The use of the Paris classification is advocated for phenotyping pediatric UC, with E1-E4, A1a-A2, and S0-S1 denoting disease extent, age of diagnosis and severity, respectively (13). Additional labels of very-early onset IBD (≤6 years of age at diagnosis) and infantile IBD (<2 years of age) may also be added (14).
In addition to providing an update of new literature, several major topics have changed from the previous guidelines. The diagnosis section has been replaced by the aforementioned IBD-Classes criteria; a discussion of IBDU has been added; fecal calprotectin has been given more emphasis; new drugs (eg, vedolizumab, golimumab, and locally active steroids) have been incorporated as off-label medications; practical recommendations for therapeutic drug monitoring have been provided; the use of thrombotic prophylaxis has been revisited based on predicting variables; sequential therapy has been newly presented; a treat to target algorithm has been added; and other sections updated and changed.
Following an open call in ECCO and the Porto plus the Interest Paediatric IBD groups of ESPGHAN, 22 international experts in pediatric IBD were selected by the steering committee, including 2 pediatric surgeons. A list of 23 questions addressing the management of UC in children was first developed (composing the subtitles of the current manuscript and the next one on ASC). Next, a systematic review of the literature was performed centrally by 2 of the authors (E.O.M. and C.S.) with the aid of an experienced librarian searching for all combinations of UC and pediatrics (Supplemental Table 1, Supplemental Digital Content 1, http://links.lww.com/MPG/B393). Electronic searches were performed in Oct 2016 using Medline, Embase, and web of science. Clinical guidelines, systematic reviews, clinical trials, cohort studies, case-control studies, diagnostic studies, surveys, letters, narrative reviews, case series, and highly relevant selected abstracts published after 1985 were all utilized if performed in children. Following elimination of duplicates, 10,096 abstracts were reviewed by EOM for eligibility. A total of 8,996 abstracts were excluded, mainly for the following reasons: clear irrelevance to the pre-defined topics, manuscripts published before 1985, review manuscripts, manuscripts focusing on CD, or on molecular/genetic pathways. Although we aimed to base our adult literature on the recently updated ECCO UC guidelines (15,16), salient adult RCTs identified in the initial search were not excluded for perusal and reference. The decision regarding questionable eligibility was made by one of the senior authors (D.T.). Finally, 1100 full-text manuscripts were retrieved and circulated to the relevant subgroups for writing their sections. Highly relevant manuscripts published after the search date were included individually.
Each of the 23 questions was allocated to a subgroup of 2 experts for drafting of the first text. The subgroup's text and recommendations were iterated by e-mail with the steering committee until refined. The guidelines include both recommendations and practice points that reflect common practice where evidence is lacking or provide useful technical details, including grading of evidence according to the Newcastle-Ottawa assessment scales for case-control and cohort studies (19) and according to the Cochrane Handbook for clinical trials (20) (Supplemental Table 2: tables of evidence with grading, Supplemental Digital Content 2, http://links.lww.com/MPG/B394). The group then voted on all recommendations and practice points while adding specific comments using a web-based voting platform. A second round of electronic voting and revisions was done, including all members of the Paediatric IBD Porto group of ESPGHAN. In addition, the draft was circulated for comments to ECCO (national representatives and governing board) and to members of the IBD Interest group of ESPGHAN.
The group met twice face-to-face: during UEGW annual meeting (Barcelona, October 2016) before drafting the initial topics and during ESPGHAN annual meeting (Prague, May 2017) after the 2 voting rounds were completed. The meetings were supplemented by an e-mail Delphi process with the entire group until agreement was reached. In total 43 pediatric IBD experts voted on all recommendations and practice points: 35 Porto group members (of whom 14 were authors) and 8 non-Porto group authors (Supplemental Table 3: names of the 43 voting experts, Supplemental Digital Content 1, http://links.lww.com/MPG/B393). All statements and practice points were supported by at least 88% of the group. Recommendations were graded according to Oxford Centre for Evidence-Based Medicine (see table at https://www.cebm.net/wp-content/uploads/2014/06/CEBM-Levels-of-Evidence-2.1.pdf (21)).
In 2 pediatric inception cohorts, disease severity during the first 3 months after diagnosis and the occurrence of an episode of ASC were associated with increased risk of refractory disease (22,23). Thus, by using constructs of disease severity it is possible to characterize children who are at high risk for a more complicated disease course and to guide management and tight monitoring.
Endoscopy is the reference standard to evaluate mucosal inflammation. Mayo endoscopic score of none, mild, moderate, or severe (0–3 points) with number of involved colonic segments (rectum, sigmoid, and descending, transverse, and ascending colon) may be used in pediatric UC (24). The modified Mayo endoscopic score is an easy to use, non-validated tool, which combines disease extent with Mayo Endoscopic score (25). The Ulcerative Colitis Endoscopic Index of Severity (UCEIS) is a convenient and validated index which includes vascular pattern, bleeding, and ulcers at the worst part (26,27). These indices are described in the coming ESPGHAN Porto group guidelines of endoscopy utilization in IBD (JPGN 2018).
Mucosal healing in UC is associated with a favorable disease outcome in adult patients (28–31). Nevertheless, clinical remission has been proven to predict long-term outcomes in UC, with no less accuracy than endoscopic evaluation, both in children using the PUCAI (23,32) and in adults (33). An adult study showed that UCEIS predicted relapse in 155 patients who were in clinical remission; however, clinical remission was not stringently defined (ie, partial Mayo score of 0–1, allowing for streaks of blood for instance) and the number needed to test was high (34). A post-hoc analysis of the adult ACT trials showed that while endoscopic inflammation predicted colectomy, this was not the case in the subgroup of patients who were in clinical remission (28). A PUCAI-defined remission at 3 months following diagnosis predicted 1-year sustained steroid-free remission (AUROC 0.7, 95% CI 0.6–0.8) and colectomy by 2 years (AUROC 0.75, 0.6–0.89). It was superior to both CRP and ESR (23) and predicted choice of treatment (35,36). Furthermore, in the prospective multicenter PROTECT pediatric cohort study, failure to achieve clinical remission (PUCAI < 10) 4 weeks after discharge of children who required intravenous corticosteroids at disease onset was highly associated with need for additional medical therapy by week 12 (37).
PUCAI cutoff scores of remission, mild, moderate, and severe disease have been validated in several cohorts (35,38,39) and were successfully utilized in the PROTECT study to guide the choice of initial treatment at disease onset, as outlined in Figure 3 (37). PUCAI at diagnosis was associated with steroid-free remission rates at week 12 and with long-term outcomes (at 54 weeks). Selected children with moderate disease activity were, however, treated with 5-aminoscalicylic acid (5-ASA) and not with oral steroids, and on average had similar outcomes at week 12; this supports our algorithm that 5-ASA may be considered also in the lower range of the moderate disease activity group (Fig. 3). The PUCAI correlates well with endoscopic appearance of the colonic mucosa, showing similar remission rates in multiple studies (38–43). In addition, the correlation of the PUCAI with Mayo score has been reported to be as high as 0.95 (32,38,39). While most aforementioned studies report a group average, on an individual basis there is a likelihood of ∼20% for a significant mucosal inflammation even in the presence of a PUCAI-defined complete remission (44). Therefore, biomarkers should be used to confirm endoscopic remission in those who are in sustained clinical remission, particularly in the presence of PSC where the PUCAI does not correlate well with mucosal inflammation (45) (Fig. 2).
Routine laboratory parameters (platelets, CRP, albumin, hemoglobin) are more frequently normal in UC than in CD during mild to moderate flares (46,47). In contrast to adult UC, high sensitivity (hs)-CRP was not suitable to differentiate between remission and relapse in children with normal standard CRP (48). In pediatric UC, ESR and CRP should be measured at least initially, since at times only 1 measure is elevated (49). Initial albumin was the only significant laboratory test that was predictive for acute severe colitis in 1 follow-up study (23). Similarly, earlier surgery was necessary in children with initially low serum albumin (HR 6.05, 99% CI 2.15–17.04) in 57 children who ultimately required colectomy (median time to surgery was 3.8 years) (50). In another study, elevated white blood cell and low hematocrit measured at diagnosis were associated with colectomy rate at 3 years (51).
Data supporting CRC surveillance recommendations can be found in extensive adult guidelines (15,16,67). Of note, a Swedish nationwide cohort study of pediatric IBD confirmed that CRC was almost non-existent during the first 5 years of follow-up, but incidence was higher after 10 years of follow-up (68). Interestingly, the incidence of CRC in the first 20 years of follow-up was considerably lower in childhood-onset IBD than in disease with onset at other ages.
Strong evidence, mostly from adult trials, supports the use of 5-ASA for induction and maintenance of remission in mild-moderate UC (41,69–72). In that context, mesalamine induces remission in 35% to 55% of children, as defined by the PUCAI (73,74).
There are no pediatric maintenance comparative trials of 5-ASA, but only ∼ 40% (86/213) of children treated with 5-ASA within 1 month of diagnosis were in steroid-free remission by 1 year in the North American registry (75). Similar data were reported from the prospective Italian pediatric IBD registry, with 45% of patients in remission at 1 year on 5-ASA therapy alone (76). EPIMAD data reported that 32% (36/113) of children with UC remained on 5-ASA therapy without steroids, by maximum follow-up (5). In a recent Cochrane analysis of adult trials, the relative risk of successful induction of clinical and endoscopic remission with 5-ASA was 1.16 (95% CI 1.12–1.21) and 1.29 (95% CI 1.16–1.69), respectively (69). No specific 5-ASA compound was superior for inducing remission, although sulfasalazine was statistically superior to other 5-ASA compounds for maintenance of remission (69,70,77,78).
Rectal therapy (as suppositories) is indicated for ulcerative proctitis, an infrequent phenotype in pediatrics (95). In order to allay concerns and ensure optimal compliance, children and their caregivers require support and reassurance when topical rectal therapies are proposed.
Second-generation topical steroids have a more favorable safety profile and may be considered before systemic steroids in selected patients (112). BDP uses gastro-resistant film coatings to target delivery to the distal small intestine and the colon. Studies in adults demonstrate the effectiveness of BDP compared with both prednisolone and mesalamine (15,113). An RCT of 30 children (weight >30 kg) with mild-to-moderate UC showed that oral BDP, 5 mg/day for 4 weeks, was well tolerated and more effective than 5-ASA in achieving both clinical remission (80% vs 33%, P < 0.025) and endoscopic remission (73% vs 27%, P < 0.025), respectively (41).
A Cochrane systematic review of older selective release budesonide in adults showed that it was less likely to induce remission than mesalamine (relative risk [RR] 0.72, 95% confidence interval [CI] 0.57–0.91) with no benefit over placebo (RR 1.41, 95% CI 0.59–3.39) (114). Budesonide-MMX is a novel oral formulation designed to extend release of the drug to the colon. Two adult trials showed significant benefit in the intention to treat (ITT) population (combined left sided and extensive), but subanalysis based upon disease extent was only significant for left-sided disease (115,116). Indeed, in a recent case series of 16 children, 15 of whom with pancolitis, budesonide-MMX showed minimal clinical effectiveness (117). Another recent RCT in adult UC refractory to 5-ASA showed superiority over placebo but with a disappointing 6% effect size difference; no subgroup analysis of disease extent was performed (118).
AS may present with non-specific symptoms (including abdominal pain, malaise, weakness/fatigue, nausea, diarrhea, headache, fever, arthralgia) or rarely adrenal crisis (hypotension, lethargy, decreased consciousness/coma, hyponatraemia, hypoglycemia, seizures) (122). There are no published consensus guidelines that advise who should be screened for AS. In 1 recent review, it was recommended to screen patients who received steroids for >3 weeks and after gradual weaning have persistent symptoms that may be attributable to AS (123). The range of 8 AM morning cortisol value at which AS is confirmed varies between studies. In 1 recent review a value of <100 nmol/L was used while >500 nmol/L virtually excluded AS (124). Another manuscript suggested that <85 nmol/L should be used to diagnose AS (123). In a study of consecutive children with IBD about to stop steroids (ie, on physiological doses of oral steroids meaning 5 to 10 mg daily prednisolone) 20% had biochemical AS using a value <69 nmol/L and of these half had an undetectable cortisol (125). Higher glucocorticoid dose and longer duration of the therapy were associated with increased risk (125). In the only study of children with IBD, all children treated with steroids for <3 months did not have biochemically confirmed AS (after gradually weaning to physiological doses of steroids) (125–127).
Prospective pediatric studies reported steroid-free remission rates of 49% at 1 year (133) and 72% at 2 years (134) in thiopurine treated children with no difference in either clinical or endoscopic end-points between early or late initiation of treatment. A few retrospective studies (135–138) in children supported the benefit of thiopurines in maintaining remission and steroid sparing with a median time to achieve steady state of thiopurine levels of 55 days (139). Cox proportional hazard modeling of retrospective data from 1175 incident children and young adults, did not demonstrate a benefit to early thiopurine use in reducing the risk of colectomy (140).
Most adult studies used doses of 2.5 mg/kg for azathioprine and 1.5 mg/kg for 6-MP. There was, however, no clear dose-response effect for azathioprine, implying that low-dose azathioprine (1.5 mg/kg) may not be inferior to standard dose (144). Children younger than 6 years may require higher doses of azathioprine per body weight with doses of up to 3 mg · kg−1 · day−1 (145,146).
A meta-analysis (25,728 IBD patient-years) demonstrated that patients younger than 30 years have a high relative risk for non-Hodgkin lymphoma (SIR = 6.99) with younger men being at the highest risk. However, the absolute risk is much higher in the elderly. In patients younger than 30 years, the absolute risk is estimated at only 1 in 4000 to 5000 (152). Hepatosplenic T-cell lymphoma (HSTCL) is a very rare but fatal complication of thiopurine therapy. Of over 40 reported cases of IBD-related HSTCL, almost all received thiopurines, with or without anti-TNF and almost all were males; there are only extremely rare and anecdotal case reports of children with HSTCL who were treated solely with anti-TNF (153,154).
In the case of hyperactive TPMT resulting in high 6-MMP and low 6-TGN, concomitant use of allopurinol with reduced dose of azathioprine may provide a valid therapeutic option (158,159) but needs to be used with caution. Adequate dose reduction and repeated monitoring of CBC and 6-TGN/6-MMP is essential to avoid myelosuppression related side effects. In adult trials, allopurinol was used at 100 mg once daily (158,160) whereas in the few pediatric case series lower doses (50 or 75 mg once daily) were utlized in younger children (159,161).
Thiopurine withdrawal after attaining sustained remission is controversial. In a retrospective study of 127 UC patients in remission, approximately one-third relapsed within 12 months following withdrawal, and two-thirds within 5 years (171). Moderate/severe relapse rate of 26% at 2 years was observed in 108 UC patients who withdrew treatment following prolonged thiopurine treatment (172).
Cochrane meta-analyses of methotrexate (MTX) for induction (2 RCTs, 101 patients) (173) or maintenance (3 RCTs, 165 patients) (174) of remission in adult UC concluded that there is no evidence supporting the use of MTX for either induction or maintenance of remission in UC. Nevertheless, this conclusion relies on low-quality evidence. In the METEOR double-blind, placebo-controlled trial of 111 steroid-dependent UC adults, steroid-free remission at week 16 was not statistically different than placebo (32% vs 20%, respectively; P > 0.05) though clinical remission did differ (42% vs 24%, respectively; P = 0.04) (175). In a retrospective study of 32 UC children unresponsive or intolerant to thiopurines, response/remission was achieved in 72%, 63% and 50% of patients treated with parenteral MTX at 3, 6, and 12 months, respectively (176).
A Cochrane systematic review of 7 adult UC trials concluded that IFX is effective in inducing clinical remission, promoting mucosal healing, and reducing the need for colectomy in patients with active UC (183). Combination therapy with IFX and azathioprine was shown to be superior in the SUCCESS trial in adult UC to monotherapy with azathioprine or IFX alone, while there was no superiority of IFX monotherapy over azathioprine (184).
In the pediatric UC regulatory RCT (ie, the T-72 study), 45 of 60 (75%) ambulatory children with moderate-severe UC responded to a standard induction protocol of IFX (40). Both clinical remission (PUCAI < 10 points) and complete mucosal healing (Mayo endoscopic subscore = 0) were achieved in 33% at week 8. Dose escalation to 10 mg/kg was required in 44% of the patients in the maintenance phase.
Adalimumab has shown efficacy and safety for induction and maintenance in the adult moderate-to-severe active UC. In the adult ULTRA-1 trial, clinical remission was obtained in 18.5% of patients in the 160/80 mg group, 10% in the 80/40 mg group and 9.2% in the placebo group (188). In the ULTRA-2 trial, overall rates of clinical remission for active drug at week 52 were 17.3%, with better results among anti-TNF-naïve patients (22%) as compared to those anti-TNF experienced (10.2%) (189). A network meta-analysis of 5 RCTs in moderate-to-severe adult UC suggested that while IFX is more effective than adalimumab in the induction of remission, response and mucosal healing, both are comparable in efficacy at 52 weeks of maintenance treatment (190). Another meta-analysis showed superiority of IFX over adalimumab in inducing and maintaining endoscopic healing in UC (191). In a propensity score adjusted analysis, a study of 419 adults with UC found no difference in the effectiveness of these agents, but the adalimumab group was relatively small (192).
Drug and antibody levels should dictate the course of action in patients with secondary loss of response (211) (Fig. 4). Ongoing symptoms despite adequate drug levels, mandates switching therapy “out of class.” High antibodies titer predicts failure of dose intensification (211) (Fig. 4).
Factors predicting lower drug levels (and thus possibly dictating higher dosing) include higher body mass index (212), low body weight <30 kg (213–215), male gender (216), high inflammatory burden (extent and severity of disease) (217), hypoalbuminemia (218), the presence of anti-drug antibodies, and the absence of a concomitant immunomodulator (184,219–221).
There is no clear evidence that pre-medication with any drug prevents the development of acute infusion reaction (226,227). A self-reporting system in the United States with >5000 documented patients calculated a rate of infusion reactions of 3% (1.1% immediate and 1.7% delayed) in IBD-treated patients (228).
DEVELOP is a prospective post-marketing industry-initiated safety registry for pediatric IBD, which includes both patients exposed and never exposed to IFX (234). In 5766 patients (29% UC; 24,543 patient years follow-up; median 4.5 years per patient follow-up) there were 15 malignancy events (13 exposed to thiopurines (10 with IFX; 3 thiopurine only); 1 only to IFX; 1 to neither biologics nor thiopurines). Comparison with rates from the SEER database of healthy controls indicated a standardized incidence rate (SIR) for neoplasia of 2.43 (95% CI 1.29–4.15) for thiopurine exposure (with or without biologic exposure), but no significant increase in neoplasia with IFX exposure in the absence of thiopurine exposure (SIR 1.49, 95% CI 0.04–8.28). Five children in total experienced hemophagocytic lymphocytic histiocytosis (HLH), 4 with primary EBV infection, one with CMV infection, and all during thiopurine monotherapy.
Apheresis acts by an extracorporeal removal of leukocytes and other cells of the immune system (granulocytes, granulocyte/monocyte) through an adsorptive system of cellulose acetate beads (Adacolumn, Otsuka Pharmaceuticals, UK), or a polyester fiber filter (Cellsorba, Asahi Medical Company). Overall, pediatric data suggest a possible clinical efficacy of apheresis in children with both steroid-dependent and resistant UC, with reported response rates ranging between 60% and 85%, although they are mainly small case series or cohort studies (246–251). Data in adults are conflicting, with some observational and randomized clinical trials suggesting benefit (252–257), others, among them a large randomized, double-blind clinical trial evaluating active versus sham apheresis, showing no efficacy (258). A systematic review published in 2010 reported that, although there may be some efficacy in specific settings, concerns about methodological quality of identified studies prevent a rigorous meta-analysis and definitive conclusions (259).
FMT is based on the transfer of stool from a healthy donor, with a presumed healthy diverse microbiome, to a patient. Related or unrelated donors can be used, and they must undergo an accurate clinical and laboratory screening before the procedure. Some studies have used specifically prepared fresh stools, although frozen stools seem to have the same efficacy and safety (260), with delivery both to the upper gastrointestinal tract through nasogastric tube or to the lower gastrointestinal tract through colonoscopy or serial enemas. A few case series on the efficacy of FMT in pediatric UC have been published, reporting inconclusive results (261–263). The largest pediatric series (9 children with UC) showed a 33% clinical remission (PUCAI < 10) with serial enemas (261). One small pediatric study reported no clinical improvement after FMT delivered via nasogastric tube (262). Overall, the safety profile appears acceptable, although mild-to-moderate side effects were common, and a case of transitory systemic reaction (profuse sweating, vomiting, paleness, tachycardia, and fever) has been reported (264). There may be a theoretical risk pertaining the transfer of an adult microbiome to a child, particularly very young with a developing microbiome, to quickening of immune aging and developing immune-related consequences (265). Rapid weight gain and the development of autoimmune disease have been reported after FMT in adults and in animal models (266–268).
Two small RCTs in adults with active UC reported different results: one showed clinical and endoscopic benefit of FMT administered via enema compared to sham (269); the other reported no difference between FMT using healthy donors or autologous feces administered via naso-duodenal tube, although the limited number of patients and the route of administration may have impacted on these results (270). Interestingly, patients who responded to FMT from a healthy donor restored their altered microbiota toward the healthy donor composition, while non-responders had no changes. Recently, the results of a third large, randomized, placebo-controlled trial in active UC resistant to conventional treatment have been reported (271). Eighty-one adults with UC were randomized to receive a single FMT or placebo colonoscopic infusion on day 1, followed by FMT or placebo enemas 5 days per week for 8 weeks. Each active enema was derived from 3 to 7 unrelated donors. Steroid-free clinical remission with endoscopic response was achieved in 11/41 (27%) patients receiving FMT compared to 3/40 (8%) patients receiving placebo (P = 0.02). Microbial diversity increased and persisted after FMT while Fusobacterium spp was associated with lack of remission. Although FMT is gaining increased enthusiasm, the ideal donor and method of administration should be first determined before this can be incorporated outside the research setting.
Probiotics have been evaluated for induction and maintenance of remission in UC. One pediatric and 3 adult trials found E coli Nissle 1917 to be as successful as mesalamine in maintaining remission (272–275). The dosage used in all these studies, including the pediatric one, is 200 mg/day (100 mg contains 25 × 109 viable E coli bacteria), administered as capsules. A recent systematic review and meta-analysis suggests that E coli Nissle is equivalent to mesalamine to prevent relapse, while its efficacy is comparable to placebo in the induction of remission (276). A previous Cochrane systematic review, however, highlighted several methodological limitations in the maintenance studies, preventing any conclusion (277).
Antibiotics have been evaluated as a therapy for UC both in the induction of remission and to prevent disease relapses as shown in 2 systematic reviews and meta-analyses (284,285). Both included 9 RCTs and concluded that antibiotics may improve outcomes in UC, but further studies are required to confirm this benefit since the included trials were very heterogeneous in their methodology and the type of drug intervention. The use of antibiotics in treating pediatric UC outside the research setting awaits further trials.
Recently, a small case series on the tolerability of curcumin added to standard therapy in pediatric IBD has been published, reporting an acceptable tolerability and a possible signal of benefit (286). Two placebo-controlled trials conducted in adults suggested the possible efficacy of curcumin in achieving and maintaining sustained clinical remission (287,288). Moreover, endoscopic remission was observed in 38% (8/22) patients treated with curcumin, compared with 0% (0/16) in the placebo group (288). A recent randomized, placebo-controlled, pilot study reported efficacy of topical curcumin as enema, added to oral mesalamine, compared to placebo, in 45 adults with mild-moderate proctitis/proctosigmoiditis (289).
Systematic review of complementary and alternative medicine treatments in IBD, including aloe-vera, andrographis paniculata, artemisia absinthium, barley foodstuff, boswellia serrata, cannabis, evening primrose oil, Myrrhinil intest, plantago ovata, silymarin, sophora, tormentil, wheatgrass-juice, and wormwood reported a possible benefit of some interventions, although, given the small number of trials and their heterogeneous methodological quality, no definite conclusions could be drawn (290,291). Of note, oral aloe vera has been evaluated in a double-blind, randomized, placebo-controlled trial as an adjuvant therapy in 44 adults with mild-to-moderate UC (292). Higher remission and response rates with improvement of the histological score were reported in the aloe vera group. These encouraging but preliminary findings await confirmation before aloe vera can be recommended for clinical practice.
Other complementary therapies, including germinated barley foodstuff and herbal medicine have been studied in adult case series or prospective cohorts. Because of sample size, study design, concomitant therapies and methodological limitations, these agents cannot currently be recommended for treating pediatric UC (290,291,293).
A systematic review and a meta-analysis reported no efficacy of omega-3 supplement for maintaining remission in UC (293–295). Recently, a retrospective individual cohort study of 24 adults with IBD suggested efficacy and safety of intravenous immunoglobulin in the short-term management, when standard therapies are contraindicated (296). There are, however, no RCTs on its role both in adults and children.
Patients with IBDU represent approximately 5% to 10% of pediatric IBD without a decline in incidence over time despite improved diagnostic measures. The rate is even higher in very early onset IBD. Complete examination is important, however, and the proportion of patients with IBDU is reduced if a full diagnostic work up is performed (297). IBDU is not a misclassification but rather a true overlap diagnosis within the spectrum of phenotypes between UC and Crohn colitis (12). Historically, patients with IBDU have often been poorly classified with no specific guidance available for detailed diagnostic criteria. The PIBD-Classes criteria were validated on a large multicenter dataset of 749 patients with colonic IBD from the Paediatric IBD Porto group of ESPGHAN (12). A diagnostic algorithm combining 23 features of different weightings (grouped in class 1, 2, and 3 features) (Table 1) may differentiate between patients with UC, atypical UC, IBDU, Crohn colitis and ileal/ileocolonic Crohn disease (Fig. 1) (12).
Given the rarity of IBDU and the hitherto lack of standardized diagnosis, there are very few studies which have been able to collect treatment information on significant numbers of patients. The aforementioned retrospective study from the Porto group of ESPGHAN utilized the data of 537 children with colonic IBD, including 260 IBDU, to explore common treatment schemes and to compare the treatment outcomes (298). This study demonstrated that treatment for IBDU and UC were broadly similar with the most common treatment used initially being 5-ASA. The use of steroids was lower than in UC; thiopurines and IFX use was broadly similar to patients with UC and lower than for patients with Crohn disease. Rates of surgery were lower than in Crohn disease and UC and the disease was more likely to be mild at follow-up compared to the other IBD subtypes, despite the similar use of medications as in UC. This suggests that treatment can follow that of UC initially with a 5-ASA regimen.
Surgery for pediatric UC may require up to 3-staged procedures—first stage, subtotal colectomy with end-ileostomy; second stage, restorative procto-colectomy with ileal pouch-anal anastomosis or ileo-rectal anastomosis (with or without covering ileostomy); third stage, closure of the covering ileostomy. The decision concerning the best combination of procedures is dictated by the clinical status of the patient. Restorative procto-colectomy and IPAA/IRA with covering ileostomy can be performed as a combined first stage for most “ambulatory” elective UC cases. The covering ileostomy is reversed several months later after confirmed healing of the pouch (299–303). Three-stage surgery (subtotal colectomy and ileostomy first) is recommended for ASC, for example, where the pre-operative PUCAI is >45, or in those on high-dose pre-operative steroids (prednisolone >0.20 mg · kg−1 · day−1) (36,301). Although single-stage restorative procto-colectomy IPAA without a covering ileostomy was not associated with increased anastomotic complications in some retrospective pediatric series (300,304–306), this cannot be recommended before more studies are available given the retrospective design of the studies and the inherent confounding by indication bias.
Emergency surgery for ASC is an initial subtotal colectomy (leaving a rectal stump) with end-ileostomy formation only. Creation of IPAA/IRA should be deferred until the clinical status of the patient has normalized, followed by stoma closure as the third stage. Laparoscopic colectomy/ileostomy for both ASC and ambulatory UC is safe and feasible in experienced hands also in children (36,307). The PUCAI has been reported in a retrospective analysis to be a useful tool when considering 1- versus 2- versus 3-stage procedures for pediatric UC (36).
As significant complication rates are reported after colectomy for both ASC and ambulatory UC in children, in particular infectious and thromboembolic events (8,308), peri-operative antibiotic and thromboembolism prophylaxis should be routine. The rectal stump can be fashioned as a mucous fistula (open or within the subcutaneous tissue) if there is significant proctitis. A more commonly used alternative is to close the rectal stump within the abdomen and place a temporary trans-anal drain (309). Length of hospital stay, short-term surgical complications and functional outcomes seem similar after open and laparoscopic procedures (300,310–312).
According to a meta-analysis of 5 pediatric studies (306 patients), straight ileo-anal anastomosis (SIAA) was associated with a higher failure rate (15% vs 8%) and perianal sepsis (20% vs 10%), as well as a higher stooling frequency as compared with a J pouch ileo-anal anastomosis (JPAA) (319). A more recent multicenter study, including 112 children with SIAA, and 91 with JPAA, reported comparable postoperative complication rates (320). Both day-time and night-time stooling frequency were higher after SIAA, although the difference became less apparent by 2 years (mean 24 hours stooling frequency 8.4 vs 6.2 at 2 years). This difference may still be clinically important, because quality of life in children after restorative proctocolectomy is inversely associated with stooling frequency (302).
JPAA, on the other hand, carries a risk of pouchitis, which clearly exceeds the incidence of enteritis following SIAA (49% vs 24%, OR 4.5; see henceforth detailed chapter on the pouch) (320). Surgical complications and functional outcomes are comparable after hand-sewn or stapled J-pouch anastomosis. For example, in 1 series, stool frequency was 4 per day after both techniques (299,321,322). A common complication of stapled IAA is, however, an undesirably long rectal stump with excessive remaining anorectal mucosa above the dentate line (>2 cm). Chronic inflammation of the rectal mucosal remnant is called “cuffitis” and discussed further below. One study reported a lower rate of small bowel obstruction during 4 post-operative years after laparoscopic IPAA compared to open procedures (310), while no difference was found in another (300).
In those undergoing IPAA, the diagnosis of UC may change to CD; ∼15% in adult series (299,302,303,323) and 11 of 128 children (9%) in a recent multicenter pediatric study from the Paediatric IBD Porto group of ESPGHAN (324,325). Three-stage IPAA has been used to reduce these complications in children with IBDU. Histology of a colectomy specimen or pre-operative diagnosis of IBDU, however, poorly predicts the long-term outcomes of IPAA in adults with UC (326,327). In most studies, the incidence of pouchitis and post-operative diagnosis of CD is similar after IPAA in patients with UC and IBDU (321). There is no published evidence on whether postponing pouch surgery after subtotal colectomy for an extended period influences the rate of complications or long-term outcome after IPAA. Overall, results from pediatric series of IPAA in terms of later pouch abandonment (<15% at median 10–20 years follow-up) are similar to adult reports, albeit with shorter length of follow-up in most series (300,302,328). A multicenter, retrospective study from the Paediatric IBD Porto Group of ESPGHAN included 129 children who underwent IPAA, showed an increased rate of surgical complications in children undergoing colectomy under the age of 10 years but there was no difference in complications rate whether the pouch surgery was delayed or not (324).
While IPAA has been shown to reduce female fecundity and fertility in adult studies (e.g. reduction of fertility rate by 52% among women aged 15 to 44 years (323)), most used the non-stringent definition of inability to become pregnant within 1-year of intent (322,323). This should be discussed with female patients and their family before any surgical procedures. Laparoscopic IPAA, as is increasingly performed, may ameliorate the risk of subfertility due to reduced adhesion formation, pelvic scarring and Fallopian tube obstruction (329–331). In 1 adult series, spontaneous pregnancy rate was higher after laparoscopic IPAA (70%) compared to open IPAA (39%, P = 0.023) among 50 women who attempted to conceive (326). Fertility is also much better preserved after IRA (300). Fecundity remained similar to the general population after IRA, but dropped to 54% after IPAA among women with familial adenomatous polyposis (327). In a recent follow-up study of 343 adults with UC, 10- and 20-year IRA failure rate was 27% and 40%, respectively (328). Secondary proctectomy was required for refractory proctitis (66%), dysplasia (11%) and for cancer (10%) (332). At the end of the follow-up, 18% had undergone secondary IPAA and 13% had permanent ileostomy. Although fecal continence and stooling frequency is better preserved after IRA compared to IPAA, most patients require anti-inflammatory medication and urgency rate is higher, while quality of life similar to that after IPAA (328).
Data from the Porto group of ESPGHAN suggest that the experience of the surgeon is associated with the likelihood of development of chronic pouchitis; (15%) in surgeons with ≥10 surgeries/year versus (41%) in surgeons with <10 per year, P = 0.013 (325). This is in line with a large study from the UK showing the pouch outcome was superior if done in centers performing at least 9 to 10 procedures annually (333).
Pouchitis, a non-specific and idiopathic inflammation of the ileal reservoir, is the most common complication of IPAA, occurring in 24% to 67% of pediatric UC patients (299,300,302,320,323,334–337). A recent multicenter, retrospective cohort study from the Paediatric IBD Porto Group of ESPGHAN included 129 children who underwent IPAA (93% UC and 7% IBDU) and showed that 86 children (67%) developed pouchitis during follow-up (325). In 33 (26%) the pouchitis was chronic, 10 of whom (8%) had Crohn-like disease of the pouch. Median time from pouch formation to the first episode of pouchitis was 10.5 months (IQR 6–22); in 54% of cases the first episode occurred within 1 year. In an older cohort of 399 UC children with a mean age of 18 ± 3 years at colectomy, 121 (36%) had at least 1 episode of acute pouchitis, and 29 (9%) pouch failure (300). Pouch type, age, and operative technique had no impact on whether patients developed pouchitis.
Symptoms and severity of pouchitis vary, but typically include increased stool frequency and urgency, tenesmus, incontinence, abdominal pain, and rectal bleeding (338). Cuffitis, residual rectal cuff inflammation, may cause symptoms similar to those of pouchitis, especially bleeding. The cuff is the remaining rectal mucosa between the dentate line and the anastomosis after restorative procto-colectomy. Symptoms of pouch dysfunction in patients with IPAA may be caused by conditions other than pouchitis, including CD of the pouch, anastomotic ulcer or stenosis. In children, the occurrence of terminal ileitis, or “pre-pouch ileitis,” has also been reported (339), and does not necessarily confirm the diagnosis of CD if it involves only mild inflammation in a short segment. Other differential diagnoses include ischemia and, rarely, infections such as CMV and C difficile. A diagnosis of irritable pouch syndrome is suspected when symptoms are present without endoscopic inflammation (340). Thus, endoscopic and histological evaluation of the pouch should be performed at the first episode of pouchitis and periodically thereafter.
Endoscopic features of pouchitis may include hyperemia, diminished vascular pattern, friability, hemorrhage, and ulcers. Abnormalities may be focal or diffuse, and unlike in UC, they may be discontinuous. Often, they are more severe in the distal compared to the proximal pouch (341–343). Mucosal biopsies typically demonstrate partial to complete villous blunting with crypt hyperplasia and increased mononuclear inflammatory cells and eosinophils in the lamina propria, crypt abscesses, and ulcerations. Mucosal biopsies should be obtained from the pouch and from the afferent ileal loop, but not from the staple line, as erosions and/or ulcers along the staple line do not necessarily indicate pouchitis (344).
Two main scoring systems exist for the diagnosis of pouchitis but their utility in clinical practice is limited as they await further validation to associate the scores with clinical outcomes (345,346). The Pouchitis Disease Activity Index (PDAI) evaluates symptoms, endoscopic findings, and histological patterns in a composite score, with a score of ≥7 indicating pouchitis (347). The Pouchitis Activity Score (PAS) incorporates similar elements to the PDAI and a score >13 is suggestive of pouchitis (348). A modified PDAI (mPDAI), omits the histology component (349).
Several variables may predict the risk of pouchitis. A small pediatric study reported that the only predictive factor associated with risk of pouchitis was a higher PUCAI score at the time of diagnosis (337). As discussed above, data suggest that the surgeon's experience is associated with risk for pouchitis (325). Chronic pouchitis was also associated with Ashkenazi Jewish ethnicity, while any-pouchitis was associated with age at diagnosis and longer disease duration. Several adult studies have reported an increased incidence of pouchitis in patients with a younger age at onset, backwash ileitis, PSC, extensive colonic disease, positive pANCA, preoperative steroid use, being a non-smoker, and carriage of genetic polymorphisms in NOD2/CARD15, which is more prevalent in Ashkenazi Jews (66,350–358).
The probiotic mixture VSL#3 was effective in maintaining remission in adult patients with chronic pouchitis as shown in 2 double-blind placebo-controlled trials from Italy (359,360). Results regarding the effectiveness of VSL#3 in preventing the first episode of pouchitis are more controversial (361,362).
Joint disease in IBD may be axial (sacro-ileitis or ankylosing spondylitis), causing lower back pain or peripheral arthritis, which is usually acute and self-limiting, seronegative and not deforming. In children, the prevalence of arthritis seems to be twice as high as in adults, (377) with a clear female predominance. There are some concerns about aggravating the bowel disease by using NSAIDs; however, the risk seems to be low if prescribed for a short course and at low doses (383). The sulfapyridine component of sulfasalazine has an anti-inflammatory effect on both the colonic mucosa and the joints (384). MTX is the cornerstone disease-modifying anti-rheumatic drug in juvenile arthritis (385) but anti-TNF regimes have emerged in the last 2 decades (386).
Being non-invasive, MRCP is the most appropriate imaging modality for diagnosing PSC in children. A pattern of irregular bile ducts, with zones of narrowing and dilatation is characteristic of PSC (389). PSC may progress to liver cirrhosis, ultimately necessitating liver transplantation. Patients with PSC and UC have a greater risk of malignancies such as CRC and cholangiocarcinoma (8%–30% of UC patients with long standing PSC) (390,391). A recent study on the cancer and mortality in children in Europe has demonstrated several cases associated with PSC (10), but CRC in UC children younger than 12 years is extremely rare. PSC is associated with more extensive disease and thus has a greater cancer risk (391) but also with milder disease course. The higher colectomy rate in these patients is secondary to dysplasia and CRC. In adults with PSC, ursodeoxycholic acid is reported to improve abnormal liver tests (392) and to reduce the risk of CRC (393), although this has not been shown by all (394,395). No therapy has been shown to reduce time to liver transplantation, cholangiocarcinoma or death (394,396,397). Recent recommendations for adult patients suggest ursodeoxycholic acid at a dose of 10 to 15 mg · kg−1 · day−1 and warn against high dose treatment (>20 mg · kg−1 · day−1), which may increase mortality (394,395,398).
Oral vancomycin may be considered for 12 weeks as it has been shown to reduce and even normalize serum liver enzymes and gGT (399–405). Both vancomycin and metronidazole have been efficacious in recent small studies; however, only patients in the vancomycin groups reached the primary endpoint, and with fewer adverse effects (403). Oral vancomycin re-treatment when needed has been associated with a rise in T regulatory cells (Treg) and normalization of liver function tests (406).
Peak bone mass attained during adolescence is the most important determinant of lifelong skeletal health. Some osteopenia is present in up to 22% of UC children (419), but severe osteopenia is only present in 3% to 6% in UC, as compared with 12% to 18% in CD (420–422). Nutritional status seems to have a greater impact on bone status than corticosteroid therapy (423). Children with IBD are at particularly risk for vitamin D deficiency, but this was not found to be directly associated with osteopenia (424). Nonetheless, vitamin D deficiency should be treated especially in children with decreased bone mineral density. A recent meta-analysis showed that low vitamin D is associated with a more active disease (425). Age-appropriate nutrition support, weight-bearing exercise, and adequate disease control using steroid-sparing strategies (410,421,426) have been suggested as means to improve bone formation but without supportive evidence. Indeed, a prospective study that followed 58 children with CD for 2 years did not show significant improvement in bone mineral density despite increased height z score and reduced disease activity (421).
The most important determinant of treating osteopenia, besides avoiding steroids, is efficient treatment aiming at mucosal healing since osteopenia may typically be a consequence of pro-inflammatory cytokines (427). Indeed, interventions that lead to mucosal healing such as anti-TNF therapy and exclusive enteral nutrition showed rapid improvement of serum bone markers in children with CD (428–432). Bisphosphonates are effective to improve bone mineral density in IBD but pediatric use should be reserved for extreme circumstances, typically when pathological fractures are present, an uncommon situation in UC.
Several systematic reviews concluded that adolescents with IBD, especially boys, have reduced health-related quality of life, including anxiety, depression, social problems, and low self-esteem (433–436). The altered quality of life of children with IBD can affect the entire family, who often lack the appropriate strategies to deal with this complicated reality (437). The rate of depression may be as high as 25% and it is often under-recognized both by parents and health care professionals. Anxiety and depression appear to be risk factors for early recurrence of the disease and adversely affect the disease course but may also commonly be a reactive response to active disease (438). Cognitive behavioral therapy has been shown to be especially effective in improving depressive symptoms and functioning in children with IBD (439).
Transition is defined as the planned move of adolescents and young adults with long-term physical conditions from child-centered to adult-orientated healthcare. The optimal timing of transition from pediatric to adult management of UC has to be decided on an individual basis by a joint team of pediatric and adult gastroenterologists (443). Several suggestions for transition programs have been published, but none has been formally evaluated (444). The transition period usually starts from the age of 14 to 18 years depending on the development of the patient and availability of qualified pediatric and adult gastroenterologists. The time of transition should be individually adapted according to the psychosocial readiness. Whenever feasible, at least 1 joint clinic with both the pediatric and the adult gastroenterologist is recommended during the transition process. The adolescent should be encouraged to assume increasing responsibility for treatment and to visit the clinic room at least once without being accompanied by the parents. The ECCO topical review on transition to adult care addresses in detail all aspects related to the steps to be followed during transition (445).
The colitis phenotype is the most common in the VEOIBD group (6 years of age and younger) (446), and even Crohn disease frequently resembles UC. Therefore, the term IBDU rather than UC may be more appropriate in this earlier age group, reported in 34% and even 71% of very young children (447,448). The differential diagnostic spectrum for this age group is challenging (448,449) since the colitis may be caused by various immunological disorders: classical immune defects (such as combined immune-deficiencies), subtle immune defects or defects of the regulation of immune responses due to a monogenetic disorder including defects in interleukin (IL)10-signaling, X-linked inhibitor of apoptosis protein (XIAP) deficiency, defective neutrophil function and many others (Table 6) (449). Since no specific biological test confirms allergic colitis, only a successful trial of elimination diet is useful diagnostically (450) and may be proposed according to the clinical context especially in those younger than 1 year.
If the molecular defect is caused by a mutation affecting predominantly immunological cells (eg, IL10 signaling defects, XIAP and chronic granulomatous disease), hematopoietic stem cell transplantation may be curative (452,453,458,468). Inhibition with IL1-antagonists may be a way to stabilize patients with IL10 signaling defects while awaiting hematopoietic stem cell transplantation (HSCT), but more confirmation is required before this can be utilized in clinical practice (469). Early HSCT improves life expectancy of IL10-deficient patients since they are at risk for developing lymphoma (470). HSCT is not always the ultimate treatment option, as shown in patients with TTC7A mutations, which involve the epithelial gut barrier rather than immunological cells. This highlights the importance of a rapid and precise molecular diagnosis in children with colitis starting early in life.
ESPGHAN and ECCO are not responsible for the practices of physicians and provide guidelines and position papers as indicators of best practice only. Diagnosis and treatment is at the discretion of physicians.
Appendix 1: The Pediatric Ulcerative Colitis Activity Index (PUCAI)
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