Fecal calprotectin and endoscopic scores: The cornerstones in clinical practice for evaluating mucosal healing in inflammatory bowel disease

Table 1 Main indications for the use of fecal calprotectin and endoscopy in patients with inflammatory bowel disease

Fecal calprotectin	Endoscopy
Differential diagnosis of IBD and irritable bowel syndrome	Differential diagnosis with mimics
Monitoring therapeutic response	Evaluation of disease extension
Monitoring mucosal healing	Monitoring therapeutic response
Monitoring histological healing	Monitoring mucosal healing
Prediction of disease activity and postoperative recurrence	Monitoring histological healing
	Prediction of disease activity and postoperative recurrence
	Dysplasia surveillance
	Treatment of some complications (e.g., strictures)

IBD: Inflammatory bowel disease.

Table 2 Advantages and limitations of fecal calprotectin and endoscopy in patients with inflammatory bowel disease

	Fecal calprotectin	Endoscopy
Advantages	Noninvasive	Direct evaluation of the mucosa
	Low-cost, cost-effective	Gold standard method to evaluate the goal of IBD treatment (mucosal healing)
	Easy collection and storage	Possibility of obtaining samples (biopsies)
	Validated in UC and CD	Validated in IBD diagnostic, monitoring, and prediction of disease activity
	Validated in both colonic and small bowel disease	Validated in adults and pediatric population
	Validated in IBD diagnostic, monitoring, and prediction of disease activity	Validated scores for both UC and CD
	Validated in adults and pediatric population
	Distinguish patients with IBD from those with IBS
Limitations	Not specific for IBD	Invasive
	Not differentiated UC from CD	Cost
	No validated cutoff to define disease activity	Availability
	Presence of a “gray zone” level between 100 and 250 μg/g, which is difficult to interpret	Inter-observer variability
	Lower accuracy in detecting inflammatory activity in patients with CD of the small intestine or of the upper gastrointestinal tract compared to predominant or extensive colonic involvement
	Variation depending on patient age, presence of obesity, and lifestyle
	The presence of mucus and blood can interfere with FC result
	High day-to-day variability
	Despite the low cost, it is not available in some locations

CD: Crohn’s disease; IBD: Inflammatory bowel disease; IBS: Irritable bowel syndrome; UC: Ulcerative colitis.

Table 3 Endoscopic indices of ulcerative colitis activity with their strengths and limitations

Indices	Endoscopic technique	Validation	Strengths	Limitations
MES	WLE	No	The easiest to use	Subjectivity
			Used in clinical trials and daily practice	Moderate reproducibility
				Not appropriate description of inflammation and severity
				Ambiguous definition of endoscopic remission
UCEIS	WLE	Yes	Easy to use	No thresholds for mild, moderate and severe disease
			Good reproducibility and agreement	No definition of superficial or deep ulcer
			High correlation with clinical, and histological indices and biomarkers
			Clear definition or ER/MH
			Clinically relevant outcomes
UCCIS	WLE	Yes	Good reproducibility and agreement	No definition of MH
			Provides details about the status of inflammation of the entire colonic mucosa	No thresholds for mild, moderate and severe disease
				Few evidence
PICaSSO	VCE-iSCAN	Yes	High reproducibility and agreement	Endoscopy experience and training required.
			Strong accuracy discriminating quiescent from mild disease.	No long-term clinical outcome
			Highest correlation with MH

Adapted from Ruscio et al[89]. ER: Endoscopic remission; HH: Histological healing; MES: Mayo endoscopic subscore; MH: Mucosal healing; PICaSSO: Paddington international virtual chromoendoscopy score; UCCIS: Ulcerative colitis colonoscopic index of severity; UCEIS: Ulcerative colitis endoscopic index of severity; WLE: White-light endoscopy; VCE: Virtual chromoendoscopy.

Table 4 Practical pearls for the use of fecal calprotectin in Crohn’s disease

FC is a reliable test in distinguishing patients with IBD from those with IBS. A cutoff of ≤50 μg/g appears to have a better sensitivity and a negative predictive value of > 95% for IBD in Western countries[18]

FC should be measured before starting or optimizing any therapy for CD, at the end of the induction phase, every 2–4 mo in patients being treated for active disease, and every 6–12 mo during the maintenance therapy in those in symptomatic remission; and in case of clinical relapse of disease[14,20]

In patients with CD in symptomatic remission with confirmation of endoscopic remission within the last 3 years, an FC of < 150 µg/g can reliably rule out active inflammation and avoid routine endoscopic reassessment with relatively low false negatives[20]

Where there is a symptom-biomarker disconnect, or in patients with mild symptoms, an FC value of > 150 µg/g is insufficient to identify endoscopically active inflammation. In this context, endoscopic or radiologic assessment is necessary to truly define the presence of active disease before making empiric treatment adjustments[20]

In the presence of moderate to severe symptoms, an elevated FC strongly suggests endoscopically active disease and can be used to make decisions regarding most changes in therapy. However, normal FC is insufficient to dismiss inflammation, and endoscopic or radiologic assessment is important in this setting[20]

In small bowel CD, where only a short segment of involvement may exist, as well as in relatively proximal disease (upper gastrointestinal, stomach, and esophagus), the FC concentrations may not be elevated to that degree and produce false negatives[57]

Many times, FC is highly effective in detecting endoscopic ulcerations regardless of the CD location. A cutoff value of > 200 μg/g in patients with isolated ileal involvement and > 250 μg/g for ileocolonic or colonic disease may be the optimal threshold to detect endoscopic ulcerations[90]

Normalization of FC (e.g., < 250 μg/g) within 12 mo of starting therapy is associated with a reduced risk of CD progression[91]

In patients with CD in surgically induced remission within the past 12 mo at a low risk of postoperative recurrence, an FC value of < 50 μg/g reliably rules out postoperative recurrence. In patients at high risk (e.g., smokers, more than one intestinal resection, surgery due to penetrating disease, perianal disease, and long segments of small bowel resection), FC cannot be used to rule out or confirm endoscopic recurrence[20]

After ileocecal resection, an FC cutoff value of > 150 μg/g is likely to have the best overall accuracy in predicting postoperative endoscopic recurrence, with a sensitivity of approximately 70%[92]

FC concentration from an ileostomy effluent can be used for assessing and monitoring small bowel inflammation and disease recurrence. An FC level of > 60 μg/g is strongly suggestive of the presence of small bowel inflammation[93]

Adapted from Dajti et al[18], Kapel et al[14], Ananthakrishnan et al[20], D'Amico et al[57], Buisson et al[90], Plevris et al[91], Tham et al[92], and Daoud et al[93]. CD: Crohn’s disease; FC: Fecal calprotectin; IBD: Inflammatory bowel disease; IBS: Irritable bowel syndrome.

Table 5 Practical pearls to the use of fecal calprotectin in ulcerative colitis

FC should be measured before starting or optimizing any therapy for UC, at the end of induction therapy, every 2–4 mo in patients being treated for active disease, and every 6–12 mo during the maintenance therapy in patients in symptomatic remission; and in case of clinical relapse of disease[94]

FC values of < 150 μg/g typically reflect remission, FC values ranging from 150–250 μg/g are a grey zone, and cutoff values of > 200–300 μg/g suggest the presence of active disease[11]

Prior to symptoms based on the diagnosis of a flare, FC is reported to be elevated approximately 8 wk in advance. Conversely, patients who maintain remission usually present FC concentrations persistently < 60 μg/g[95]

FC is a reliable biomarker to evaluate the response to treatment. A post-induction FC concentration of ≤ 250 µg/g vs > 250 µg/g is associated with a substantially higher probability of achieving clinical, endoscopic, and histologic remission[46]

FC is a valuable marker of endoscopic inflammation, being useful in distinguishing Mayo endoscopic subscores of 0 from 1–3 using the FC cutoff of 60 μg/g[96]

Persistent high values of FC are an important predictor of disease flare in asymptomatic patients[94]

In patients with mild-to-moderate UC who achieve complete endoscopic healing, a FC cutoff value between 75 and 100 µg/g can be used to discriminate patients with ongoing microscopic inflammation from those with histologic remission[97]

In patients with ileal pouch-anal anastomosis, FC values of > 100 µg/g are suggestive of endoscopic or histological inflammation of the pouch (e.g., pouchitis)[57]

Adapted from D'Amico et al[94], Turner et al[11], Yamamoto et al[95], D'Amico et al[57], Dulai et al[46], Suttichaimongkol et al[96], D'Amico et al[94], and Stevens et al[97]. FC: Fecal calprotectin; UC: Ulcerative colitis.