INTRODUCTION — Inflammatory bowel disease (IBD) is comprised of two major disorders, ulcerative colitis (UC) and Crohn disease (CD). These disorders have distinct pathologic and clinical characteristics (table 1), but their pathogenesis remains poorly understood. (See "Definitions, epidemiology, and risk factors for inflammatory bowel disease".)
Approximately 20 percent of patients with CD and 12 percent of those with UC develop symptoms before 20 years of age [1]. The development of IBD early in life has implications that are not encountered in adults. Clinicians caring for children and adolescents with CD or UC not only must treat the underlying disease and its complications but must also carefully monitor linear growth, skeletal development, and puberty, as well as how the child's maturation and psychological health are affected by living with a chronic disease. In addition, some therapies used for older patients cannot be applied to young children, because many children are unable to swallow pills or refuse enema therapy.
The treatment of UC in children and adolescents is reviewed here. Other aspects of the diagnosis and management of children with UC are discussed in separate topic reviews:
●(See "Clinical presentation and diagnosis of inflammatory bowel disease in children".)
●(See "Important health maintenance issues for children and adolescents with inflammatory bowel disease".)
●(See "Management of severe or refractory ulcerative colitis in children and adolescents".)
CLINICAL MANIFESTATIONS — UC in children principally occurs in teenagers but can also occur earlier in life [2]. The presentation in children is similar to that in adults. Affected patients usually present with a subacute illness characterized by diarrhea frequently containing blood, weakness, anemia, abdominal pain, and sometimes weight loss. Those with a more fulminant presentation (acute severe UC) also may have severe abdominal pain, frankly bloody diarrhea, tenesmus, fever, leukocytosis, and hypoalbuminemia. Some children have more insidious onset of symptoms, with nonbloody diarrhea and sometimes poor weight gain prior to the development of more overt symptoms or signs [3]. (See "Growth failure and pubertal delay in children with inflammatory bowel disease" and "Clinical presentation and diagnosis of inflammatory bowel disease in children", section on 'Clinical manifestations'.)
Children with UC are more likely than adults to present with pancolitis (approximately 80 percent in children versus 40 to 50 percent in adults) [4]. Younger children with inflammatory bowel disease (IBD; ie, those presenting prior to six years of age) are more likely to present with isolated colonic disease, and distinguishing between UC and Crohn disease (CD) may be more difficult in this age group [5-8]. Young children typically present with rectal bleeding. Older children are more likely to present with abdominal pain, weight loss, and fever, in addition to bleeding [7]. There are no clear differences in disease severity and clinical course among children presenting with IBD between one and six years of age compared with those presenting after six years [9]. By contrast, cases presenting in infancy have a distinct clinical course that is often more severe because such cases are often related to immunodeficiencies or other causes of "monogenic IBD." (See "Clinical presentation and diagnosis of inflammatory bowel disease in children", section on 'Very early-onset inflammatory bowel disease'.)
Extraintestinal manifestations of IBD may precede the gastrointestinal symptoms and are somewhat different in UC as compared with CD, as outlined in the table (table 2) and described in detail separately [10]. (See "Clinical presentation and diagnosis of inflammatory bowel disease in children", section on 'Extraintestinal manifestations'.)
PROCTITIS — Patients with disease limited to the rectum (ie, inflammation that extends no more than 15 cm proximal to the anal verge) are good candidates for receiving topical therapy.
Moderately active inflammation is treated best initially with a topical 5-aminosalicylate (5-ASA; eg, mesalamine) enema or suppository preparation; a topical (rectal) hydrocortisone enema, foam, or suppository; or budesonide enema. A combination of topical and oral mesalamine is also useful in inducing remission and may be necessary if topical therapy alone is ineffective [11]. In patients who have not responded to topical aminosalicylates, topical corticosteroid preparations can be utilized for induction of remission, although evidence from pediatric studies is lacking. Topical budesonide can treat proctosigmoiditis effectively and may have fewer side effects than conventional glucocorticoids. If topical administration of medication is not possible due to parent or child refusal, oral administration of a 5-ASA medication is a reasonable alternative, although oral 5-ASA usually requires more frequent dosing and is probably less effective than topical 5-ASA for proctitis. (See "Sulfasalazine and 5-aminosalicylates in the treatment of inflammatory bowel disease", section on '5-ASA formulations'.)
Less commonly, immunosuppressive therapy (with immunomodulators or biologics) or colectomy is required for refractory proctitis. Most such therapy involves systemic immunosuppression (eg, anti-tumor necrosis factor [anti-TNF]), but there are also case reports describing use of tacrolimus enemas in adults and children [12,13]. (See "Medical management of low-risk adult patients with mild to moderate ulcerative colitis", section on 'Ulcerative proctitis or proctosigmoiditis' and "Management of severe or refractory ulcerative colitis in children and adolescents", section on 'Refractory disease'.)
Once a patient's symptoms are controlled, patients should be transitioned to a maintenance aminosalicylate (rectal or oral), so that corticosteroids may be discontinued, to minimize long-term corticosteroid toxicity [14]. The choice of medication and route of administration depends on the child and family's preference and on the patient's individual responsiveness to the treatment. In some patients, transition to oral aminosalicylate therapy may result in relapse of the proctitis, which requires the reinstitution of rectal treatment. (See "Medical management of low-risk adult patients with mild to moderate ulcerative colitis".)
Relapses in proctitis may be caused by poor adherence to therapy or to proximal extension of the disease over time. As an example, in an observational study in 149 children with ulcerative proctitis, 49 percent had colonic extension of disease at last follow-up; the risk for extension was 10, 45, and 52 percent at 1, 5, and 10 years, respectively [15]. Similarly, in a separate study of children with ulcerative proctitis, the risk for proximal extension to left-sided colitis or pancolitis was 54 percent among those followed for more than five years [16]. Thus, patients with proctitis should be reevaluated endoscopically if they have recurrent or refractory symptoms.
Relapses in proctitis also may be triggered by an enteric infection, especially Clostridioides difficile. Therefore, patients presenting with a flare of proctitis or colitis should be screened for bacterial causes of colitis, with stool cultures and testing for C. difficile toxin. (See "Clinical presentation and diagnosis of inflammatory bowel disease in children", section on 'Stool testing for enteric pathogens'.)
LEFT-SIDED DISEASE AND PANCOLITIS — For patients with mild or moderate colitis, medical therapy usually is successful in achieving remission and often maintains long-term remission as well. The basic principles of medical therapy are similar to those in adults with UC, although the chronic use of glucocorticoids in children is particularly problematic because of potential linear growth impairment and bone demineralization. Thus, aminosalicylates or glucocorticoids are used for induction, depending on the severity of presentation (algorithm 1). The aim is to transition patients to aminosalicylate maintenance therapy. However, fewer than 50 percent of patients maintain corticosteroid-free remission on aminosalicylates alone [17,18]. The remainder of patients require long-term treatment with immunomodulators or biologic agents. (See 'Subsequent management' below.)
Management of children with severe or refractory colitis is discussed separately. (See "Management of severe or refractory ulcerative colitis in children and adolescents".)
Clinical assessment
Diagnosis — The diagnosis of UC is made on the basis of clinical, laboratory, radiologic, and endoscopic/histologic information. Clinical manifestations are as described above (see 'Clinical manifestations' above). The steps in diagnosis, including the differentiation between UC and Crohn disease (CD), are described separately. In patients younger than six years who have features suggestive of monogenic inflammatory bowel disease (IBD) (table 3), more extensive evaluation should be considered (algorithm 2) because management strategies may differ. (See "Clinical presentation and diagnosis of inflammatory bowel disease in children".)
Disease severity — A pediatric UC activity index (PUCAI) has been developed to assess the activity of disease (table 4) (calculator 1) [19]. Numerical scores are given to symptoms of abdominal pain, rectal bleeding, stool consistency, stool frequency, presence of nocturnal stools, and activity level, adding to a maximum score of 85. Of these components, rectal bleeding has the greatest impact on the score, contributing up to 30 points.
PUCAI scores are interpreted as follows:
●0 to 9 – Remission
●10 to 34 – Mild disease
●35 to 64 – Moderate disease
●65 to 85 – Severe disease
In addition to clinical disease severity, endoscopic assessment should be performed because endoscopic evidence of inflammation can predict the potential for disease relapse [20]. Endoscopic disease severity is usually assessed by the Mayo score in both adults and children. In pediatric patients, there is moderate correlation between endoscopic disease severity (Mayo score) and clinical disease activity (PUCAI) [21]. Increasingly, patient- and observer-reported outcomes are being utilized to monitor disease activity in adult and pediatric chronic illness. A measure designed for children with UC is under development [22,23]. Disease severity is one of several predictors of outcomes after one year of therapy, as discussed below. (See 'Prognosis' below.)
Evaluation for infectious colitis — Infectious etiologies or superimposed infections should be excluded by stool cultures for enteric pathogens (Salmonella, Shigella, Yersinia, Campylobacter, Escherichia coli, and if appropriate, Amoeba), as well as tests for C. difficile toxin. Although most colitis flares are not triggered by pathogenic bacterial infection, between 5 and 25 percent of children presenting with a flare of UC have underlying C. difficile [24-26]. In an immune-compromised patient, evaluation for cytomegalovirus infection should also be considered. Details of this evaluation to exclude other causes of colitis are discussed separately. (See "Clinical presentation and diagnosis of inflammatory bowel disease in children", section on 'Differential diagnosis'.)
Determination of response to therapy — The long-term aim of treatment is to induce a remission, including resolution of symptoms, normalization of inflammatory markers (C-reactive protein and calprotectin), normalization of growth, and mucosal healing of the colon as assessed by endoscopy, as outlined in guidance from the STRIDE group [27].
Accordingly, the response to therapy is typically determined by a combination of clinical symptoms (PUCAI) and laboratory testing, supplemented with endoscopy with biopsies when indicated:
●PUCAI score – Changes in clinical symptoms should be monitored by determining the PUCAI score at each clinical encounter (table 4) (calculator 1). The goal of therapy is complete resolution of symptoms, reflected by a PUCAI score of <10. For patients with moderate or severe UC, a marked improvement in PUCAI (eg, PUCAI <35 or a PUCAI decrease of ≥20 points) provides an initial indication of successful medical therapy (algorithm 1).
●Blood and stool tests – Laboratory tests should be monitored regularly, at least every three months during immunosuppressive therapy and at least annually for patients not on immunosuppressive agents. These tests should be interpreted in conjunction with clinical symptoms and in the context of the patient's historical results [26].
•Complete blood count (CBC), albumin, and C-reactive protein (CRP), or erythrocyte sedimentation rate (ESR).
•Additional laboratory tests to monitor for comorbidities or adverse effects of drugs are typically performed at the same time, including alanine aminotransferase (ALT), gamma-glutamyl transpeptidase (GGTP), as well as therapeutic drug monitoring for infliximab, adalimumab, or thiopurines. Therapeutic drug monitoring can also be considered for some of the newer biologics (vedolizumab, ustekinumab), though it is less established. (See 'Thiopurines' below and 'Infliximab' below.)
•Fecal markers of inflammation, such as lactoferrin and calprotectin, are also useful biomarkers of clinical response and mucosal healing [28]. For calprotectin, values >250 mg/g are usually associated with significant mucosal inflammation and values <100 mg/g generally reflect remission, although improvement in calprotectin may lag behind mucosal healing by several months [26]. (See "Clinical presentation and diagnosis of inflammatory bowel disease in children", section on 'Stool tests'.)
●Endoscopy – Endoscopic grading of disease severity is increasingly used for assessing response to therapy. Colonoscopy is recommended before making major changes in therapy or when it is unclear whether symptoms are disease-related [26]. Colonoscopy is not routinely indicated for mild or moderate relapses. During severe exacerbations of colitis, sigmoidoscopy may be indicated to exclude concomitant cytomegalovirus infection.
When endoscopic grading is used to assess treatment response, the goal is improvement and/or resolution of the grossly visible signs of active colitis, such as friability, erythema, erosions, ulcerations, and bleeding. The most commonly utilized scoring system for this purpose is the endoscopy component of the Mayo score [29]. While a Mayo endoscopy subscore of 0 (no grossly visible disease activity at endoscopy) is the ideal goal of treatment, this is not always achievable. Alternatively, some experts have advocated that histologic remission (resolution of microscopic abnormalities) should be the ultimate treatment goal, but benefits of this stringent target are not established and the measure is complicated by sampling error and lack of consensus about definitions of abnormal histology [30].
Colonoscopy is also recommended for colorectal cancer surveillance, beginning 8 to 10 years after disease onset. For patients with IBD-associated primary sclerosing cholangitis, a European guideline suggests surveillance colonoscopy every one to two years, but this recommendation is based largely on data from adults [31]. (See "Important health maintenance issues for children and adolescents with inflammatory bowel disease", section on 'Surveillance for cancer'.)
Initial management
Mild disease — In patients with mild disease extending beyond the rectum (ie, fewer than four bowel movements daily without significant abdominal pain, anemia, or fever, and PUCAI score 10 to 34), we suggest a trial of oral 5-aminosalicylate (5-ASA; usually mesalamine or sulfasalazine) as first-line therapy (algorithm 1) [26]. These drugs are moderately effective for mild disease and have fewer side effects than systemic glucocorticoids [17]. Combination therapy with oral and topical (rectal) 5-ASA should be used for induction of remission, if acceptable to the patient, because this is more effective than topical therapy alone [26,32]. Mild, left-sided disease may also respond to topical treatment alone (eg, mesalamine enemas), and a trial of this approach is reasonable in patients who are willing and adherent to enema treatment [26]. However, we find that most children and families prefer orally administered medications and are more likely to adhere to an oral regimen. (See "Sulfasalazine and 5-aminosalicylates in the treatment of inflammatory bowel disease".)
Oral 5-ASA preparations include the following:
●Mesalamine – Mesalamine (also known as mesalazine or unconjugated 5-ASA) is typically given at an oral dose of 60 to 80 mg/kg/day, divided twice or three times daily (up to the adult dose of 4.8 g/day) [26]. Some clinicians use mesalamine doses up to 100 mg/kg/day (maximum 4.8 g/day) for induction of remission in children, based on data extrapolated from trials in adults [33]. Limited information from studies in adults and children suggests that sustained-release preparations of mesalamine (Multi Matrix System [MMX] mesalamine) also are effective [34]. These preparations may increase adherence by reducing the frequency of dosing and have been approved in the United States for children weighing ≥24 kg [35].
●Sulfasalazine – Sulfasalazine is a prodrug composed of 5-ASA linked to sulfapyridine through an azo bond, which is split in the colon. It is given as an initial dose of 25 mg/kg/day divided twice or three times daily and advanced over one week to the full dose of 60 to 80 mg/kg/day divided twice or three times daily (up to a maximum dose of 4 g daily); some clinicians use doses above or below this range. In larger children and adults, initial doses are 1 to 2 g/day, titrated to 4 to 6 g/day, divided three to four times daily. Supplemental folic acid (1 mg/day) should be given to all patients taking sulfasalazine. Sulfasalazine has the advantage that it can be compounded into a liquid and easily taken by children. However, mesalamine and other 5-ASA agents have fewer side effects than sulfasalazine, including reduced headache and skin rashes. Sulfasalazine contains a sulfapyridine component that can trigger allergic reactions (including rare cases of Stevens-Johnson syndrome) in patients with sulfa hypersensitivity.
●Balsalazide – Balsalazide is split in the colon by colonic bacteria, releasing mesalamine. Typical doses in children are 75 to 100 mg/kg/day divided three times daily, up to a maximum dose of 6.75 g divided three times daily in larger children or adults. In adults, the initial dose is typically given for eight weeks, then reduced to a maintenance dose of 3 to 4 g daily, divided into two doses. The adult dose cited above was used in a small clinical trial in children 5 to 17 years of age; there were no significant differences in adverse effects or efficacy as compared with a smaller dose of 2.25 g/day, but this may have been because of the small size of the trial [36]. (See "Sulfasalazine and 5-aminosalicylates in the treatment of inflammatory bowel disease", section on '5-ASA formulations'.)
Few studies have compared the efficacy of different aminosalicylates in children. Most experiences in children have been with mesalamine or sulfasalazine, but these drugs have not been directly compared. In our practice, we often use mesalamine as the first-line choice because sulfasalazine has a higher risk for allergic reactions and side effects, such as photosensitivity, due to the sulfonamide component. However, sulfasalazine has the advantage of lower cost and is a reasonable alternative in patients without a history of sulfa sensitivity, provided that folic acid supplements are also given. Also, sulfasalazine may be helpful in managing IBD-associated arthritis, if present [26].
Most children over five years of age can learn how to swallow pills. Techniques for learning to swallow pills, including practicing with small pieces of food or candy, are outlined on a tip sheet from the Crohn's and Colitis Foundation. Options for children who cannot swallow pills despite this training include:
●Mesalamine capsules (eg, Pentasa) – These capsules can be opened into water or acidic food (consumed immediately and without chewing).
●Balsalazide capsules – These capsules can be opened and sprinkled onto applesauce. The mixture may be chewed and should be swallowed promptly. It should not be stored for future use.
●Sulfasalazine – Sulfasalazine tablets can be made into a suspension by a compounding pharmacy.
Slight exacerbation of watery diarrhea is common during the first few weeks of therapy with 5-ASA preparations and particularly with olsalazine and balsalazide [37]. In addition, approximately 3 percent of patients treated with mesalamine have a paradoxical worsening of their colitis symptoms (acute mesalamine intolerance), with increased cramps, diarrhea, and rectal bleeding, usually developing within the first month of treatment. Recurrence on rechallenge confirms the diagnosis of mesalamine intolerance; in this case, 5-ASA agents should no longer be used. (See "Sulfasalazine and 5-aminosalicylates in the treatment of inflammatory bowel disease", section on '5-aminosalicylic acid (5-ASA)'.)
Moderate disease — Patients with moderate disease (PUCAI score of 35 to 64) typically have more than four bloody bowel movements per day and intermittent abdominal pain but no tenesmus or fever. The most common approach for patients with moderate symptoms is a course of systemic glucocorticoids, especially if systemic symptoms such as fever or anorexia are present. However, for patients who are reluctant to use glucocorticoids, it is reasonable to offer a trial of 5-ASA, similar to patients with milder disease, using doses at the high end of the range (see 'Mild disease' above). A third option that is used for selected patients at some centers is early use of a biologic agent (typically in hospitalized patients using infliximab or adalimumab), similar to the approach for patients with more severe disease. (See 'Infliximab' below and 'Adalimumab' below.)
●Oral glucocorticoids – For patients with frequent stools and mild or moderate abdominal pain, we suggest oral glucocorticoid therapy (algorithm 1). Prednisone (1 to 1.5 mg/kg once daily, to a maximum of 40 to 60 mg/day) usually induces remission [26]. Steroid-responsive patients usually show some clinical signs of improvement within one week of starting treatment.
Oral budesonide has been suggested as an alternative to prednisone because it has fewer side effects. Budesonide MMX extends the release of drug in the colon and has been shown to effectively treat moderate disease; dosing for children >30 kg is 9 mg daily for eight weeks [38,39]. Although budesonide has fewer side effects than prednisone, chronic use can still lead to significant steroid-associated toxicity. (See "Medical management of low-risk adult patients with mild to moderate ulcerative colitis", section on 'Induction of remission'.)
The full dose of oral glucocorticoid usually is continued for two to three weeks, then gradually tapered over the next 8 to 10 weeks. The oral glucocorticoid is usually combined with mesalamine (or another 5-ASA), which can be started during the glucocorticoid treatment course (see 'Subsequent management' below). Some patients respond to steroids very quickly, and in this case, the taper can be started somewhat sooner. For budesonide MMX, which is formulated in 9-mg capsules, we taper by dosing every two days, then every three days, before stopping.
●Intravenous glucocorticoids – For patients who are unresponsive to oral glucocorticoid therapy within one to two weeks or those with poor fluid intake, severe abdominal pain, vomiting, and/or poor nutrition, we suggest hospitalization and intravenous glucocorticoids (algorithm 1). Bowel rest and intravenous fluids have not been shown to hasten remission but may relieve symptoms of abdominal cramping associated with oral intake and decrease stool frequency.
Dosing and duration of therapy depends on the severity of symptoms and response to treatment and is based on clinical experience because of lack of precise clinical evidence, as outlined in consensus guidelines [26]. Typical management in our practice is:
We initiate treatment with methylprednisolone (1 mg/kg per dose, given every 12 hours to a maximum of 40 to 60 mg/day).
•Practice varies among experts regarding the timing of transition to oral glucocorticoids. In our practice, we transition to oral glucocorticoids approximately 24 to 48 hours after noting a definite clinical response to treatment (eg, PUCAI <35 or a PUCAI decrease of ≥20 points).
We start oral prednisone at 1 to 2 mg/kg/day (maximum of 40 to 60 mg/day). This dose usually is continued for two to four weeks, then gradually tapered over the next two months. The oral glucocorticoid is usually combined with mesalamine (or another 5-ASA). (See 'Maintenance of remission' below.)
•For patients with no clear response to treatment after five days of intravenous therapy, we initiate an evaluation for other potential contributing factors and a discussion of second-line therapies, including colectomy and medical therapies (infliximab, calcineurin inhibitors) for steroid-refractory or acute severe colitis. Flexible sigmoidoscopy is helpful in this setting in order to gather more information on disease activity and to search for concomitant infection with cytomegalovirus, which, if found, could significantly alter treatment. (See "Management of severe or refractory ulcerative colitis in children and adolescents", section on 'Evaluation for infectious colitis'.)
•For patients with partial response to intravenous therapy (eg, some improvement, but PUCAI remains >35), we may continue intravenous treatment for up to two weeks before moving on to second-line therapies. The timeline for making this decision varies substantially in clinical practice. (See "Management of severe or refractory ulcerative colitis in children and adolescents", section on 'Refractory disease' and "Management of severe or refractory ulcerative colitis in children and adolescents", section on 'Severe disease'.)
●Antibiotics – Some clinicians utilize systemic antibiotic therapy empirically in the treatment of colitis flares (typically for patients with steroid-refractory or steroid-dependent disease). Because evidence on this practice is limited, guidelines do not support antibiotic use as a routine option in UC [26]. However, a few reports, including a small observational study in children, suggest that broad-spectrum oral antibiotics are sometimes effective, though long-term outcomes are not well known [40,41]. Therefore, an empiric trial of antibiotics may be appropriate in selected cases in which 5-ASA and glucocorticoids are not effective or are rejected by the patient [42].
Subsequent management
Maintenance of remission
●5-ASA – For patients who achieve remission of their colitis through the above interventions, maintenance with a 5-ASA agent is preferred [26].
●Thiopurines – Patients who are intolerant of, or do not remain in remission with, a 5-ASA agent alone can be treated with mercaptopurine (also known as 6-mercaptopurine [6-MP]) or azathioprine (AZA) [26,43,44]. However, the benefits of using these immunosuppressive agents as maintenance therapy must be weighed against the risks (infection, lymphoma) and compared with the benefits and risks of anti-tumor necrosis factor (anti-TNF) agents or colectomy. Colectomy has the benefit of removing the disease and allowing discontinuation of immunosuppression [45]. While there is some support for the early use of thiopurines in children with CD, at least one retrospective study did not find support for early introduction of AZA (<6 months after diagnosis) compared with later AZA initiation (6 to 24 months after diagnosis) in children with UC [46]. (See "Management of the hospitalized adult patient with severe ulcerative colitis" and "Sulfasalazine and 5-aminosalicylates in the treatment of inflammatory bowel disease" and "Surgical management of ulcerative colitis".)
●Biologics – Increasingly, biologics (especially anti-TNF agents such as infliximab and adalimumab) have displaced thiopurines as maintenance therapy in children with mild to moderate IBD that cannot be kept in remission with aminosalicylates. While biologics are much more expensive than thiopurines, they may carry a lower risk of lymphoma. Dosing and other considerations are outlined below. (See 'Infliximab' below and 'Adalimumab' below.)
Other biologic and small-molecule therapies used to treat UC in adults (vedolizumab, golimumab, ustekinumab, tofacitinib, ozanimod) are sometimes used off-label in children. (See 'Second-line options' below and 'Other options' below.)
●Other – While probiotics are commonly taken by patients with UC and prescribed by some clinicians, their efficacy for UC remains unproven. VSL#3 may have some efficacy in treating active disease as an adjunctive approach. Details of these and other studies are discussed in a separate topic review. (See "Probiotics for gastrointestinal diseases", section on 'Ulcerative colitis'.)
Curcumin is an extract of turmeric root that appears to have a protective role in a mouse model of UC, purportedly by modulating the release of tumor necrosis factor-alpha (TNF-alpha) and nitric oxide. One study suggests that it is tolerated well in children [47].
Steroid-dependent disease — Patients are considered to be steroid-dependent if they have been on high-dose glucocorticoids for more than two to three months or daily glucocorticoids for four to six months, or frequently flare when the glucocorticoid dose is reduced (eg, two or three relapses per year). For such patients, we suggest transitioning to a thiopurine or biologic agent to avoid the high morbidity associated with prolonged glucocorticoid therapy [26,44]. The optimal approach has not been established, and either approach is reasonable.
For patients with steroid-dependent disease, we suggest maintenance therapy with either infliximab, adalimumab, or a thiopurine. Considerations are outlined below.
Infliximab — Infliximab is another first-line option and a reasonable alternative to a thiopurine for maintenance therapy in patients with steroid-dependent disease. The main rationale for choosing infliximab over thiopurines as maintenance is the concern about an increased relative risk of lymphoma associated with thiopurine use. However, the absolute risk of lymphoma with thiopurines is very low, and some patients prefer thiopurines because of the oral rather than parenteral administration.
Infliximab is a highly effective anti-TNF agent that is US Food and Drug Administration (FDA)-approved for pediatric UC in children six years and older. Many clinicians are using it instead of immunomodulators to treat corticosteroid refractory colitis because evidence suggests that infliximab monotherapy does not increase the risk of lymphoma [48]. The routine dose is 5 mg/kg given at zero, two, and six weeks, then every eight weeks. The initial response rate to infliximab in children with UC is approximately 70 percent after eight weeks (three doses of therapy), but the long-term remission rate after one year is approximately 30 percent [48,49]. Increasing the dose of infliximab (to 10 mg/kg/dose), reducing the interval of infliximab infusions (to every four to six weeks), and therapeutic drug monitoring may increase the response to infliximab. (See "Medical therapies for Crohn disease in children and adolescents", section on 'Monitoring infliximab levels and antibodies'.)
In adults, combination therapy with AZA and infliximab has been shown to be more effective than using either agent alone [50]. The benefit of this approach must be weighed against the rare risk of lymphoma, including hepatosplenic T cell lymphoma. However, anti-TNF agents are not risk-free. Their risks include opportunistic infection (particularly lung infections), infusion reactions, development of anti-drug antibodies, loss of response, skin complications including psoriasis, and rare neurologic conditions, such as demyelination or weakness.
Adalimumab — Adalimumab is also a first-line option for maintenance therapy in children with steroid-dependent disease. It is approved in the United States for children five years and older with UC. Recommended doses are:
●Children 20 to 40 kg:
•Induction – 80 mg on day 1, 40 mg on day 8, and 40 mg on day 15
•Maintenance – 40 mg every two weeks (or 20 mg weekly)
●Children ≥40 kg:
•Induction – 160 mg (as a single dose or split over two consecutive days) on day 1, 80 mg on day 8, and 80 mg on day 15
•Maintenance – 80 mg every two weeks (or 40 mg weekly)
Of note, this dosing schedule is more frequent than used for children with CD.
The approval of adalimumab for pediatric UC was based on the ENVISION trial, the results of which have not been published but are available in abstract form and in the manufacturer's prescribing information. In this study of 93 patients with moderate to severe UC, adalimumab induced clinical response and sustained remission in at least 40 percent of subjects, with safety signals similar to those in adults [51,52]. Prior case series in children also reported successful use as a second-line biologic therapy [53,54]. (See "Overview of dosing and monitoring of biologic agents and small molecules for treating ulcerative colitis in adults", section on 'Tumor necrosis factor inhibitors' and "Management of severe or refractory ulcerative colitis in children and adolescents", section on 'Anti-tumor necrosis factor antibodies'.)
Thiopurines — Some expert clinicians prefer to transition to thiopurines rather than infliximab because of the loss of response over time seen with infliximab [55,56]. Thiopurines should not be used for induction of remission. The therapeutic effect typically increases gradually during the first two to three months of therapy. It may be helpful to continue 5-ASA therapy concomitantly, if tolerated. If a patient has been in remission for 6 to 12 months, the clinician can review the risks and benefits of discontinuing the aminosalicylate and leaving the patient on thiopurine monotherapy. One study in adults suggests that the efficacy or thiopurine monotherapy is similar to that of combination treatment with thiopurines and aminosalicylates [57].
Prior to initiating treatment with either 6-MP or AZA, it is important to measure the patient's thiopurine methyltransferase activity (TPMT phenotype) and/or genotype (TPMT genotype) [19]. This is because approximately 10 percent of individuals are heterozygotes for a TPMT mutation and are at risk for toxicity if standard dosing of these drugs are used. Moreover, approximately 0.3 percent of individuals are homozygotes for a TPMT mutation, in which case treatment with either 6-MP or AZA is contraindicated because of a high risk for bone marrow suppression. (See "Thiopurines: Pretreatment testing and approach to therapeutic drug monitoring for adults with inflammatory bowel disease".)
In patients with normal TPMT activity or genotype, we dose 6-MP at 1 to 1.5 mg/kg/day or AZA at 2 to 3 mg/kg/day. In one nonrandomized study, the addition of 6-MP permitted the discontinuation of glucocorticoids in 75 percent of 20 children [43]. In an observational study that included nearly 1500 children with UC, 50 percent of those treated with 6-MP or AZA were in remission without glucocorticoids one year later [58]. Only subjects without previous or concomitant treatment with biologic agents or calcineurin inhibitors (cyclosporine or tacrolimus) were included in this study.
All patients treated with 6-MP or AZA should undergo routine monitoring for the possible toxicities of bone marrow suppression and hepatotoxicity. We use the same approach to monitoring as for patients with CD:
●Monitoring to detect bone marrow toxicity and hepatotoxicity. (See "Medical therapies for Crohn disease in children and adolescents", section on 'Safety and monitoring'.)
●Measurement of 6-MP metabolite levels during therapy in selected patients to optimize drug therapy and limit toxicity. In particular, measurement of metabolite levels is useful in patients who have developed toxicity during treatment or in those who are not responding to what is believed to be a therapeutic dose of 6-MP or AZA. (See "Thiopurines: Pretreatment testing and approach to therapeutic drug monitoring for adults with inflammatory bowel disease".)
Like other immunomodulators or biologic agents, treatment with 6-MP or AZA increases a patient's susceptibility to bacterial, fungal, and viral infections. We suggest pretreatment screening for tuberculosis and special considerations for vaccines, as outlined in separate topic reviews. (See "Important health maintenance issues for children and adolescents with inflammatory bowel disease", section on 'Infection risk' and "Important health maintenance issues for children and adolescents with inflammatory bowel disease", section on 'Immunizations'.)
Sequential or combination therapy — For patients with steroid-dependent disease who do not respond to thiopurines, it is common practice to transition to infliximab therapy. As an example, in the large trial cited above, approximately one-half of the subjects had been treated with thiopurines before proceeding to the trial of infliximab [49]. Similarly, for patients who do not respond to infliximab, it is common practice to offer treatment with a second biologic agent (eg, vedolizumab). Although this type of sequential therapy is common, the risks and benefits compared with proceeding to colectomy have not been assessed. We suggest explicit consideration of colectomy for patients who have failed infliximab or any other biologic agent. (See 'Second-line options' below.)
The use of combination therapy in pediatric UC (thiopurines simultaneously with infliximab or adalimumab) is more controversial, though there are good data from the adult literature to support improved control of colitis [50,59]. The potential risks and benefits of this approach are probably similar to those for patients with CD. (See "Medical therapies for Crohn disease in children and adolescents", section on 'Anti-TNF monotherapy versus combination therapy with an immunomodulator'.)
Second-line options — For glucocorticoid-dependent patients who do not respond to therapy with thiopurines or infliximab or who develop an adverse event (ie, pancreatitis), either surgery or alternate medical therapy can be offered. These second-line options are not approved by the FDA for children with UC ("off-label use"), but they may be appropriate for selected patients based on individual characteristics and if recommended by an expert clinician [60]. (See 'Medical necessity of off-label use of medications in pediatrics' below.)
Options supported by expert consensus and clinical experience include [26]:
●Colectomy – Colectomy should be discussed as an option and is appropriate in patients who wish to avoid taking immunosuppressive agents or who cannot be weaned off prednisone despite immunomodulator or infliximab therapy. (See "Management of severe or refractory ulcerative colitis in children and adolescents", section on 'Surgery' and "Surgical management of ulcerative colitis".)
●Vedolizumab – Vedolizumab, a gut-selective alpha-4-beta-7 integrin antibody, has been FDA-approved in adults with moderate to severe UC, although time to remission was more gradual than for other biologic agents [61]. In one observational study, 80 percent of anti TNF-naïve patients had reached clinical remission at week 6 [62]. Endoscopic remission was seen in 59 percent of anti-TNF-naïve versus 15 percent anti-TNF-exposed patients [63]. Due to this relatively slow response to induction therapy, corticosteroids may be used as a bridge therapy while transitioning from failed treatment with anti-TNF-alpha. In treatment-naïve adults with UC, vedolizumab was superior to adalimumab in achieving endoscopic remission (29 versus 11 percent) [64]. Observational studies report clinical benefit with vedolizumab in some children [62,63,65,66]. Patients previously exposed to anti-TNF agents (infliximab or adalimumab) seem to have somewhat lower rates of clinical and endoscopic remission compared with treatment-naïve patients, similar to findings in adults. While this is a new agent, there is good evidence that the short-term safety profile is highly favorable [26,62]. While dosing of vedolizumab has not been formally established in children under 18, practicing clinicians typically utilize a dose of approximately 6 mg/kg to 10 mg/kg per infusion (maximum 300 mg). (See "Management of severe or refractory ulcerative colitis in children and adolescents", section on 'Refractory disease' and "Management of moderate to severe ulcerative colitis in adults", section on 'Vedolizumab'.)
●Golimumab – Golimumab, another anti-TNF agent, has been FDA-approved for induction and maintenance in adults with UC. It has the convenience of subcutaneous dosing (ie, no infusion necessary) and once-monthly dosing. Pediatric data are limited, though studies are underway. The adult dosing regimen is 200 mg for the initial dose, 100 mg two weeks later, then 100 mg every four weeks. A phase 1b study observed stable trough levels of golimumab in pediatric UC patients at these doses [67]. (See "Overview of dosing and monitoring of biologic agents and small molecules for treating ulcerative colitis in adults", section on 'Tumor necrosis factor inhibitors' and "Management of moderate to severe ulcerative colitis in adults", section on 'Anti-tumor necrosis factor (TNF) agent-based therapy'.)
Other options — Several other medications have been used for children with steroid-dependent UC but appear to be less effective than biologics (methotrexate, thalidomide) or are still experimental:
●Methotrexate – Methotrexate is another immunomodulator and has been used for patients who are intolerant of or unresponsive to 6-MP or AZA, but it has not been investigated extensively in UC. While methotrexate was commonly used in the past off-label as a maintenance agent for UC, trials in adults found no superiority to placebo [68,69].
●Thalidomide – Thalidomide treatment for UC was evaluated in a small, randomized trial in 26 pediatric patients with UC that was refractory to various other immunosuppressive regimens [70]. Thalidomide treatment resulted in significantly higher rates of clinical remission at eight weeks of treatment (83 percent for thalidomide versus 18.8 percent for placebo) and longer maintenance of remission (135 weeks for thalidomide versus eight weeks for placebo). Thalidomide is thought to work through inhibition of TNF-alpha production and has demonstrated some promise as second- or third-line therapy in a small trial of refractory pediatric CD [71]. However, due to thalidomide's known potential adverse effects and risk of teratogenesis, the FDA has limited its use through a restricted distribution program.
●Tofacitinib – Tofacitinib (a Janus kinase inhibitor) has been shown to be effective in adults with moderate to severe UC, but there is limited evidence in children. In a retrospective report of 21 adolescents and young adults with UC or colonic IBD that was refractory to one or more other biologic agents, 47 percent had a clinical response to tofacitinib by week 6 and 41 percent were in steroid-free remission at week 52 [72]. Safety concerns include risks for major adverse cardiac events [73], as well as deep vein thrombosis and pulmonary embolism with higher doses of tofacitinib, based on a study in adults with rheumatoid arthritis that may have positioned its use as second-line therapy to anti-TNF-alpha treatment failures [74]. (See "Management of moderate to severe ulcerative colitis in adults", section on 'Janus kinase (JAK) inhibitors'.)
●Ustekinumab – Ustekinumab is a human monoclonal antibody targeting p40 subunit of interleukin-12 and interleukin-23. It is FDA-approved for the treatment of adults with moderate to severe UC [75]. Small retrospective studies in children suggest efficacy and safety similar to those in adults, but larger prospective studies are needed to confirm these observations [76].
●Calcineurin inhibitors – Case series have described the use of cyclosporine and tacrolimus as "rescue therapy" for patients with severe or refractory UC, but these agents have little role in moderate disease. (See "Management of severe or refractory ulcerative colitis in children and adolescents", section on 'Refractory disease'.)
●Fecal microbiota transplantation (FMT) – Preliminary data suggest that FMT has the potential to be an effective and safe treatment for some UC patients when standard treatments have failed. Most data are from small trials in adults. However, studies in children with UC are limited to small patient cohorts, most of whom have recurrent C. difficile infection. We do not recommend FMT in patients with UC unless they either have comorbid recurrent C. difficile infection or are enrolled in a clinical trial. (See "Management of moderate to severe ulcerative colitis in adults", section on 'Investigational therapies'.)
Medical necessity of off-label use of medications in pediatrics — Use of second- or third-line agents and/or escalation of doses beyond those approved by the FDA may be appropriate and medically necessary for selected children with UC. The decision should be based on individual patient characteristics and clinical judgement by an expert clinician. In the United States, some insurance companies and payors have been denying coverage for these medically necessary therapies, stating that the use is "experimental," which usually is not the case. According to a position statement by the American Academy of Pediatrics: "The purpose of off-label use is to benefit the individual patient. Practitioners use their professional judgment to determine these uses. As such, the term 'off-label' does not imply an improper, illegal, contraindicated, or investigational use. Therapeutic decision-making must always rely on the best available evidence and the importance of the benefit for the individual patient" [60].
Substantial evidence supports a role for dose escalation, therapeutic drug monitoring, and utilization of drugs that are approved in adults in the management of pediatric UC. In many cases of refractory IBD, off-label use is medically necessary and is in the patient's best interest. The evidence supporting these off-label uses is outlined in the above description of each drug. If the medically necessary treatment is denied by a payer, the clinician may advocate for the patient by providing medical details on the patient case and including relevant medical literature supporting the utilization of an off-label treatment [77,78]. (See 'Second-line options' above.)
PROGNOSIS — The disease course of UC varies markedly and is only partially correlated with disease severity at presentation. Data about short-term (52-week) outcomes come from a multicenter registry study that included more than 400 subjects who were treated using a standardized protocol starting with either aminosalicylates or corticosteroids depending on disease severity, then advancing therapy as needed [79]. At presentation, most patients (83 percent) had extensive disease or pancolitis and 42 percent had mild disease severity (defined in this study as pediatric UC activity index [PUCAI] score <45). After one year of therapy, 38 percent of subjects were in corticosteroid-free remission (98 percent on aminosalicylates alone and 2 percent on no therapy) and the remainder had advanced to immunomodulators (19 percent), anti-tumor necrosis factor (anti-TNF) antibodies (31 percent), or colectomy (6 percent). The best predictors of remission at one year were low disease severity and hemoglobin >10 g/dL at baseline, and initial response to therapy (at week 4).
IMPORTANT HEALTH MAINTENANCE ISSUES — Patients with inflammatory bowel disease (IBD) require close health supervision for a number of issues, which are discussed in detail in a separate topic review (see "Important health maintenance issues for children and adolescents with inflammatory bowel disease"):
●Nutritional status and growth failure.
●Infection risk and immunizations – Because many patients are treated with immunosuppressive medications.
●Monitoring for extraintestinal manifestations – Especially hepatobiliary and eye disease.
●Psychological issues and support.
●Risk of colorectal cancer – The risk for developing colorectal cancer in patients with UC increases with disease duration and is higher in those who have had extensive colitis, even if the disease is subsequently controlled. We suggest beginning surveillance colonoscopy for cancer screening starting 8 to 10 years after the diagnosis of UC and annually from the time of diagnosis in patients with comorbid sclerosing cholangitis [26,80,81].
●Transition to adult health care.
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Inflammatory bowel disease in children".)
INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.
Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword[s] of interest.)
●Basics topic (see "Patient education: Ulcerative colitis in children (The Basics)")
●Beyond the Basics topic (see "Patient education: Ulcerative colitis (Beyond the Basics)")
SUMMARY AND RECOMMENDATIONS
●Proctitis – For patients with ulcerative colitis (UC) that is limited to the distal rectum (proctitis), we suggest initial treatment with topical rectal 5-aminosalicylic acid (5-ASA, such as mesalamine) or glucocorticoid enemas, foam, or suppositories, with or without concurrent oral 5-ASA, rather than treatment with systemic glucocorticoids (Grade 2B). If the symptoms respond to this treatment, we suggest maintenance therapy with either topical or oral 5-ASA rather than no treatment (Grade 2C). The choice of medication and route of administration depends on the child and family's preference and on the patient's individual responsiveness to the treatment. (See 'Proctitis' above.)
●Colitis – For patients with left-sided UC (colitis primarily involving the rectum and descending colon), extensive disease (colitis extending proximal to the splenic flexure), or pancolitis (involving the entire colon), the initial treatment options depend on the severity of the disease. We select the medical therapy based on disease severity and escalate to more intensive therapies or consideration of surgical colectomy for patients whose disease is refractory to treatment. (See 'Left-sided disease and pancolitis' above.)
•Mild – For patients with mild colitis (ie, fewer than four bowel movements daily without significant abdominal pain, anemia, or fever), we suggest initial treatment with oral 5-ASA (eg, mesalamine) or sulfasalazine, rather than systemic glucocorticoids (Grade 2C). (See 'Mild disease' above.)
•Moderate – For patients with moderate colitis (ie, more than four bloody bowel movements per day, usually with intermittent abdominal pain but without tenesmus or fever):
-For most such patients, we suggest initial treatment with oral glucocorticoids rather than oral 5-ASA or sulfasalazine (Grade 2B). We typically use prednisone at a dose of 1 to 1.5 mg/kg/day (maximum dose 40 to 60 mg daily). However, for patients who are reluctant to use glucocorticoids, it is reasonable to offer a trial of 5-ASA, using doses at the high end of the range.
-For those with poor fluid intake, abdominal pain, and/or lack of nutrition or for those who are unresponsive to oral glucocorticoid therapy, we suggest hospitalization and intravenous glucocorticoids. Another possibility is early use of a biologic agent (infliximab or adalimumab). (See 'Moderate disease' above.)
•Severe – (See "Management of severe or refractory ulcerative colitis in children and adolescents".)
●Treatment goals – Disease activity and response to therapy is typically determined by changes in clinical symptoms but can be reliably measured using the pediatric UC activity index (PUCAI) score (table 4) (calculator 1). In addition, resolution of active disease on endoscopy is increasingly used for documenting response to therapy. (See 'Determination of response to therapy' above.)
●Steroid-dependent colitis – For patients with steroid-dependent colitis (those who respond to glucocorticoid therapy but experience recurrent flares when the glucocorticoids are weaned):
•We suggest treatment with either infliximab, adalimumab, or an immunomodulator (6-mercaptopurine [6-MP] or azathioprine [AZA]), rather than colectomy or chronic treatment with corticosteroids (Grade 2C). All patients should undergo testing for thiopurine methyltransferase (TPMT) activity or genotype prior to initiating treatment with 6-MP or AZA. (See 'Steroid-dependent disease' above.)
•For patients who cannot be weaned from glucocorticoids despite the above medical therapies, the clinician should engage the patient and/or family in an informed decision about colectomy versus second-line medical therapy. Alternative medical therapies to be considered include vedolizumab, golimumab, tofacitinib, ustekinumab, or thalidomide. (See "Management of severe or refractory ulcerative colitis in children and adolescents", section on 'Refractory disease'.)
●Prognosis – The disease course of UC varies markedly and is only partly predicted by disease severity at baseline. After one year, approximately 40 percent of patients achieve corticosteroid-free remission (most on aminosalicylates) and most others advance to immunosuppressive or biologic therapy, while 5 to 10 percent undergo colectomy. (See 'Prognosis' above.)
●Cancer risk – The risk for developing colorectal cancer in patients with UC increases with disease extent and duration. We suggest beginning surveillance colonoscopy for cancer screening starting 8 to 10 years after the diagnosis of UC. (See 'Important health maintenance issues' above.)
ACKNOWLEDGMENTS — The UpToDate editorial staff acknowledges Tyler Burpee, MD, Alan Leichtner, MD, and George H Russell, MD, MS, who contributed to earlier versions of this topic review.
Dr. Bousvaros acknowledges the Clark, MacInnes, Rasmussen, Stefanis, Ward, and Wolfman families for support of his work.
