Abstract
Despite continued advances in treatment strategies, the management of ulcerative colitis in children continues to be challenging. We have learned that initial response to therapy, whether mesalamine or corticosteroids, is highly prognostic of future course. Overall, only about 40% of all newly diagnosed children are able to be successfully managed long term on mesalamine with the remainder requiring immunomodulators or more commonly today biologics. While anti-TNF therapy remains the mainstay for severe disease, other options now include anti-adhesion molecule therapy, anti-IL12/23 agents, and emerging small molecules. Nonetheless, approximately 5–10% of newly diagnosed children are or become medically refractory and require colectomy in the first 3 years after diagnosis. This challenging group will require breakthroughs in understanding disease pathogenesis and novel approaches.
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Keywords
Introduction
We continue to strive to change the natural history of ulcerative colitis which is often marked by intermittent or continuous disease activity despite treatment with 5-aminosalicylates and corticosteroids. While the data presented in this chapter reflect the effect of our current therapies, we hope that management advances in the next decade will achieve greater disease control without increasing risk. This chapter will focus on natural history elements pertaining to clinical remission, endoscopic remission, and colectomy. Discussion of drugs will focus mainly on maintenance of remission. Lastly, new insights in predicting response to therapy and altering natural history will be addressed.
Overview
Clinical reports from the 1970s and 1980s describe a severe clinical course for children newly diagnosed with ulcerative colitis resulting in chronic activity, recurrent hospitalizations, frequent colectomy, and rare deaths [1, 2]. Subsequently, a report in 1996 of 171 subjects seen at two large pediatric inflammatory bowel disease centers in the Northeastern United States found that 43% of patients had mild disease and 57% moderate to severe disease at presentation. Forty three percent had pancolitis [3]. Over 80% had resolution of symptoms within 6 months of diagnosis, and during subsequent yearly follow-up intervals, 55% were symptom free, 38% had chronic intermittent symptoms, and 7% had continuous symptoms. Corticosteroid therapy was used in 27% of those with initially mild disease and 70% of those with moderate/severe disease by 1 year. Eleven percent of those with moderate/severe disease received additional immunomodulatory therapy (azathioprine/6-mercaptopurine or cyclosporine) during the first year. The colectomy rate during this time period of widespread immunomodulator use ranged from 1% to 8% at 1 year and 9% to 26% at 5 years, with initial disease severity and progression of disease greatly affecting colectomy rates [3,4,5,6].
More recent cohorts have encompassed populations that were diagnosed in the era of biologic agents. Much of our recent understanding of ulcerative colitis in children has been informed by the PROTECT Study: Predicting Response to Standardized Pediatric Colitis Therapy which was a 29 center North American inception cohort of children newly diagnosed with ulcerative colitis who were treated with standardized treatment protocols based on initial disease severity [7]. In this cohort of 428 children newly diagnosed with UC, 7% had proctosigmoiditis, 10% had left-sided colitis, and 83% had extensive colitis or pancolitis. Of the 400 patients who remained evaluable at 52 weeks, 25 (6%) had colectomy within that first year. The majority of the patients going on to colectomy had moderate to severe disease at diagnosis. A retrospective study from 25 centers across Europe and North America between 2009 and 2011 found that 83% of patients admitted for acute severe colitis, defined as PUCAI ≥ 65, had extensive colitis or pancolitis at diagnosis, versus 16% with left-sided disease [8]. In total, 16/141 (11.3%) of patients underwent a colectomy during their initial admission for acute severe colitis. Of those who had a colectomy, 82% had extensive colitis or pancolitis at diagnosis, while 18% had left-sided disease. Long-term follow-up showed colectomy rates of 28.7%, 33.6%, and 36.4% at 1, 3, and 5 years after initial acute severe colitis admission, respectively. A retrospective chart review of 110 patients from a center in Italy reported 29% of patients initially presenting with proctitis, 22% left-sided colitis, 15% extensive colitis, and 34% pancolitis [9]. Disease extension at follow-up was noted in 29% of patients and cumulative rates of colectomy were 9% and 14% at 2 and 5 years, respectively. A review of the published literature on population-based natural history studies of pediatric ulcerative colitis suggested an overall colectomy rate of between 4% and 17% at 1 year [7, 10, 11] and about 20% at 5 years follow-up [5]. All studies indicate that more severe disease at diagnosis correlates strongly with need for colectomy within the first several years after diagnosis.
Of course, the natural history of any disease is largely a function of the efficacy of medications used to treat it. Large-scale, blinded, placebo-controlled trials are generally lacking in the pediatric population, and much of what is done is extrapolated from adult studies.
Aminosalicylates
Data supporting the use of 5-aminosalicylate (5-ASA) compounds for the induction and maintenance therapy in adult ulcerative colitis (UC) are strong [12, 13]. Data in adults suggest that higher dose 5-ASA may be more effective in inducing remission (4.8 g mesalamine vs. 2.4 g mesalamine), but this added efficacy seemed limited to patients with moderate disease, and was not observed in those with mild disease [14].
One randomized, double-blind, controlled study of children with mild-to-moderately active ulcerative colitis compared the safety and efficacy of high-dose and low-dose oral, delayed-release mesalamine, and found that both doses were equally effective as short-term treatment, without a specific benefit or risk to using either dose [15]. Dosing was weight-dependent, with the low-dose group receiving 27–71 mg/kg/day and high-dose group receiving 53–118 mg/kg/day, within the constraints of using a 400 mg tablet. Twenty-three of 41 (56%) and 22 of 40 (55%) of patients achieved PUCAI-defined treatment success in the low- and high-dose groups, respectively (P = 0.924) after 6 weeks of treatment. No differences in efficacy, tolerability, or adverse reactions with either high- or low-dose mesalamine were noted but the large overlap in potential doses between the two groups makes interpretation of this study difficult.
In the PROTECT study mentioned previously, patient outcomes at one year from diagnosis were determined after the start of standardized treatment regimens based on initial disease severity. One-hundred fifty out of 400 (38%) patients achieved corticosteroid-free clinical remission (PUCAI<10) on mesalamine only at week 52 without the need for immunomodulators or biologics [7]. Of the initial cohort about two-thirds started therapy with corticosteroids (oral or intravenous) with an opportunity to transition to mesalamine maintenance if they responded to corticosteroids. Initial therapy used in this study was based on disease severity using Pediatric Ulcerative Colitis Activity Index (PUCAI) scores, as well as a joint decision by the prescribing physician, patient, and family. For patients with mild disease at diagnosis, mesalamine only was started with weight-based daily dosing given in two divided doses (range 50–75 mg/kg/day) to a maximum dose of 4 g/day. In this mild group, slightly less than half of all patients (48%) achieved PUCAI<10 with no other therapy at week 52. In PROTECT, about 5–7% of patients were intolerant of mesalamine and 1% developed pancreatitis.
The use of adjunctive rectal mesalamine therapy (suppositories, enemas) is often encouraged in those with limited distal disease or proctitis. However, many children and adolescents are unwilling to accept this type of therapy. When used, however, it is often quite helpful.
Corticosteroids
Corticosteroids remain the mainstay of induction therapy for moderate to severe ulcerative colitis, and therefore, understanding the course of disease following these medications is critical to understanding natural history. Corticosteroid use is more widespread in the treatment of pediatric ulcerative colitis compared with adults, with a rate of 79% reported in an observational registry [16]. Traditional corticosteroid therapy has usually meant prednisone for moderate to severe disease, though budesonide MMX has been used for mild to moderate disease [17]. There are minimal published data on budesonide for the treatment of pediatric UC.
In the PROTECT study, data are available on one-year outcomes in large groups of patients started on either oral prednisone or intravenous corticosteroids [7]. In this study, following standardized treatment guidelines, corticosteroids were used as initial therapy for moderate to severe disease (PUCAI score > 45), with goal of weaning steroid dosing and starting mesalamine based on response at 2 weeks. Prednisone was used at a dose of 1–1.5 mg/kg/day to a maximum dose of 40–60 mg in a single morning dose. For those hospitalized with severe disease at time of diagnosis, treatment with intravenous corticosteroids was started, with a suggested dose of 1–2 mg/kg/day of methylprednisolone to a maximum of 60 mg. Of the 400 patients who were followed to week 52, 140 (35%) were initially given oral corticosteroids and 135 (34%) initially received intravenous corticosteroids. If patients showed a response to corticosteroids at 2 weeks, defined by PUCAI decrease of at least 20 points with resulting PUCAI < 35, mesalamine was added, and the initial dose of oral corticosteroids was continued for one more week prior to tapering. Of the 275 patients initially treated with corticosteroids, at week 52 after diagnosis, 32% achieved corticosteroid-free remission on mesalamine only, 9% neither achieved corticosteroid-free remission nor required additional therapy, 22% required escalation to an immunomodulator only, and 37% required escalation to anti-TNFα therapy.
Optimal dosing regimens for corticosteroids have not been established though there appears to be little advantage to exceeding the equivalent of 40–60 mg/day in adults. An exhaustive description of the mechanisms underlying corticosteroid resistance is beyond the scope of this discussion and has been reviewed elsewhere [18]. In a study of 128 children hospitalized with ulcerative colitis (OSCI) and treated with intravenous corticosteroids, non-response to therapy was associated with overexpression of several genes involved in inflammatory pathways [19]. In vitro studies have identified the expression of certain microRNAs as potential mediators of glucocorticoid (GC) resistance [20], but few clinical studies have been published that support this relationship. One clinical study investigated a possible correlation between microRNA expression and variability in GC-resistant and GC-sensitive patients [21]. Assessing serum microRNA of patients with UC, it was noted that downregulated microRNAs had a significant correlation with several signal transduction pathways, including the PI3K-Akt and MAPK signal pathways, and to target genes, including HSP90B1, MAPK13, MAPK9, PIK3AP1, and TLR4, related to GC resistance. This study also found six specific microRNAs (miR-16-2-3p, miR-30e-3p, miR-32-5p, miR642a-5p, miR150-5p, and miR-224-5p) that were significantly downregulated in GC-resistant patients.
Immunomodulators
The use of immunomodulators, such as thiopurines, for the treatment of corticosteroid-dependent ulcerative colitis has greatly diminished with the emergence of more effective and perhaps safer biologic agents. A review of seven blinded, controlled trials of azathioprine in ulcerative colitis highlighted the methodological issues with many early studies of adults which left unanswered the question of whether this drug was useful in maintaining remission [22]. A review of the 30-year experience with azathioprine in a large cohort of adult patients in Oxford, England suggested significant utility of azathioprine in maintaining remission [23]. Almost two-thirds of patients maintained remission for up to 5 years, and median time to relapse upon stopping the drug was 18 months. The addition of the 5-aminosalicylate olsalazine to azathioprine did not improve the maintenance of remission rate compared to azathioprine alone in steroid-dependent adults with ulcerative colitis.
Pediatric data are more limited. One report detailed thiopurine use in 133 children from an inception registry cohort in North America [24]. Of these, 65 (49%) had CS-free inactive UC without rescue therapy at one year from thiopurine start. CS-free inactive disease at 1 year after initiating thiopurine was not affected by starting thiopurine ≤ 3 months versus >3 months from diagnosis, gender, age, or concomitant treatment with 5-aminosalicylates. Kaplan–Meier analysis showed that the likelihood of remaining free of rescue therapy (surgery, calcineurin inhibitors, or biologic therapy) in the thiopurine-treated patients was 73% at 1 year.
A more recent pediatric study looked to assess the efficacy of azathioprine comparing the outcomes of early (0–6 months) versus late (6–24 months) initiation of therapy from time of diagnosis with UC [25]. Of the 121 children, 76 (63%) started AZA between 0 and 6 months after diagnosis and 45 (37%) started between 6 and 24 months. By 6 months, 21 patients withdrew due to either lack of efficacy, adverse events, or lost to follow-up. Seventy-five percent of the early group received CS at diagnosis, with 30 (50%) achieving CS-free remission at one year. Fifty-three percent of the late group received CS at diagnosis, with 23 (57%) achieving CS-free remission at one year. Mucosal healing was also assessed at one and two years, with either endoscopy (49%) or fecal calprotectin (51%). Mucosal healing only occurred in 37% of patients at one year and 40% of patients at 2 years, with no difference between the early and late groups.
Overall, the use of thiopurines has increasingly fallen into disfavor among many pediatric gastroenterologists in North America because of concerns for malignancy, particularly hepatosplenic T-cell lymphoma, and hemophagocytic lymphohistiocytosis (HLH). Although quite rare, these devastating conditions have been linked to thiopurine therapy [26]. The reluctance to use thiopurines in UC is generally not shared in Europe as they remain part of standard treatment options [27].
The use of methotrexate as an immunomodulator for the treatment of ulcerative colitis remains controversial. A recently published study was the first randomized, placebo-controlled study comparing the efficacy of 25 mg parenteral methotrexate weekly compared to placebo in adults with UC who had previously responded to open-label methotrexate [28]. One hundred and seventy-nine patients with active UC based on Mayo score were first given open-label methotrexate for a 16-week induction period with a 12-week steroid taper. At week 16, 91 (51%) patients achieved steroid-free clinical response and 84 of these patients were randomly assigned to 32-week maintenance period with either 25 mg/week subcutaneous methotrexate (n = 44) versus placebo (n = 40) until week 48. Of the 84 patients, 25/40 (63%) and 27/44 (61%) were in steroid-free remission and 15/40 (37%) an 17/44 (39%) were in steroid-free response in the placebo and methotrexate groups, respectively. Sixty percent (24/40) and 66% (29/44) of patients in the placebo and methotrexate groups, respectively, discontinued their therapy before week 32 of the maintenance period, with lack of efficacy or relapse of UC being the main reason for discontinuation in 22 patients in each group. At week 48, 30% (12/40) of patients in the placebo group and 27% (12/44) of patients in the methotrexate group were in steroid-free clinical remission without the need for additional therapies (p = 0.91). This study provided similar findings to the METEOR trial, with a large proportion of patients achieving steroid-free response and remission during open-label induction phase [29]. However, parenteral methotrexate monotherapy was not superior to placebo in maintaining steroid-free clinical response or remission and preventing relapse in patients with UC.
Although calcineurin inhibitors are widely accepted as effective therapy for inducing remission in severe ulcerative colitis [30,31,32], their use as maintenance therapy is uncommon. In children, there are limited data on the use of these agents and while short-term response averages about 80% the majority of treated children still require colectomy within 2–3 years of their use [33]. Additionally, because of their nephrotoxicity, increased susceptibility to infection, and other side-effects, the use of calcineurin inhibitors is generally limited to several months as a bridge to other immunomodulators, infliximab, vedolizumab, or surgery.
Biologics
There are ample data supporting the use of anti-TNF therapy in children with ulcerative colitis. In a formal clinical trial of 60 children and adolescents with active ulcerative colitis despite treatment with corticosteroids, immunomodulators, and 5-aminosalicylates, a response as defined by a decrease in Mayo score by ≥30% and ≥3 points was seen at 8 weeks in 73% of patients following a 3-dose induction of 5 mg/kg at 0, 2, and 6 weeks [34]. Clinical remission by Mayo score, as defined by a score ≤ 2 with no individual subscore > 1, was seen in 40% at 8 weeks. At 54 weeks, in those patients treated with this induction regimen followed by maintenance therapy every 8 weeks, remission was noted in 38% of subjects. Similar to the experience in adults, a direct relationship was found between serum infliximab levels and a positive therapeutic response [35].
It has been demonstrated that low-serum trough levels of infliximab as well as the development of antibodies to infliximab negatively affect response and durability [36]. One such retrospective chart review of 129 children with IBD treated at a tertiary care pediatric IBD center included 278 samples of infliximab levels and antibodies to infliximab, determined that for those who were treated with a dose of 5 mg/kg, 6 week dosing had significantly higher infliximab levels compared to 8 week dosing (p = 0.009) [37]. Out of the 129 patients, 48 (37.2%) demonstrated low infliximab levels (<3 μg/ml) and 24 of those 48 (50%) demonstrated antibodies to infliximab. Twenty-nine (22.5%) developed antibodies to infliximab, and low or undetectable serum infliximab levels were associated with the development of antibodies. This review was in line with prior studies [38, 39] showing the association that low infliximab levels have to the development of immunogenicity to infliximab as measured by antibodies to infliximab.
Therapeutic drug monitoring for IBD patients on anti-tumor necrosis factor (anti-TNF) therapy has become more common, though reactive versus proactive monitoring has not yet been standardized. A 2017 multicenter, retrospective study of 167 adults with Crohn disease and 97 with UC on infliximab maintenance therapy received either proactive (n = 130) or reactive (n = 134) monitoring and was followed to assess long-term outcomes including treatment failure, first IBD-related surgery or hospitalization, serious infusion reactions, and detection of antibodies to infliximab [40]. This study found that proactive drug monitoring was independently associated with reduced risk of treatment failure (p < 0.001), IBD-related surgery (p = 0.017), IBD-related hospitalization (p < 0.001), antibodies to infliximab (p = 0.025), and serious infusion reaction (p = 0.023) when compared to reactive monitoring. Rapid clearance of anti-TNF medications has been noted in patients with extensive disease and high C-reactive protein levels, likely through multiple mechanisms including the concept of a “large antigen-sink” of TNF, hypoalbuminemia, and loss in the stool [36, 41,42,43]. As rapid clearance can lead to loss of response or drug-related adverse events, the results of this study suggest that it is better to optimize infliximab therapy with use of proactive therapeutic drug monitoring rather than wait for these undesirable outcomes to occur before testing.
There are limited data on the use of adalimumab to treat pediatric ulcerative colitis. In a retrospective study assessing the effectiveness and safety of adalimumab in children with UC, all of whom were previously treated with infliximab, 32 patients received adalimumab, and at week 52, 13 (41%) were in corticosteroid-free remission, of whom 9 (28%) had mucosal healing [44]. 17 (53%), 15 (47%), and 13 (41%) were in steroid-free remission at 12, 30, and 52 weeks, respectively. Ten patients (31%) had a primary failure and 5 (15%) a loss of response to adalimumab. And, 12.5% of this study population required colectomy at 1-year follow-up, a rate that is consistent with previous data on disease course in UC. No serious side effects, including deaths or malignancies, were reported. Overall, adalimumab seemed to be effective in inducing clinical and endoscopic remission in children with UC who previously failed or were intolerant to infliximab therapy.
Golimumab is another humanized IgG1 antibody to TNFα, used in adults for the treatment of UC, as well as select other diseases. Although few pediatric studies have been performed, one multicenter, prospective, open-label study evaluated the safety, outcomes, and pharmacokinetics of golimumab in anti-TNF naïve children with moderate to severe active UC [45]. Thirty-five patients were enrolled in the study and received golimumab induction at weeks 0 and 2. Of the 35 participants, a total of 15 (43%) discontinued the medication prior to week 14; 3 after the 2 induction doses, 11 were not in Mayo clinical response at week 6 and medication was discontinued per study protocol, and 1 discontinued the medication prior to week 14 due to a disease flare. At week 6 following induction, Mayo clinical response was induced in 21 (60%) patients, Mayo clinical remission in 15 (43%), PUCAI clinical remission in 12 (34%), and mucosal healing (Mayo subscore 0/1) in 19 (54%), with 8 (23%) achieving complete mucosal healing (Mayo subscore 0). No malignancies, deaths, or serious infections were reported in this small cohort. Overall, the outcome data at week 6 of this study suggest that in pediatric patients with UC, golimumab offers generally comparable clinical benefits to the adult UC population.
Anti-integrin therapy has shown efficacy in the treatment of adults with ulcerative colitis [46], and published data in children are available. Vedolizumab is an α4β7 anti-integrin monoclonal antibody with gut specificity. A retrospective, multicenter review of 52 pediatric IBD patients (58% Crohn disease and 42% ulcerative colitis) receiving vedolizumab was performed to examine efficacy in pediatric IBD. Ninety percent of (47/52) patients had previously failed ≥ 1 anti-TNF agent. All patients received vedolizumab at 0, 2, and 6 weeks, then approximately every 8 weeks thereafter. At week six and week 14, 14/22 (63%) and 13/17 (76%) of UC patients were in clinical remission based on PUCAI score ≤ 10, respectively. Patients with UC were more likely to be in remission at week 14 compared to those with Crohn disease (76% vs. 42%, P < 0.05). Week 6 corticosteroid-free remission was associated with week 14 corticosteroid-free remission among both groups (P < 0.0001). At week 33, anti-TNF-naïve patients had a higher remission rate compared to TNF-exposed patients (100% vs. 45%, P = 0.04). This study also found that both pediatric Crohn disease and UC patients with colonic-only disease had higher rates of remission at multiple time points throughout the study. No infusion reactions or serious adverse events, including tuberculosis, meningitis, or progressive multifocal leukoencephalopathy were observed at last follow-up.
Ustekinumab is a monoclonal antibody to the p40 subunit of interleukin-12 and interleukin-23 that is approved for use in the treatment of psoriasis, psoriatic arthritis, Crohn disease, and most recently ulcerative colitis in adults. The phase 3 UNITI trial recently evaluated 961 adults with moderate-to-severe ulcerative colitis in a randomized, double-blind, placebo-controlled study, with the primary end point being clinical remission at week 8 after induction and week 44 for the maintenance trial [47]. Nine-hundred and twelve (94.9%) patients completed the induction trial, either receiving approximately 6 mg/kg dose, 130 mg dose, or placebo intravenously, with 783 (81.5%) entering into the maintenance trial. Of these 783 patients, 523 underwent randomization into the maintenance population (primary population) receiving 90mg every 8 weeks, every 12 weeks, or placebo every 8 weeks subcutaneously; and 260 were placed in a nonrandomized maintenance population (157 receiving 90 mg every 8 weeks and 103 placebo). Histo-endoscopic mucosal healing, improvements in partial Mayo scores, and reductions in serum and fecal concentrations of inflammatory biomarkers were observed in inductions and sustained in maintenance by both doses of ustekinumab. Ustekinumab was found to be more effective in achieving induction of clinical remission at 8 weeks when compared to placebo, and for those who achieved response to induction and underwent second randomization into the maintenance population, the patients receiving ustekinumab were more likely to be in clinical remission at week 44 compared to those assigned to placebo.
Off-label use in the pediatric IBD population has been increasing, though no controlled clinical trials in this population have been performed. One observational cohort study followed 52 pediatric IBD (42 Crohn disease, 4 ulcerative colitis, and 6 IBD-unspecified) patients receiving ustekinumab for steroid-free remission at 52 weeks [48]. For this patient population, 81% had failed >1 anti-TNF, 37% failed anti-TNF and vedolizumab, and 10 patients were biologic-naïve. At week 52, 39 patients (75%) were still receiving ustekinumab (31 CD, 8 UC/IBDU), with 30 patients in steroid-free remission (25 CD, 5 UC/IBDU). No significant associations were round in respect to disease type or location and remission outcomes. At week 52, biologic-naïve patients (90%, n = 9) were significantly more likely to achieve steroid-free remission compared to biologic-exposed patients (50%, n = 21) (P = 0.03). With regard to safety, no serious infections or other serious adverse events were reported in this cohort.
Small Molecules
Due to a lack of universal response, risks of infections and neoplasia, parenteral administration, and risk of developing antidrug antibodies with use of immunomodulators and biologics, oral non-biologic small molecule therapies are now being investigated for the treatment of ulcerative colitis. The OCTAVE trials [49, 50] investigated tofacitinib, an oral small-molecule Janus kinase (JAK) inhibitor that inhibits all JAKs, but preferentially JAK1 and JAK3, for use of induction and maintenance therapy for adults with moderate to severely active ulcerative colitis. In the OCTAVE Induction 1 trial, remission at 8 weeks occurred in 18.5% (88 of 476) of patients receiving 10 mg tofacitinib twice daily versus 8.2% (10 of 122) in the placebo group (P = 0.007) and in OCTAVE Induction 2 trial, remission occurred at 16.6% (71 of 429) of the tofacitinib group versus 3.6% (4 of 112) in the placebo group (P < 0.001). In the OCTAVE Sustain trial, 34.3% (68 of 198) of patients in the 5mg bid and 40.6% (80 of 197) of patients in the 10 mg tofacitinib bid groups achieved remission at 52 weeks compared to 11.1% (22 of 198) in the placebo group (P < 0.001 for both comparisons with placebo). In the OCTAVE Sustain trial, the rate of herpes zoster infections was higher among those treated with tofacitinib (n = 13; 3 receiving 5 mg and 10 receiving 10 mg) compared to placebo (n = 1). Across all three trials, non-melanoma skin cancer and cardiovascular events occurred in more patients who received tofacitinib (n = 5) compared to placebo (n = 0). Although no formal trials have yet been performed in the pediatric ulcerative colitis population, tofacitinib has started to be used off-label by some centers for children who have been refractory to biologics.
Ozanimod is the newest small molecule oral therapy showing promising outcomes for the treatment of ulcerative colitis in adults. Ozanimod is an oral agonist of the sphingosine-1-phosphate receptor subtypes 1 and 5, which induces peripheral lymphocyte sequestration, leading to potential decrease in the number of activated lymphocytes in the gastrointestinal tract. Preliminary data from phase 2 of the TOUCHSTONE trial [51], a double-blind, placebo-controlled trial of 197 adults with moderate-to-severe active ulcerative colitis, showed that daily use of 1 mg ozanimod resulted in a slightly higher rate of clinical remission, based on Mayo clinic scores (Mayo score ≤2, with no subscore >1) at week 8, compared to placebo. At week 8, clinical remission occurred in 16% who received 1mg dosing (P = 0.048) and 14% who received 0.5 mg dosing (P = 0.14), when compared to the placebo group, of which 6% achieved clinical remission. At week 32, exploratory outcome measures showed that those receiving 1mg of ozanimod daily continued to have higher rates of clinical remission, clinical response, mucosal healing, histologic remission, and lower Mayo scores compared to those with placebo. One limitation of this study was the use of 8 weeks at the timepoint for the primary outcome analysis, as this might not have been sufficiently long enough for ozanimod to target lymphocyte tracking.
Antibiotics
In recent years, there has been an increase in use of broad-spectrum antibiotics as salvage therapy in refractory colitis. In one small pediatric cohort of 15 children with moderate to severe refractory UC, almost half (7/15) entered complete clinical remission defined as PUCAI < 10 when treated with a 2–3 week oral broad-spectrum antibiotic regimen consisting of metronidazole, amoxicillin, doxycycline, or ciprofloxacin, and, in hospitalized patients only, the addition of vancomycin [52].
In a single-center retrospective study of 63 children with refractory UC, Crohn’s colitis, or IBD-U given the same 3 or 4 antibiotic regimen, 40/63 (63.5%) experienced a clinical response, defined as PUCAI change ≥20 points, and 25/63 (39.7%) achieved clinical remission, defined as PUCAI < 10 [53]. The combination antibiotics led to a significant decrease in median PUCAI score from 55 (40–65) to 10 (0–40; p < 0.0001) over 3 ± 1 weeks after initiation of antibiotics. In a subset analysis of only patients with acute severe colitis (n = 26), the median PUCAI decreased from 65 (60–70) at baseline to 35 (10–65) at 3 ± 1 weeks after initiation of antibiotics (p < 0.0001).
In the first randomized controlled trial conducted in pediatric acute severe colitis (ASC), 28 hospitalized children with ASC were randomized to receive the quadruple oral antibiotic cocktail (amoxicillin, vancomycin, metronidazole, and doxycycline or ciprofloxacin) and intravenous corticosteroids (n = 16), or intravenous corticosteroids only for 14 days (n = 12). There was a significant difference in the mean day 5 PUCAI score, 25 ± 17 vs 40 ± 20, respectively (p = 0.037) [54]. Secondary endpoints of remission rate and calprotectin values were numerically better in the antibiotic + intravenous corticosteroid group, but did not reach statistical significance in this small study.
Can We Predict the Course of Disease?
The wide range in phenotypic expression of pediatric ulcerative colitis and its response to therapy has heretofore made prediction of disease course difficult. Clinical factors examined have included features such as severity of disease (i.e., fulminant features requiring hospitalization), endoscopic appearance, laboratory markers, and early response to therapy [55,56,57]. Specific laboratory markers present at diagnosis, including hypoalbuminemia [7], elevated CRP [58], and anemia [11, 59], have shown to be predictive of eventual colectomy. Clinical severity at diagnosis, the need for hospitalization at diagnosis, and the need for rapid rescue with immunomodulators or biologics remain the greatest risk factors for early colectomy.
Pediatric data of early outcomes following standardized therapy after initial diagnosis suggest that baseline PUCAI < 35, higher baseline albumin, and week 4 clinical remission are predictors of week 12 corticosteroid-free remission (PUCAI < 10) [60]. Following this same cohort of patients, predictors for achieving week 52 corticosteroid-free remission for all patients included PUCAI < 35 at diagnosis, higher baseline hemoglobin and albumin, and week 4 clinical remission [7]. Assessing for biological predictors of disease course, this study showed that patients with rectal eosinophil count < 32 per high power field before treatment and those with Vitamin D-25(OH) level <20 ng/mL were more likely to escalate to anti-TNFα therapy during the first year. Using RNA sequencing to assess the pattern of rectal gene expression and fecal microbiota profiles, it was also found that lower levels of an antimicrobial peptide gene signature and Sutterella organisms, and a higher relative abundance of Ruminococcaceae were independently associated with week 52 corticosteroid-free remission. Specifically, it was found that the α-defensin antimicrobial peptide pathway showed a stronger negative association with week 52 corticosteroid-free remission, and that a greater number of α-defensin 5 positive cells were present in rectal biopsy samples from patients who did not achieve week 52 corticosteroid-fee remission, compared to those who did and healthy controls. Those with more severe disease in this same cohort of patients were found to have a significant increase in bacteria typically found in the oral cavity within their gut mucosa at both baseline and in follow-up [61].
Attempts have also been made to try to correlate disease course with genetic profiles. An association between severe and extensive disease and the major histocompatibility complex (MHC) genes DRB1*0103 and DRB1*15 has been identified in adults [62,63,64]. Human leukocyte antigen (HLA) DRB1*0103 has shown an association with both UC and colonic Crohn disease, strongly suggesting that this allele is critically involved in determining the colonic immune response to local flora [65, 66]. A genome-wide association study (GWAS) compared 324 adults with ulcerative colitis who required colectomy for refractory disease with 537 ulcerative colitis patients who did not [67]. A risk score determined from a combination of 46 single nucleotide polymorphisms (SNPs) associated with the medically refractory group accounted for a little less than 50% of the variance for the colectomy risk. Specifically, the known IBD susceptibility gene TNFSF15 (TL1A) on chromosome 9q32 was implicated in UC severity. The sensitivity and specificity of the risk score were over 90%.
Microarray of RNA isolated from colonic biopsy tissue has identified genes that may predict the response to infliximab in adults [68]. This panel of five genes (osteoprotegerin (OPG), stanniocalcin-1, prostaglandin-endoperoxide synthase 2 (COX2), interleukin 13 receptor alpha2 and interleukin 11) discriminated responders from non-responders with 95% sensitivity and 85% specificity. Another study of mucosal gene expression found a positive correlation between high IL-17 and IFN-γ expression and response to infliximab [69]. Variants of the IL-23R gene that increase susceptibility to UC seem to improve response to infliximab [70]. One study used a pharmacogenetics GWAS to evaluate infliximab non-response in a combined pediatric ulcerative colitis and Crohn disease group, finding BRWD1, TACR1, FAM19A4, and PHACTR3 to predict non-response [71].
In pediatric patients, elevated fecal levels of osteoprotegerin (OPG) are associated with failure to respond to intravenous corticosteroids in children with severe ulcerative colitis [72]. One study found that 41 genes, with statistical significance, were differentially expressed between IV corticosteroid responders and non-responders in children with severe ulcerative colitis [73]. Two of the genes, CEACAM1 and MMP8, are possibly inhibited by methylprednisolone through IL-8, and found to be over-expressed in corticosteroid non-responsive patients. The expression pattern of 10 out of the 41 genes were able to classify the treated patients with 80% sensitivity and specificity. Emerging areas of research into biologic molecules (e.g., metabolomics, proteomics, and epigenomics) have the potential to clarify disease phenotypes, behavior, and responsiveness to medications [74,75,76].
Summary
The optimal therapy for ulcerative colitis quickly induces and then effectively maintains remission with healing of the colonic mucosa and presents minimal toxicity to the patient. While 5-aminosalicylates are effective in inducing and maintaining remission in some patients, their efficacy in both aspects of therapy is limited for those with more severe disease. Nonetheless, 5-aminosalicylates should be the cornerstone of therapy if possible. Immunomodulators and anti-TNFα therapy are effective in many patients not maintained in remission on 5-aminosalicylates, but remission at one year is noted in less than half of patients treated with these agents, and disease flares are still common. Evidence suggests that the short-term impact of biological agents on disease course is positive, though it is still not clear that disease course is altered for those who present with fulminant disease. This group continues to exhibit a greater degree of treatment unresponsiveness and has an unacceptably high rate of colectomy. Long-term observations will be required to better understand the changing natural history of ulcerative colitis in children with the emergence of new therapies. Current research holds the promise of development of risk assessment (e.g., gene expression, microbiome, and genetics) promptly following diagnosis that will facilitate treatment design, decreasing the likelihood of treatment failure, and complications of ineffective treatments.
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Dailey, J., Hyams, J.S. (2023). Natural History of Ulcerative Colitis in Children. In: Mamula, P., Kelsen, J.R., Grossman, A.B., Baldassano, R.N., Markowitz, J.E. (eds) Pediatric Inflammatory Bowel Disease. Springer, Cham. https://doi.org/10.1007/978-3-031-14744-9_8
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