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Original Articles: Gastroenterology: Inflammatory Bowel Disease

Moderate-to-severe Endoscopic Inflammation is Frequent After Clinical Remission in Pediatric Ulcerative Colitis

Sarbagili-Shabat, Chen∗,†; Weiner, Dror; Wardi, Joram; Abramas, Lee; Yaakov, Michal; Levine, Arie∗,†

Author Information
Journal of Pediatric Gastroenterology and Nutrition: April 2021 - Volume 72 - Issue 4 - p 569-573
doi: 10.1097/MPG.0000000000003018

Abstract

What Is Known/What Is New

What Is Known

  • Paediatric ulcerative colitis is characterized by frequent or early relapses despite clinical remission and a tendency to become extensive.
  • Presence of moderate-to-severe inflammation (Mayo score 2–3) is associated with early relapse.
  • There are no prospective available data regarding the state of the mucosa after clinical remission is obtained in ulcerative colitis in children.

What Is New

  • Fifty percentage of children in clinical remission 3 to 5 months after remission was first documented and had moderate-to-severe inflammation upon endoscopy.
  • Those patients in remission with early assessment by Mayo score with Mayo endoscopic score 2 to 3 were less likely to have sustained remission than patients with Mayo scores of 0 to 1.

Ulcerative colitis (UC) in children is a chronic inflammatory disorder of the colon associated with a more severe phenotype and extensive disease as compared with adult onset (1–7). Similar to adults, newly diagnosed pediatric patients with mild-to-moderate UC are usually treated with mesalamine, whereas moderate-to-severe disease patients will often be initially treated with corticosteroids (8–10). Children, however, appear to have a more relapsing course of the disease (9,11). In 2 large inception cohorts, sustained remission on the first-line therapy was only present in 38% by 1 year (9) and in 22% by 5 years (11). The PROTECT study, was a prospective inception cohort of children with newly diagnosed UC that followed 400 children treated by medical therapy. Among the children who achieved remission with the initial treatment at week 4, 49% eventually had disease recurrence during the first year and lack of sustained remission was high even in mild disease (9). A review of 5 population-based studies in children with UC demonstrated that nearly 50% of children without pancolitis will have disease extension (6), and that even children with proctitis do not have a benign course (7).

It is also recognized that patients who will achieve early mucosal healing are more likely to have better sustained remission and are less likely to develop possible complications of the disease (12–14). There are, however, no prospective data regarding early endoscopic response in children and adults as follow-up endoscopies after remission is induced are not currently part of the standard of care. Although studies have shown a fair correlation between clinical and endoscopic disease activity (15–18), this may be because of the correlation derived from clinically active disease or prolonged sustained remission and not because of clinical correlation after induction of remission.

One possible explanation for the high relapse rate and disease extension that characterize pediatric UC may be significant under treated mucosal inflammation, which is not addressed because of absence of symptoms after clinical remission is obtained.

In order to provide data for early mucosal healing and to evaluate the hypothesis that significant endoscopic inflammation may remain present despite clinical remission for several months in children, we prospectively evaluated patients after documentation of clinical remission for presence and severity of endoscopic disease activity.

METHODS

Design and Study Population

This was a single-center prospective study with blinded assessment of endoscopic Mayo score and MH, involving consecutive pediatric patients ≤19 years old in sustained clinical remission for 3 months after treatment of a flare. Follow-up data for relapse and medications were collected retrospectively from the charts. Patients were recruited from the pediatric inflammatory bowel diseases (IBD) clinic at Wolfson medical center after signing informed consent. Inclusion criteria were established diagnosis of UC; age ≤19 years; in clinical remission based on a paediatric UC activity index (PUCAI) score less than 10, sigmoidoscopy between 3 and 5 months after remission was documented. This time frame, which corresponds to 5 to 7 months after treatment was started for a flare and was chosen as we hypothesized that performing a sigmoidoscopy earlier might not provide enough time for mucosal healing, while waiting longer might allow patients with significant inflammation to flare leading to selection bias because of exclusion of the most inflamed patients. We wished to have at least 3 months of continuous remission before assessment. Patients with IBD unclassified, those with a PUCAI 10 or above before sigmoidoscopy, those who did not have the endoscopy performed within the designated time (24 weeks) or those who refused sigmoidoscopy were excluded. The primary end point was defined as active endoscopic disease according to Mayo score. The local research committee approved the study. Informed consent was obtained from all participants and assent as appropriate. NIH number: NCT03179865.

Evaluation of Ulcerative Colitis Clinical and Endoscopic Activity

Patients with active disease were seen for follow-up after therapy was instituted (around 6–12 weeks) and if in clinical remission, were referred to sigmoidoscopy at least 3 months after the visit. PUCAI was calculated and registered before endoscopy by the endoscopist to ensure that patients had remained in remission since the last evaluation. Mayo endoscopic score was performed at time of endoscopy by the endoscopist and rectum and sigmoid were photographed. Mayo endoscopic score was reviewed independently by another experienced adult gastroenterologist blinded to the pediatric endoscopists assessment. The highest Mayo score of either segment was used as the patient endoscopic Mayo score. Clinical and demographic data, such as disease extent, current medical therapy, onset of UC, and age were recorded from the patient's file and were confirmed by the patients and their parents. Biopsies were not required to be obtained by the protocol.

Follow-up

Relapses or change in medical therapy because of symptoms during the 18 months of follow-up after the sigmoidoscopy were collected retrospectively from the patient's charts. Duration of follow-up was recorded until first relapse or last visit up to 18 months. Sustained steroid-free remission was defined as PUCAI <10 without a flare or without change in medical therapy.

Statistical Analysis

Descriptive statistics are expressed as mean ± SD for continuous variables or as frequency counts or percentages for categorical variables. Cohen kappa and Cramer V coefficient were used to measure agreement between the Mayo score of 2 experts independently for categorical variable of Mayo 0, Mayo 1, Mayo 2 to 3. For patients who were retrospectively followed-up, the association between Mayo score at baseline and duration until clinical recurrence was assessed using the Kaplan-Meier method, and the difference between the groups was analyzed using the log-rank test. Also, categorical data of sustain remission rates were compared using Fisher exact test. All of the statistical analyses were performed with IBM SPSS Statistics Version 25.

RESULTS

Study Population

Forty-two children were screened between January 2016 to October 2020, 14 patients were excluded due to exclusion criteria (Figure 1, Supplementary Digital Content, https://links.lww.com/MPG/C124), thus 28 patients with informed consent were included. Demographic data at entry is presented in Table 1. The majority were treated with 5-aminosalicylic acid (5ASA) or biologics (3 vedolizumab, 2 infliximab, 2 adalimumab on weekly dosing) and none of the patients were on steroids at the time of endoscopy (Table 1).

TABLE 1 - Characteristics of the study population
Characteristic Total (n = 28)
Female gender, n (%) 14 (50.0)
Age, years; mean (SD) 15.6 (2.2)
Disease duration, years; mean (SD) 2.7 (2.8)
Disease extent, n (%)
 Pancolitis 10 (37.7)
 Extensive 3 (10.7)
 Left sided 14 (50.0)
 Proctitis 1 (3.6)
 PUCAI score at prior flare, median (range) 40 (30–49)
 PUCAI score at endoscopy, median (range) 0 (0–0)
 CRP (mg/dL), mean (SD), n = 20 0.40 (0.2)
 Hemoglobin (g/dL), mean (SD), n = 22 12.2 (1.3)
Therapy at endoscopy, n (%)
 5-ASA (oral or oral and topical) 17 (60.7)
 Biologics 7 (25.0)
 Immunomodulators 3 (10.7)
 Antibiotic 1 (3.6)
 Curcumin 1 (3.6)
 None 2 (7.1)
5-ASA, 5-aminosalicylic acid; CRP, C-reactive protein; PUCAI, paediatric ulcerative colitis activity index; SD, standard deviation.

Endoscopic Activity

Mucosal healing reflected by endoscopic Mayo score 0 was present in 12 patients (42.9%). Active disease was present in the remaining 16, Mayo score 1 was present in 2 endoscopies (7.1%), moderate-to-severe endoscopic Mayo scores 2 to 3 were present in 14 endoscopies (50.0%) (Fig. 1A). Therefore, 57.1% of patients in remission for at least 3 months had endoscopic activity. There were no differences between Mayo 0 to 1 and Mayo 2 to 3 for disease duration, use of 5ASA (64.3% both groups), biologics or disease extent (Table 2).

F1
FIGURE 1:
(A) Distribution of endoscopic activity according to Mayo score in patients with clinical remission. (B) Distribution of endoscopic activity according to Mayo score in patients with clinical remission: expert 1 (n = 28) versus expert 2 (n = 26).
TABLE 2 - Disease characteristics in patients with Mayo 0 to 1 and Mayo 2 to 3
Characteristic Mayo 0–1, n = 14 Mayo 2–3, n = 14
Disease duration, years, mean (SD) 2.1 (2.0) 3.2 (3.5)
Disease extent, n (%)
 Pancolitis 4 (28.6) 6 (42.9)
 Extensive 2 (14.3) 1 (7.1)
 Left sided 8 (57.1) 6 (42.9)
 Proctitis 1 (7.1)
Therapy at endoscopy, n (%)
 5-ASA (oral or oral and topical) 9 (64.3) 9 (64.3)
 Biologics 4 (28.6) 3 (21.4)
 Immunomodulators 1 (7.1) 2 (14.3)
 Antibiotic 1 (7.1)
 Curcumin 1 (7.1)
 None 2 (14.3)
Therapy at induction before endoscopy, n (%)
 5-ASA (oral or oral and topical) 8 (57.1) 8 (57.1)
 Biologics 4 (28.6) 3 (21.4)
 Antibiotic 3 (21.4)
 Steroids 2 (14.3) 2 (14.3)
 Immunomodulators 1 (7.1)
 Curcumin 1 (7.1)
 PUCAI score at prior flare, median (range) 40 (34–50) 40 (20–52)
Disease severity at prior flare, n (%)
 Mild 3 (21.4) 5 (35.7)
 Moderate 8 (57.2) 7 (50.0)
 Severe 3 (21.4) 2 (14.3)
5-ASA, 5-aminosalicylic acid; PUCAI, paediatric ulcerative colitis activity index; SD, standard deviation.

There was a strong interobserver agreement on the Mayo score, which was evaluated by 2 experts independently (Kappa 0.87, Cramer V 0.84). Mayo score 2 or 3 was present in 50.0% (14/28) of patients recorded by the paediatric endoscopist and in 42.3% (11/26) of the blinded observer (in 2 patients, Mayo score could not be evaluated by the blinded observer because of poor quality of the images and the paediatric endoscopist report was used) (Fig. 1B).

Endoscopic Activity and Sustained Remission

Follow-up data of last visit up to 18 months was available for 23/28 patients with a median of 9.0 months (IQR 5.0–18.0) of follow-up duration. Among the patients on anti TNF who relapsed (n = 2) both were on Adalimumab weekly dosing with good trough levels (8 and 16.4 μg/mL) at the time of endoscopy. Sustained clinical remission at last follow-up was present in 6/12 patients (50%) with a Mayo endoscopic score of 0 or 1, versus 2/11 (18.2%) among patients with an endoscopic score of Mayo 2 or Mayo 3 (P = 0.193) (Fig. 2A). In a Kaplan-Meier analysis, the probability of sustained remission was more than twice as high in patients with a Mayo endoscopic score of 0 or 1 versus Mayo endoscopic score of 2 or 3 at 18 months (46.3% vs 18.2% respectively, log rank test, P = 0.279) (Fig. 2B).

F2
FIGURE 2:
Comparison of sustained remission by Mayo score result. (A) Distribution of patients in sustained remission among patients with a Mayo endoscopic score of 0 or 1 versus patients with a Mayo endoscopic score 2 or 3. (B) Time to relapse by Mayo score result.

DISCUSSION

In our study, we have provided first evidence for the state of the mucosa 3 to 5 months after clinical remission was achieved. Our study is novel in that it evaluated patients prospectively at a defined time point after remission, included only asymptomatic patients, used blinded reading for assessment of severity and provides follow-up data. We found that 50% of children and adolescents in symptom-free clinical remission had moderate-to-severe inflammation upon endoscopy during remission. This may be an underestimation of endoscopic inflammation as 8 patients had already developed recurrence of symptoms within those 3 months before the endoscopy, and were therefore, excluded from the analysis. Aside from the high proportion with moderate-to-severe disease, we also found that those patients in remission with Mayo endoscopic score 2 to 3 were less likely to have sustained remission than patients with Mayo scores of 0 to 1, though this did not reach statistical significance, likely because of the small sample size. Fifty percentage of patients who had developed early MH or had only mild endoscopic disease (Mayo 0–1) were in sustained remission at 18 months or last follow-up, whereas only 18.2% were in sustained remission with Mayo 2 to 3 endoscopic scores after remission.

It is unclear at the present time why children are so prone to relapse with UC. The PROTECT study demonstrated that even patients with mild disease were unlikely to have sustained remission during the first year (9). In this study, only 40% of patients with mild disease were in steroid-free remission at 1 year (9). One possible explanation is the lack of MH, irrespective of initial disease severity is present in a significant proportion of children in clinical remission. Presence of clinical remission may lead to undertreatment if clinical indices without mucosal evaluation are the primary measure of success.

Our finding of active disease despite clinical remission has been demonstrated previously in a prospective adult study unrelated to timing of a previous flare that showed high correlation between clinical and endoscopic disease activity with active UC; however, the correlation was poor for remission as the proportion of endoscopic remission was only 30% to 50% among patients with clinical remission (17). Clinical indices of activity might be most useful for determining severity of disease during active disease but might underperform during remission. Kerur et al (19) retrospectively correlated PUCAI with endoscopic Mayo score in children with UC being examined in various clinical states from remission to severe disease. They found that the correlation between clinical disease and endoscopic activity was best for the groups with higher disease activity, whereas 20% of patients in clinical remission defined by PUCAI had Mayo 1 to 2 scores. Taken together, it appears that a clinically significant segment of patients in remission remain inflamed and at risk for relapse.

These results are consistent with another retrospective adults study that demonstrated only 35% endoscopic remission among patients with clinical remission (20). This may be true even in patients with more prolonged remission. In a retrospective cross sectional paediatric study of mucosal healing unrelated to when remission was obtained, only 10/28 (35.7%) of patients with remission had a Mayo score of 0, suggesting that clinical assessment may be insufficient to identify mucosal activity (21).

Every increase in Mayo endoscopic score increases the risk for early relapse. Yokoyama et al demonstrated that the Mayo endoscopic score was highly predictive for disease relapse within 6 months, with relapse rates of 0% with Mayo 0, 7% for Mayo 1, while the rates climbed to 30% with Mayo 2 and 50% for Mayo 3 (22). Even patients with Mayo score 1 left untreated may have a worse outcome. Fukuda et al evaluated 220 adults’ patients with Mayo score 1 in clinical remission who had an intervention or no intervention because of the endoscopic results. Patients left untreated with only Mayo score 1 were more likely to have both a clinical and endoscopic worsening of the disease compared with those treated because of mild residual inflammation (23).

A recent systematic review demonstrated that patients with Mayo 1 score had twice the relapse score of Mayo 0 score (29% vs 14%) at 1 year (24).

These findings have clinical ramifications for management of paediatric UC. Routine endoscopic evaluation after a defined time period is not currently a standard of practice. The current ECCO ESPGHAN guidelines provide guidance that a colonoscopy should only be performed if fecal calprotectin (FC) is >250 μg/g and that “there is currently no evidence whether measuring FC in a child who is in a PUCAI-defined remission has an added value for predicting disease course” (8). The reasoning behind the current guidelines is absence of evidence for benefit of either endoscopy or FC over a clinical index of disease severity.

Although a normal calprotectin is quite convincing with regard to endoscopic remission, an elevated calprotectin cannot predict the severity of inflammation or the degree of severity in adults with UC. There is considerable overlap between disease states and endoscopic severity and extent (25–27). A recent study from Oxford evaluated the UC endoscopic index of severity with simultaneous FC over a 6-month period in adults. Amongst patients with mild disease, the FC levels ranged from 25 to 1313 μg/g and among moderately active it ranged from 214 to 1089 μg/g (27) demonstrating considerable overlap of calprotectin levels between mild and severe endoscopic disease. Falvey et al found that determining endoscopic remission in adults with UC was precarious with cutoffs between 25 and 480 μg/g performing similarly with an accuracy of only of 76% or endoscopic remission (26).

The inability to distinguish between grades of mucosal severity because of significant overlap between remission to moderate disease is important as increased risk of early flare is associated primarily with Mayo 2 to 3 inflammation, and in adults, calprotectin seems underwhelming for this purpose.

Presence of unaddressed inflammation might also underly the tendency for disease extension noted in several pediatric studies though this remains a hypothesis at present (1,6). In a recent study from the EPIMAD group, 45% of children presenting with proctitis had disease extension and required the same therapies including anti TNF therapy as patients presenting with more extensive disease at onset (7).

MH may be a continuous process and the optimal timing for assessment is unknown. Deferring assessment has the benefit of allowing more time for complete healing but may also allow relapse and extension to occur. In Crohn disease, assessment requires a full colonoscopy, whereas in UC a sigmoidoscopy, which is easier, quicker, and involves less sedation and bowel prep makes a sigmoidoscopy a feasible strategy to employ especially if calprotectin is elevated.

Limitations of this challenging study include the small sample size, which was because of loss of eligible patients because of incomplete remission at the 3 months follow-up or by early recurrence of symptoms (usually residual bleeding or diarrhea) before endoscopy. Although the sample size is small, we provide first paediatric evidence for the state of the mucosa at a defined time period after precisely defined remission. We regret that FC was not performed in this study. Having FC before endoscopy would have allowed a more precise comparison between clinical disease activity, biomarkers, and actual endoscopic scores; however, assessment of biomarkers was not the goal of the present study. Lastly, disease relapse based on endoscopic activity was likely not statistically significant because of the small cohort size despite being almost 3 times higher. Determination of significant endoscopic inflammation as a reason for disease extension would have required repeat endoscopies at predefined time points, which was beyond the scope of this study. Presence of endoscopic inflammation may have also driven treatment change more for Mayo 2 to 3 patients and acted as a self-fulfilling prophecy.

In conclusion, in this study, we demonstrated that 50% of children assessed for MH have residual moderate-to-severe endoscopic inflammation 3 to 5 months after clinical remission is obtained even if they have no symptoms. Our study suggests that perhaps we should be more liberal in performing a sigmoidoscopy after remission in children and adolescents especially if calprotectin remains elevated 3 months after remission was documented. Importantly, we also need prospective studies to evaluate if early intervention for inadequate early MH could reduce early relapse and disease extension in paediatric UC.

REFERENCES

1. Gower-Rousseau C, Dauchet L, Vernier-Massouille G, et al. The natural history of pediatric ulcerative colitis: a population-based cohort study. Am J Gastroenterol 2009; 104:2080–2088.
2. Limbergen J. Van, Russell RK, Drummond HE, et al. Definition of phenotypic characteristics of childhood-onset inflammatory bowel disease. Gastroenterology 2008; 135:1114–1122.
3. Duricova D, Burisch J, Jess T, et al. ECCO-EpiComAge-related differences in presentation and course of inflammatory bowel disease: an update on the population-based literature. J Crohn Colitis 2014; 8:1351–1361.
4. Ruemmele FM, Turner D. Differences in the management of pediatric and adult onset ulcerative colitis--lessons from the joint ECCO and ESPGHAN consensus guidelines for the management of pediatric ulcerative colitis. J Crohns Colitis 2014; 8:1–4.
5. Mataly HM, Abraham BP, Mehta S, et al. The natural history of ulcerative colitis in a pediatric population: a follow-up population-based cohort study. Clin Exp Gastroenterol 2013; 6:77–83.
6. Fumery M, Duricova D, Gower-Rousseau C, et al. Review article: the natural history of paediatric-onset ulcerative colitis in population-based studies. Aliment Pharmacol Ther 2016; 43:346–355.
7. Hochart A, Gower-Rousseau C, Sarter H, et al. Epimad GroupUlcerative proctitis is a frequent location of paediatric-onset UC and not a minor disease: a population-based study. Gut 2017; 66:1912–1917.
8. Turner D, Ruemmele FM, Orlanski-Meyer E, et al. Management of paediatric ulcerative colitis, part 1: ambulatory care-an evidence-based guideline from European Crohn's and Colitis Organization and European Society of Paediatric Gastroenterology, Hepatology and Nutrition. J Pediatr Gastroenterol Nutr 2018; 67:257–291.
9. Hyams JS, Davis Thomas S, Gotman N, et al. Clinical and biological predictors of response to standardised paediatric colitis therapy (PROTECT): a multicentre inception cohort study. Lancet 2019; 393:1708–1720.
10. Rubin DT, Ananthakrishnan AN, Siegel CA, et al. ACG Clinical Guideline: ulcerative colitis in adults. Am J Gastroenterol 2019; 114:384–413.
11. Henriksen M, Jahnsen J, Lygren I, et al. IBSEN Study GroupUlcerative colitis and clinical course: results of a 5-year population-based follow-up study (The IBSEN Study). Inflamm Bowel Dis 2006; 12:543–550.
12. Pineton de Chambrun G, Peyrin-Biroulet L, Lémann M, et al. Clinical implications of mucosal healing for the management of IBD. Nat Rev Gastroenterol Hepatol 2010; 7:15–29.
13. Frøslie KF, Jahnsen J, Moum BA, et al. IBSEN GroupMucosal healing in inflammatory bowel disease: results from a Norwegian population-based cohort. Gastroenterology 2007; 133:412–422.
14. Reinink AR, Lee TC, Higgins PDR. Endoscopic mucosal healing predicts favorable clinical outcomes in inflammatory bowel disease: a meta-analysis. Inflamm Bowel Dis 2016; 22:1859–1869.
15. Turner D, Otley AR, Mack D, et al. Development, validation, and evaluation of a Pediatric Ulcerative Colitis Activity Index: a prospective multicenter study. Gastroenterology 2007; 133:423–432.
16. Turner D, Griffiths AM, Veerman G, et al. Endoscopic and clinical variables that predict sustained remission in children with ulcerative colitis treated with infliximab. Clin Gastroenterol Hepatol 2013; 11:1460–1465.
17. Rutka M, Milassin Á, Szepes Z, et al. Is mucosal healing more common than clinical remission in ulcerative colitis? - is it the truth or only a myth coming from the studies? Scand J Gastroenterol 2015; 50:985–990.
18. Fluxá D, Simian D, Flores L, et al. Clinical, endoscopic and histological correlation and measures of association in ulcerative colitis. J Dig Dis 2017; 18:634–641.
19. Kerur B, Litman HJ, Stern JB, et al. Correlation of endoscopic disease severity with pediatric ulcerative colitis activity index score in children and young adults with ulcerative colitis. World J Gastroenterol 2017; 23:3322–3329.
20. Krugliak Cleveland N, Rubin DT, Hart J, et al. Patients with ulcerative colitis and primary sclerosing cholangitis frequently have subclinical inflammation in the proximal colon. Clin Gastroenterol Hepatol 2018; 16:68–74.
21. Santha SL, Shankar PR, Pan A, et al. Mucosal healing in clinical practice: a single-center pediatric IBD experience. Inflamm Bowel Dis 2017; 23:1447–1453.
22. Yokoyama K, Kobayashi K, Mukae M, et al. Clinical study of the relation between mucosal healing and long-term outcomes in ulcerative colitis. Gastroenterol Res Pract 2013; 2013:192794.
23. Fukuda T, Naganuma M, Sugimoto S, et al. Efficacy of therapeutic intervention for patients with an Ulcerative Colitis Mayo Endoscopic Score of 1. Inflamm Bowel Dis 2019; 25:782–788.
24. Yoon H, Jangi S, Dulai PS, et al. Incremental benefit of achieving endoscopic and histologic remission in patients with ulcerative colitis: a systematic review and meta-analysis. Gastroenterology 2020; 159:1262.e7–1275.e7.
25. Cremer A, Ku J, Amininejad L, et al. Variability of faecal calprotectin in inflammatory bowel disease patients: an observational case-control study. J Crohns Colitis 2019; 13:1372–1379.
26. Falvey JD, Hoskin T, Meijer B, et al. Disease activity assessment in IBD: clinical indices and biomarkers fail to predict endoscopic remission. Inflamm Bowel Dis 2015; 21:824–831.
27. Walsh A, Kormilitzin A, Hinds C, et al. Defining faecal calprotectin thresholds as a surrogate for endoscopic and histological disease activity in ulcerative colitis-a prospective analysis. J Crohns Colitis 2019; 13:424–430.
Keywords:

child; inflammatory bowel disease; Mayo score; mucosal healing; relapse

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