Very high levels of FC on admission were associated with an increased risk of colectomy in a study that included 90 patients hospitalized for acute severe UC,79 with an area under the curve of 0.65 (P < 0.05). Kaplan–Meier analyses showed that 87% of the patients with an initial FC level over 1900 μg/g underwent a colectomy over the course of the next 13 months.
Fecal biomarkers were also evaluated as a monitoring tool to assess response to treatment. A majority of these studies evaluated patients treated with TNF inhibitors. In a study from Finland,78 15 patients were evaluated with ileocolonoscopy, FC, and LF before and 3 months after start of anti-TNF treatment. Eighty percent of the patients responded to treatment. Median CDEIS fell from 13.0 to 4.8 (P < 0.002) and CDAI from 158 to 68 (P < 0.005). The decrease in CDEIS and CDAI was paralleled by a decrease in FC from 1173 to 130 μg/g (P = 0.001) and LF from 105 to 2.7 μg/g (P = 0.001).78 FC levels normalized in patients, who achieved clinical remission, but did not change significantly from baseline level in nonresponders. In another study, 644 patients with IBD treated with anti-TNF antibodies were evaluated for clinical response and remission using the Harvey–Bradshaw index score, endoscopy (CDEIS), CRP, and FC. Endoscopic activity demonstrated a stronger correlation with FC and CRP than with the clinical index. Neither the clinical index nor CRP was reliable at identifying endoscopic remission. However, FC (using a cutoff value of 94 μg/g) identified endoscopic remission with a sensitivity of 84% and specificity of 74%.57 Another European study correlated FC levels with endoscopic response to infliximab in a cohort of 53 patients with active UC. Endoscopic remission defined by a Mayo score of 0 to 1 was achieved in 58% of the patients and was paralleled by a decrease of FC levels to <50 μg/g in all patients achieving remission. Moreover, a sharp decrease of FC levels as early as week 2 from the initial infusion was well correlated with endoscopic remission at week 10. FC <50 μg/g or a decrease of 80% predicted remission with a specificity of 67% and sensitivity of 54%.80 This observation may have a significant clinical application allowing early evaluation of response to treatment and prompt identification of patients in need of dose intensification or additional treatment modifications. In a follow-up study, patients with UC were followed prospectively after achieving response to infliximab with serial endoscopic and clinical evaluations and FC measurements. A group of patients in sustained deep remission (defined as partial Mayo score <3 at all times with an endoscopic score of 0 to 1 at week 52) had FC levels below 40 μg/g at all time points. Patients who flared had significantly higher calprotectin levels (median >300 mg/kg) 3 months before the flare. Two consecutive calprotectin measurements of >300 mg/kg with an 1-month interval were identified as the best predictor of a flare (61.5% sensitivity and 100% specificity). FC level at the moment of relapse was significantly better correlated with endoscopic index than the blood CRP concentration (area under the curve, 0.85 versus 0.58; P <0.015).81
Little data exist on correlation of fecal biomarkers with endoscopic outcomes and mucosal healing in randomized prospective clinical trials in IBD. In a recent abstract evaluating this correlation in patients with active UC treated by Tofacitinib, an oral Janus Kinase Inhibitor, an FC cutoff of 150 μg/g achieved the highest summation of specificity and sensitivity for clinical remission (0.79 and 0.68, respectively; kappa, 0.44) and endoscopic remission (0.75 and 0.79, respectively; kappa, 0.38), considered fair to good correlation.82 Additional data from randomized prospective clinical trials may provide important high-quality data on the relative accuracy of the clinical and biological activity markers (including fecal biomarkers) for prediction of mucosal healing.
Patients with IBD, especially those with CD, frequently present with nonspecific symptoms that may overlap with those of IBS. Identification of patients with symptoms that are not associated with mucosal inflammation is of considerable importance, because it may prevent unnecessary escalation of IBD treatment. Patients in clinical remission defined by clinical indices had 31% prevalence of IBS-related symptoms defined by Rome criteria.83 The levels of FC were much lower than those reported by other studies for active CD, yet higher than those associated with IBS without IBD.32,37 Interestingly, FC levels were not significantly different in patients with CD with and without IBS symptoms (111 μg/g versus 45.5 μg/g, respectively, P = 0.17). In another study, the levels of FC were similar in patients with CD and clinical remission with and without IBS-related symptoms (42 ± 11.6 (21–65) and 38.3 ± 9.8 (20–67), P = 0.3), with very similar results observed for UC.84 An important limitation of these studies is the lack of endoscopic ascertainment of remission, as FC assays were compared with clinical, but not endoscopic, indices. Although data are limited, the current literature suggests that in patients with clinical remission and IBS-related symptoms, the FC levels should be expected to be significantly lower than in active IBD. Studies employing endoscopic definitions of remission may provide more accurate data on the expected cutoff values of FC in this challenging patient cohort.
Several studies evaluated calprotectin as a predictor of relapse in patients in clinical remission in both UC and CD43,85–89 (Table 5). In a recent meta-analysis of these studies, the pooled sensitivity and specificity of FC to predict relapse of quiescent IBD within 12 months was 78% (95% CI, 72–83) and 73% (95% CI, 68–77), respectively, with comparable accuracy in UC and CD. Within the cohort of patients with CD, FC seemed to be more accurate in prediction of relapse in ileocolonic and colonic disease. However, the data on isolated small bowel CD was limited.90 In UC, a recent study evaluated the cost-effectiveness of an inflammation-based treatment strategy for quiescent disease (that included adjustment of mesalamine dosage from 2.4 g/d to 4.8 g/d if active inflammation was detected by FC test performed once every 3 mo) with strategies based on treatment of symptomatic relapse only with or without baseline mesalamine treatment. FC-based strategy was the least costly strategy, while achieving similar clinical efficacy.91
FC and LF have been studied as potential biomarkers to detect early recurrence of disease postsurgical resection before onset of symptoms.92 FC and LF levels have been shown to normalize by 2 months postoperatively with any subsequent rise in levels correlating with recurrence of active gut inflammation.93 FC and LF levels were strongly correlated with each other and with endoscopic indices of disease activity.93 A recent study by Lobaton et al94 looked at FC levels in 29 patients with CD who had undergone ileocecal resection. FC levels were able to distinguish between those with no postoperative recurrence as demonstrated by a Rutgeert's scores of 0 to 1 and those with evidence of recurrence (2–4). FC levels were significantly different using both an ELISA and the rapid quantitative test. The ELISA provided a sensitivity of 75% and a specificity of 72% using a cutoff value of 203 μg/g, and the rapid test has a sensitivity of 67% and 72% with a higher cutoff of 283 μg/g.95 Another study found similar results whereby using a cutoff of 200 μg/g at 3 months postresection. The sensitivity of FC was 63% and the specificity was 75% for postoperative recurrence. This study also compared FC with ultrasound for the detection of postoperative recurrence and found FC more sensitive but less specific.92 Nevertheless, others have found high levels of LF and FC in postoperative patients who remain in clinical remission based on a rise in the CDAI.96 The interpretation of these results is questionable give that the correlation between clinical symptoms and endoscopic disease activity is poor. Further research with larger numbers of patients is necessary to confirm the utility of these promising biomarkers for the early detection of postoperative recurrence.
FC has been evaluated as an indicator of pouchitis in patients who have undergone proctocolectomy with ileoanal pouch anastomosis for UC. CRP as a biomarker in this setting has a low accuracy. FC has been shown to correlate with the frequency of pouchitis in the pediatric age group even after as long as 11 years postpouch creation.97 In this study, FC levels were correlated with no history, a single episode or recurrent episodes of pouchitis.97 For FC levels >300 μg/g, the sensitivity and specificity for recurrent pouchitis were 57% and 92%, respectively. A smaller study showed that a single morning FC sample was highly correlated with a 24-hour calprotectin level and was able to predict the presence of active inflammation due to pouchitis.98 Higher levels of FC have been reported in patients with pouch creation for severe UC compared with those with pouches for familial adenomatous polyposis, consistent with the known higher risk of pouchitis in patients with UC.99
LF has been shown to be able to distinguish irritable pouch syndrome from pouchitis, cuffitis, and CD with a sensitivity of 100% and a specificity of 85%, using a cutoff of 7 μg/g.100 LF has also been used to confirm the resolution of pouchitis post antibiotic therapy.101 In this study, LF was 100% sensitive and 92% specific for biopsy-proven pouchitis. For the 7 patients who were treated for pouchitis, LF was able to accurately predict the resolution or persistence of pouchitis.101
M2-PK levels have been shown to correlate with objective pouchitis scores, the pouch disease activity index and the endoscopic and histologic appearances of active inflammation, with a sensitivity of 80% and a specificity of 70.6%.27 Similar findings were obtained in another study where M2-PK levels were significantly higher in those with pouches than in HC.102 Furthermore, even higher levels were evident in those with a pouch disease activity index >7 suggesting active pouchitis. FC, LF, and M2-PK all may represent viable alternatives to pouchoscopy and biopsy for both diagnosis and evaluation of response to treatment.
Fecal biomarkers such as FC and LF provide accurate and convenient tools for screening of IBD in the setting of patients with symptoms consistent with either IBD or IBS. They are also useful for the management and monitoring of patients with IBD in various clinical situations. Fecal biomarkers reflect mucosal inflammation and are better correlated with mucosal healing than CRP or clinical indices. Rapid POT further improve the accessibility and the feasibility of fecal biomarkers, without compromising accuracy. Utilization of these markers can significantly reduce the number of invasive procedures needed for diagnosis and monitoring of IBD.
Several additional directions need to be explored to further optimize the utilization of fecal biomarkers in IBD. Primarily, it is important to understand whether fecal biomarkers can be true surrogates of mucosal healing, with the same impact on the natural history of IBD. Recently, complete mucosal healing (Mayo score of 0) with histologic healing have been suggested to be better associated with long-term prognosis than the commonly used definition of a Mayo score <2.103 It is currently unclear whether and how fecal biomarkers can serve as reliable surrogate markers for these novel treatment goals. When using FC for monitoring of disease activity and response to treatment, the optimal testing time after induction treatment needs to be established. It is also unclear whether measuring change from baseline levels will provide more accurate estimation of response than relying on absolute cutoff values that may vary significantly between individual patients.
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