoms, rather than symptoms alone. (C, M)
Comment:
  • Patients who place high value on avoiding burden of biomarker testing, over a potentially higher risk of flare or overtreatment, may reasonably choose interval symptom-based monitoring.

Implementation considerations:
  • Interval biomarker monitoring may be performed every 6–12 mo.
  • Fecal biomarkers (fecal calprotectin or fecal lactoferrin) may be optimal for monitoring and may be particularly useful in patients where biomarkers have historically correlated with endoscopic disease activity.
  • A biomarker-based monitoring strategy, especially using stool-based tests, however, may be inconvenient and elevated biomarkers in otherwise asymptomatic individuals may lead to high patient anxiety.
  • It is important to think about the downstream consequences of testing and associated costs. The optimal management strategy in cases of discrepancy between symptoms and biomarkers is unclear and would generally trigger additional endoscopic testing for confirmation or repeat biomarker testing.
620
In patients with UC in symptomatic remission, the AGA suggests using
fecal calprotectin <150 μg/g (C, L)
Implementation consideration:
  • In patients who have recently achieved symptomatic remission after treatment adjustment in the preceding 1–3 mo, fecal calprotectin <50 μg/g may be preferred over <150 μg/g to detect endoscopic improvement (Mayo Endoscopic Score [MES] 0 or 1).
620
normal fecal lactoferrin (C, L)
620
normal CRP (C, VL)
Implementation consideration:
  • Normal CRP may be less informative to rule out moderate to severe active endoscopic inflammation in patients with UC in symptomatic remission, particularly in patients who have recently achieved symptomatic remission after treatment adjustment. However, if CRP was elevated at time of initial flare, then normalization of CRP may suggest endoscopic improvement (MES 0 or 1).
620
to rule out active inflammation and avoid routine endoscopic assessment of disease activity.
In patients with UC in symptomatic remission but elevated stool or serum markers of inflammation (fecal calprotectin >150 μg/g, elevated fecal lactoferrin, elevated CRP), the AGA suggests endoscopic assessment of disease activity rather than empiric treatment adjustment. (C, VL)
Implementation consideration:
  • In patients with UC in symptomatic remission but elevated biomarkers of inflammation, repeat measurement of biomarkers (in 3–6 mo) may be a reasonable alternative to endoscopic assessment. However, if biomarkers are elevated on repeat evaluation, then endoscopic assessment may be warranted.
620
In patients with symptomatically active UC, the AGA suggests an evaluation strategy that combines biomarkers and symptoms, rather than symptoms alone, to inform treatment adjustments. (C, L)
Comment
  • Patients, particularly those with severe symptoms, who place high value in avoiding burden of biomarker testing, over a potentially higher risk of inappropriate overtreatment, may reasonably choose symptom-informed treatment decisions.
620
In patients with UC with moderate to severe symptoms suggestive of flare, the AGA suggests using
fecal calprotectin >150 μg/g (C, L)
620
elevated fecal lactoferrin (C, VL)
620
elevated CRP (C, M)
620
to rule in active inflammation and inform treatment adjustment and avoid routine endoscopic assessment solely for establishing presence of active disease.

Comment:
  • Patients who place greater value in confirming inflammation, particularly when making significant treatment decisions (such as starting or switching immunosuppressive therapies) and lesser value on the inconvenience of endoscopy, may choose to pursue endoscopic evaluation before treatment adjustment.
In patients with UC with mild symptoms, with elevated stool or serum markers of inflammation (fecal calprotectin >150 μg/g, elevated fecal lactoferrin, or elevated CRP), the AGA suggests endoscopic assessment of disease activity rather than empiric treatment adjustment. (C, VL)
Implementation consideration
  • In patients with UC who underwent recent adjustment of treatment in response to moderate to severe symptomatic flare, and now have mild residual symptoms, elevated stool or serum markers of inflammation may be used to inform treatment adjustments (such as dose adjustments of therapy).
620
In patients with UC with mild symptoms, with normal stool or serum markers of inflammation (fecal calprotectin <150 μg/g, normal fecal lactoferrin, normal CRP), the AGA suggests endoscopic assessment of disease activity rather than empiric treatment adjustment. (C, VL)
Implementation consideration
  • In patients with UC with mild symptoms (eg, slight increase in stool frequency and/or infrequent rectal bleeding), it may be reasonable to proceed directly with endoscopic assessment rather than testing biomarkers of inflammation.
  • In patients with UC with mild symptoms and normal biomarkers of inflammation who prefer to avoid endoscopic assessment or empiric treatment escalation, repeat measurement of biomarkers (in 3–6 mo) may be a reasonable alternative.
620
In patients with UC, the AGA makes no recommendation in favor of, or against, a biomarker-based monitoring strategy over an endoscopy-based monitoring strategy to improve long-term outcomes. (U, U)
620

Tables

Summary of Key Considerations When Using Biomarkers for Monitoring in Ulcerative Colitis

  1. Considerations of test performance and specificity of biomarkers: CRP, fecal calprotectin, and fecal lactoferrin may be elevated because of nonintestinal sources of infection or inflammation. In patients with UC who present with elevated biomarkers and disease-related symptoms, stool testing for Clostridioides difficile and other enteric pathogens is important to help rule out other sources of gastrointestinal infections.
  2. Role of endoscopic evaluation for other indications: Biomarkers of inflammation have no role in dysplasia detection and surveillance and ruling out cytomegalovirus colitis, and endoscopic evaluation is the main strategy for evaluating these. Endoscopic evaluation may be useful for prognostication in patients hospitalized with acute severe UC.
  3. Association between treatment target and biomarker performance: Test performance of all biomarkers in this guideline reflect their ability to rule out moderate to severe endoscopic inflammation (MES 2 or 3 [or equivalent]). Biomarkers may be suboptimal for detecting more rigorous treatment targets such as endoscopic remission (MES 0) or histologic remission. Biomarkers may also be suboptimal in detecting the presence of mild endoscopic activity (MES 1) in patients with mild symptoms.
  4. Influence of disease extent on biomarker performance: Biomarkers may be less accurate in detecting endoscopic inflammation in patients with ulcerative proctitis or limited segmental disease.
  5. Interpreting biomarker performance for low-risk vs high-risk treatment adjustments: Application of all biomarkers in clinical practice should be guided by downstream implications, including risk of consequent treatment decisions (low-risk treatment adjustment vs high-risk treatment adjustment). Test performance thresholds (acceptable FP and FN rates) may vary for patient–provider teams depending on what treatment adjustment is being considered.
  6. Inter- and intra-assay test variability: Fecal calprotectin assays may not be interchangeable and the same assay should be used for a given patient to compare results over time. Because there can be substantial within-stool and within-day variations of fecal calprotectin measurements from a single patient, confidence in any single measurement may be limited. Hence, if there is uncertainty of results (such as borderline or unexpected results), repeat fecal calprotectin testing or endoscopic evaluation for confirmation may be required.
  7. Inter-individual heterogeneity in biomarkers responsiveness: There are inter-individual differences in biomarker elevation in patients with intestinal inflammation, and in a subset of patients, biomarkers may correlate poorly with endoscopic activity. The overall performance and confidence in the use of biomarkers for treatment decisions in a particular patient may be higher when these biomarkers have been longitudinally observed to correlate with the patient’s endoscopic disease activity (both active disease and remission).

Consequences of Diagnostic Test Results on Patient-Important Outcomes

  • TP
    • Patients correctly diagnosed as having moderate to severe endoscopic activity would be eligible to undergo treatment adjustment, which may improve symptoms and decrease risk of disease-related complications and morbidity, without being subject to risk, invasiveness, and cost of endoscopic assessment.
  • FP
    • Patients incorrectly labeled as having moderate to severe endoscopic activity, when actually they are in endoscopic remission or have only mild endoscopic activity, may undergo unnecessary testing (endoscopy) and/or treatment adjustment, and have avoidable anxiety, potential testing- or treatment-related complications, and increased resource utilization.
  • TN
    • Patients correctly diagnosed as being in endoscopic remission or having only mild endoscopic activity would be reassured and obviate the need for invasive testing with endoscopy, although they may need to undergo serial assessment of biomarker at periodic intervals.
  • FN
    • Patients incorrectly labeled as being in endoscopic remission or having only mild endoscopic activity, when actually they have moderate to severe endoscopic activity would be falsely reassured, may have avoidable anxiety about unexplained symptoms, and may not receive appropriate treatment adjustment, potentially leading to increased disease related complications, morbidity, and mortality.

Recommendation Grading

Overview

Title

Role of Biomarkers for the Management of Ulcerative Colitis

Authoring Organization

American Gastroenterological Association

Publication Month/Year

February 20, 2023

Last Updated Month/Year

October 23, 2024

Document Type

Guideline

Country of Publication

US

Document Objectives

The objective of this guideline was to provide guidance about the use of well-established and commonly available biomarkers as surrogate tests for endoscopic assessment of disease or in longitudinal monitoring of patients with an established diagnosis of ulcerative colitis (UC) primarily in the ambulatory setting. Predictive biomarkers for assessment of hospitalized patients with acute severe colitis is beyond the scope of this guideline. This guideline focuses on the following biomarkers: serum C-reactive protein (CRP), fecal calprotectin, and fecal lactoferrin.

Target Patient Population

Patients with ulcerative colitis (UC)

Target Provider Population

Primary care and gastroenterology health care professionals, patients, and policy makers

PICO Questions

  1. In patients with UC in symptomatic remission, is interval biomarker-based monitoring superior to symptom-based monitoring to improve long-term outcomes?

  2. In patients with UC in symptomatic remission, at what (A) fecal calprotectin, (B) fecal lactoferrin, and (C) serum C-reactive protein cutoff can we accurately rule out active inflammation, obviating routine endoscopic assessment?

  3. In patients with symptomatically active UC, is an evaluation strategy that combines biomarkers and symptoms superior to symptom-based evaluation for making treatment adjustments?

  4. In patients with symptomatically active UC, at what (A) fecal calprotectin, (B) fecal lactoferrin, and (C) serum CRP cutoff can we accurately diagnose active inflammation, obviating routine endoscopic assessment?

  5. In patients with established UC, is interval biomarker-based monitoring strategy superior to interval endoscopy-based monitoring strategy to improve long-term outcomes?

Inclusion Criteria

Male, Female, Adolescent, Adult, Child, Older adult

Health Care Settings

Ambulatory, Laboratory services, Outpatient

Intended Users

Nurse, nurse practitioner, physician, physician assistant

Scope

Diagnosis, Assessment and screening

Diseases/Conditions (MeSH)

D003093 - Colitis, Ulcerative, D015415 - Biomarkers

Keywords

biomarkers, inflammatory bowel disease, ulcerative colitis, IBD, fecal calprotectin, serum CRP, fecal lactoferrin

Source Citation

Singh S, Ananthakrishnan AN, Nguyen NH, Cohen BL, Velayos FS, Weiss JM, Sultan S, Siddique SM, Adler J, Chachu KA; AGA Clinical Guidelines Committee. Electronic address: clinicalpractice@gastro.org. AGA Clinical Practice Guideline on the Role of Biomarkers for the Management of Ulcerative Colitis. Gastroenterology. 2023 Mar;164(3):344-372. doi: 10.1053/j.gastro.2022.12.007. PMID: 36822736.

Supplemental Methodology Resources

Evidence Tables, Methodology Supplement

Methodology

Number of Source Documents
48
Literature Search Start Date
December 31, 1995
Literature Search End Date
November 20, 2021
Specialties Involved
Gastroenterology