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Medical therapies for Crohn disease in children and adolescents

Medical therapies for Crohn disease in children and adolescents
Authors:
Naamah Zitomersky, MD
Athos Bousvaros, MD
Section Editor:
Melvin B Heyman, MD, MPH
Deputy Editor:
Alison G Hoppin, MD
Literature review current through: Dec 2022. | This topic last updated: Sep 09, 2022.

INTRODUCTION — Crohn disease (CD) is a chronic inflammatory condition that can affect any portion of the gastrointestinal tract from the mouth to the perianal area. Medical therapy is a cornerstone of management in all age groups. The choice of therapy varies depending upon the anatomic location and severity of the disease and treatment stage (induction versus maintenance of remission).

This review focuses on the characteristics of the medications used for CD in children. Other aspects of the diagnosis and management of children with CD are discussed in separate topic reviews:

(See "Overview of the management of Crohn disease in children and adolescents".)

(See "Clinical presentation and diagnosis of inflammatory bowel disease in children".)

(See "Clinical manifestations and complications of inflammatory bowel disease in children and adolescents".)

(See "Important health maintenance issues for children and adolescents with inflammatory bowel disease".)

(See "Growth failure and pubertal delay in children with inflammatory bowel disease".)

OVERVIEW — For CD affecting the ileum and/or colon, a variety of medications are available (table 1). The choice of medication typically depends on disease location, severity, response, and benefits and risks of each therapy. These therapies can be grouped as induction therapies, which have relatively rapid onset of action, and maintenance therapies, which are appropriate for long-term use. Some treatments, such as anti-tumor necrosis factor (anti-TNF) therapies, are appropriate for both induction and maintenance.

The main options and general considerations are:

Glucocorticoids – Systemic glucocorticoids (eg, prednisone, methylprednisolone) or budesonide are appropriate for induction in moderate to severe CD [1]. In the United States, glucocorticoids are a common but declining initial treatment for the acute therapy. (See 'Glucocorticoids' below.)

Exclusive or partial enteral nutrition – Exclusive enteral nutrition (EEN) is an appropriate approach for induction in patients with moderate to severe CD, especially for those with extensive small bowel involvement or growth failure. This approach is common in Canada and the United Kingdom and less widely used in the United States [2,3]. A form of partial enteral nutrition combined with a specific exclusion diet (known as the "CD exclusion diet") shows some promise for improving symptoms in children with mild to moderate CD. (See 'Exclusive or partial enteral nutrition' below and "Overview of the management of Crohn disease in children and adolescents", section on 'Nutritional therapy'.)

Infliximab or adalimumabInfliximab or adalimumab, which are anti-TNF antibodies, are the main biologic agents used for CD in children. These drugs are used for initial medical treatment of high-risk patients with severe disease or for those with moderate disease due to patient preference and other patient-specific considerations (see 'Anti-tumor necrosis factor antibody medications' below). They are also common choices for maintenance therapy in patients with moderate or severe disease. (See 'First-line biologic agents' below.)

Immunomodulators – Immunomodulators used for CD are thiopurines (6-mercaptopurine [6-MP] or azathioprine [AZA]) and methotrexate (MTX). These are appropriate only for maintenance because of delayed onset of action. (See 'Mercaptopurine and azathioprine' below and 'Methotrexate' below.)

Aminosalicylates – Aminosalicylates are sometimes utilized for induction and maintenance in mild CD; they have low toxicity but questionable efficacy. The choice of agent depends on disease location. (See 'Aminosalicylates' below.)

Antibiotics – Antibiotics are important components of treatment for patients with abdominal abscess and are used in conjunction with percutaneous drainage. Oral antibiotics such as ciprofloxacin, azithromycin, and metronidazole also have a limited role in the treatment of mild to moderate active CD, especially for patients with perianal disease but also for those with colonic disease. (See 'Antibiotics' below.)

Other medications – A variety of therapies, including vedolizumab, ustekinumab, certolizumab, golimumab, and thalidomide, have been used for children with refractory CD. Because of limited pediatric data, these drugs are usually used as second-line therapy in patients who fail treatment with immunomodulators and anti-TNF antibodies. However, there are pediatric data that support the efficacy and safety of some of the newer biologic agents, including ustekinumab and vedolizumab. (See 'Other medications' below.)

The properties of these medications are discussed below. An approach to selecting among these medications is outlined in the algorithm (algorithm 1) and discussed in more detail separately. (See "Overview of the management of Crohn disease in children and adolescents", section on 'Selection of medical treatment'.)

INDUCTION THERAPY

Glucocorticoids — In the United States, glucocorticoids remain a common initial medical treatment for the acute therapy of moderate to severe CD. Glucocorticoids are considered short-term induction therapies. Patients who respond to induction with glucocorticoids should transition to a long-term maintenance treatment (usually an immunomodulator or biologic).

Glucocorticoids are not appropriate for maintenance therapy, because they are associated with important long-term side effects, including growth failure, osteopenia, hirsutism, diabetes, psychosis, cataracts, and altered body shape and image. Moreover, they are not effective for maintaining remission [4]. (See "Major side effects of systemic glucocorticoids".)

Methylprednisolone — For patients with severe disease at presentation, an intravenous glucocorticoid (eg, methylprednisolone) is given initially because it provides the most rapid glucocorticoid effect. This drug is typically given as 1 mg/kg per dose every 12 hours, up to a maximum of 30 mg every 12 hours, then transitioned to oral glucocorticoids if the patient demonstrates a good clinical response. Some clinicians use higher doses (eg, 2 mg/kg every 12 hours, maximum 40 mg per dose).

Prednisone — In patients with moderate disease and active mucosal inflammation, prednisone or prednisolone given orally usually brings rapid improvement in most patients. Starting doses are 1 to 2 mg/kg/day (maximum 60 mg daily). Once remission is achieved, glucocorticoids can be tapered.

Although glucocorticoids are effective for inducing remission in most patients, many become glucocorticoid dependent or require surgery. This was illustrated in a retrospective study that described the natural history of CD from 1970 to 1993, a period when glucocorticoids were the most effective available medical therapy for CD [5]. Although 80 percent of patients were in remission after 30 days, after 12 months, 28 percent were still glucocorticoid dependent and 38 percent had undergone surgery.

Budesonide — Enteric-coated budesonide (eg, Entocort), designed for release in the ileum and cecum, is an alternative to oral prednisone. Budesonide is probably less effective than prednisone, but also has fewer side effects, because of high first-pass hepatic metabolism. It is only effective for disease in the ileum and ascending colon (right colon) (see "Overview of budesonide therapy for adults with inflammatory bowel disease"). A newer formulation, budesonide MMX, is a once-daily oral formulation of budesonide that is designed to release budesonide throughout the colon using Multi-Matrix System (MMX) technology. This formulation has been studied in mild to moderate ulcerative colitis [6]. Budesonide MMX has not been studied in children with CD. However, based on its efficacy in ulcerative colitis, it is a potential option in children with CD limited to the colon and may help to reduce toxicity from systemic steroids.

The initial starting dose of the ileal-release form of budesonide for an adolescent or adult is 9 mg/day, tapered by 3 mg increments. There are few data on the optimal dosing in children. The adult dose of 9 mg/day has been used in clinical trials in children six years and older [7,8]. A retrospective study of 62 children used oral budesonide in doses of 0.45 mg/kg/day (maximum dose 9 mg/day) for the treatment of mild to moderate CD [9]. Budesonide MMX comes only in 9 mg preparations, so tapering of this agent involves going to 9 mg every other day for two weeks, then 9 mg every three days for two weeks, then discontinuing it.

Studies in adults and small pediatric studies suggest that budesonide is slightly less effective than prednisone in inducing remission in active disease but is associated with fewer side effects (moon facies, acne, adrenal suppression) [7]. One pediatric study showed that the response rate to budesonide for induction is approximately 48 percent, compared with 77 percent for prednisone, and that prednisone is effective rescue therapy in approximately 75 percent of patients who do not respond to budesonide [9,10].

Budesonide should not be used as long-term maintenance therapy of CD. Although it offers the advantage of less systemic toxicity compared with other glucocorticoids, patients treated long-term with budesonide still may experience growth failure, either because of direct suppression of linear growth or an inability to fully control disease activity [11]. Moreover, placebo-controlled trials in adults showed that it was not effective for maintenance therapy [12].

Topical budesonide (liquid or foam enema) may be used for patients with left-sided colonic disease. (See "Overview of budesonide therapy for adults with inflammatory bowel disease", section on 'Rectal formulations'.)

Exclusive or partial enteral nutrition — Exclusive enteral nutrition (EEN; also known as primary nutritional therapy) can be used as an alternative or supplement to glucocorticoids or other antiinflammatory medications. It is a good option for motivated children and families who wish to avoid glucocorticoids and other medications (at least in the short term). It promotes mucosal healing in a patient with active disease and suppresses intestinal inflammation, possibly by altering the gut microflora [13-15].

EEN consists of providing all nutritional needs through a liquid formula. If a course of EEN is successful, the patient is typically transitioned to one of the maintenance medications described below. Additional courses of EEN can be used for re-induction after a relapse. Because long courses of EEN are a major burden to the patient, EEN is rarely used as a maintenance therapy, although periodic use of EEN (eg, four weeks every four months) may help promote weight gain and maintain remission [16]. Details about the technique, efficacy, and patient selection are discussed separately.

An alternative approach is to combine partial enteral nutrition with a specific whole foods-based exclusion diet, known as the CD exclusion diet. This form of nutritional therapy is more easily accepted by patients than EEN and appears to be at least as effective in inducing remission [17]. This approach is undergoing further study but is increasingly utilized in clinical practice. (See "Overview of the management of Crohn disease in children and adolescents", section on 'Nutritional therapy'.)

Anti-tumor necrosis factor antibody medications — In certain high-risk patients, treatment with infliximab or adalimumab early in the disease course may be beneficial compared with other induction therapies (algorithm 2). We usually use this strategy for patients with extensive small bowel disease, severe ulcerating colonic disease, growth failure in mid- to late puberty, severe perianal disease, or steroid-unresponsive disease because these patients have an increased risk of poor disease outcome. The decision is also guided by the preferences of the patient and family or caregivers. For patients without these risk factors, it is unclear whether this approach is beneficial compared with other induction therapies. The limited evidence about potential benefits and risks for early use of these drugs is discussed separately. (See "Overview of the management of Crohn disease in children and adolescents", section on 'High-risk patients'.)

Details about the use of infliximab and adalimumab, including dosing, efficacy, safety, and decisions about use in combination with other immunosuppressive medications, are discussed below. (See 'Infliximab' below and 'Adalimumab' below and 'Anti-TNF monotherapy versus combination therapy with an immunomodulator' below.)

Aminosalicylates — 5-aminosalicylates (5-ASA) are sometimes used for induction in patients with mild disease (eg, mild colitis, limited ileal disease). If the patient responds, the drug is continued for maintenance of remission. However, no formal trials have assessed the efficacy of these agents for induction in pediatric CD. The use of aminosalicylates for CD is controversial, with some meta-analyses suggesting lack of efficacy, while others suggest moderate effectiveness in colonic disease [18]. Nevertheless, many clinicians do a trial of 5-ASA for patients with mild CD because they have low toxicity. If a patient does not enter clinical, laboratory, or endoscopic remission after six months of use, other alternatives are strongly encouraged. (See 'Aminosalicylates' below.)

MAINTENANCE MEDICATIONS

First-line biologic agents — Infliximab and adalimumab are monoclonal antibodies directed against tumor necrosis factor (TNF). These drugs are important options for patients with moderate or severe CD and have become the mainstay of induction and maintenance treatment for CD in North America and Europe (algorithm 2). They are also appropriate as initial therapy for patients with moderate or severe disease, especially those with features suggesting a high risk of complications (see 'Anti-tumor necrosis factor antibody medications' above). Other anti-TNF agents that are less often used for pediatric patients are discussed below. (See 'Second-line biologic agents' below.)

Infliximab — Infliximab is a chimeric monoclonal antibody directed against the cytokine TNF-alpha. It is approved by the US Food and Drug Administration (FDA) for treatment of moderate to severe CD in children who have had an inadequate response to conventional therapy [19]. It is also increasingly used as first-line maintenance therapy and as induction therapy for patients with moderate to severe CD, especially those at high risk for complications [3]. (See 'Anti-tumor necrosis factor antibody medications' above.)

The pharmacology, efficacy, and safety of infliximab are discussed in detail separately. Data particularly relevant to its use in children are discussed here. (See "Treatment of Crohn disease in adults: Dosing and monitoring of tumor necrosis factor-alpha inhibitors".)

Dose and administration — The typical regimen for infliximab consists of three initial "loading" doses of 5 mg/kg each at zero, two, and six weeks, with follow-up infusions at eight-week intervals if the patient responds. Regularly scheduled treatment rather than episodic use is important to optimize efficacy and avoid loss of response.

Patients who do not respond to the 5 mg/kg dose sometimes respond to dose intensification by either increasing the infliximab dose (maximal dose usually up to 10 mg/kg every four weeks) or increasing the frequency of infusions (decreasing the interval to every four to six weeks) [20-22]. Indeed, a large case series from a tertiary care center found that 40 percent of children initially treated with 5 mg/kg required dose intensification [23]. Other studies also suggest that doses of 5 mg/kg every eight weeks are insufficient to achieve optimal infliximab levels in 40 to 60 percent of children, especially in children <11 years or more severe disease [24-27]. (See 'Monitoring infliximab levels and antibodies' below.)

Patients with very early-onset inflammatory bowel disease (VEO-IBD) may require accelerated induction with high-dose infliximab, guided by therapeutic drug monitoring, or alternative treatment options for certain types of VEO-IBD [28-31]. (See "Clinical presentation and diagnosis of inflammatory bowel disease in children", section on 'Very early-onset inflammatory bowel disease'.)

Increasing evidence suggests that prompt dose intensification reduces the risk of developing anti-infliximab antibodies, reduces the risk of loss of response to therapy, and often achieves a sustained clinical response [32,33]. (See 'Medical necessity of off-label use of medications in pediatrics' below.)

A good response is suggested by improvement in clinical symptoms (eg, abdominal pain, fatigue, diarrhea, rectal bleeding) within four to eight weeks (table 2). The response should ideally be confirmed within three to six months by objective data, such as improvements in erythrocyte sedimentation rate (ESR) or C-reactive protein (CRP), repeat imaging with magnetic resonance enterography (MRE), or colonoscopy. (See "Overview of the management of Crohn disease in children and adolescents", section on 'Assessment of disease activity'.)

Monitoring infliximab levels and antibodies — Infliximab trough levels and anti-infliximab antibodies are increasingly being utilized to monitor patients receiving infliximab therapy and to optimize dosing for each patient [34], although the optimal way to monitor patients has not yet been determined and the monitoring is costly [35,36].

Infliximab concentrations – The typical target for infliximab trough concentration is >5 micrograms/mL before the week 14 infusion. Several studies suggest that concentrations above this threshold are associated with a higher likelihood of remission in adults and children [20,26,37-39] and other studies support the use of higher thresholds and/or earlier monitoring [40,41]. Indeed, combination therapy (utilizing infliximab together with either methotrexate [MTX] or a thiopurine) may work in part because the immunomodulator may raise infliximab levels [42]. (See 'Anti-TNF monotherapy versus combination therapy with an immunomodulator' below.)

Some experts have advocated for routine monitoring of infliximab trough levels at week 14 (the fourth infusion), permitting dose escalation before the development of clinical or laboratory disease activity [20]. In a prospective study in adult and pediatric patients, low anti-TNF drug concentrations at week 14 were associated with lower odds of remission at week 54 [40].

Experience with infliximab monitoring in adults with CD is discussed separately. (See "Treatment of Crohn disease in adults: Dosing and monitoring of tumor necrosis factor-alpha inhibitors", section on 'Therapeutic drug monitoring'.)

Anti-infliximab antibodies – In patients with low trough infliximab concentration (eg, <5 micrograms/mL) and active disease, the interpretation depends on the presence of anti-infliximab antibodies (table 3), which develop in at least 25 percent of patients [43]:

Patients with low or no levels of anti-infliximab antibodies (eg, <10 U/mL) are likely to benefit from dose escalation [44]. In some cases, this may be due to increased stool losses of infliximab due to colonic inflammation, which is often correlated with low serum albumin concentrations or increased disease burden (ie, with more TNF to inhibit) [24,34,45]. A majority of these patients respond to dose optimization, and many of these revert to antibody-negative, as suggested by observational studies in children [43] and adults [46].

Patients with high titers of anti-infliximab antibodies (eg, >10 U/mL) and who are not responding to treatment are less likely to respond to dose escalation of infliximab because infliximab clearance is increased in patients with high anti-infliximab antibody titers [21]. However, it may be worth attempting dose escalation for these patients because a minority will respond [43,46]. Those who do not respond to dose escalation will need a different agent.

Efficacy — Infliximab is generally more effective than AZA, 6-MP, or other immunomodulators in treating moderate to severe CD. It is typically used to treat patients whose disease is resistant to steroids [47] and also can help heal perianal fistulas refractory to therapy with antibiotics and AZA/6-MP [48-50]. It is also increasingly used early in the course of disease to treat patients with high risks for complicated CD, as discussed above. (See 'Anti-tumor necrosis factor antibody medications' above and "Treatment of Crohn disease in adults: Dosing and monitoring of tumor necrosis factor-alpha inhibitors".)

Initial studies in children suggest efficacy comparable with that achieved in adults [51-55]. Approximately 80 percent of children or adults have a response to infliximab [56,57]. Among those children who respond to infliximab, approximately 50 percent will remain in remission after one year. Approximately 20 percent of patients require dose intensification to maintain remission, which is accomplished by an increase in drug dose or an increase in infusion frequency [58]. An additional subset of patients experience loss of response despite dose intensification, which is in part mediated by the development of antibodies to infliximab. In one case series, loss of response was experienced by 10 percent of responders over a five-year period (2 to 6 percent per year), despite optimization of the regimen [57]. Concurrent treatment with immunomodulators (6-MP or AZA) modestly improves the response rate to infliximab [59-61]. Overall, approximately one-third of patients discontinue infliximab within two to three years, either because of primary nonresponse (2 to 13 percent), loss of response despite dose intensification (8 to 30 percent), or adverse events (5 to 8 percent) [57,58,62-65]. Many of these patients change to another agent (eg, adalimumab). (See "Treatment of Crohn disease in adults: Dosing and monitoring of tumor necrosis factor-alpha inhibitors" and 'Anti-TNF monotherapy versus combination therapy with an immunomodulator' below.)

In a multicenter open-label trial of infliximab in combination with an immunomodulator in 112 pediatric patients, 88 percent of subjects responded to 10 weeks of treatment with infliximab and 59 percent achieved clinical remission [56]. Among the responders, there were superior sustained remission rates in children receiving infusions every eight weeks compared with infusions every 12 weeks (56 versus 24 percent of patients were still in remission at 56 weeks). In a subpopulation of 23 patients with perianal disease, the perianal symptoms resolved in 70 percent and remained in remission through 54 weeks of maintenance therapy [66]. Seven percent of the subjects developed serious infections (pneumonia or Crohn-associated abscess, sepsis, or enterocolitis) [56]. Eighteen percent had an infusion reaction, but these usually did not require discontinuation of infliximab therapy. With long-term maintenance therapy, 80 percent had little or no disease activity for up to three years [62]. Limited data suggest that very young patients may not respond as well to infliximab therapy. In an observational study of 33 children younger than seven years of age with IBD (20 with CD, four with ulcerative colitis, and nine with indeterminate colitis), remission rates were 36 percent at one year, 18 percent at two years, and 12 percent at three years [67].

Adverse effects — Infliximab is generally well tolerated, but as experience with the drug increases, concerns have been raised about the possibility of some rare but serious adverse effects. (See "Tumor necrosis factor-alpha inhibitors: An overview of adverse effects".)

Infusion reactions – The most common adverse effect of infliximab is an infusion reaction, which occurs in 15 to 35 percent of patients (approximately 5 percent of infusions) [55,68-70]. Infusion reactions can present with acute symptoms (chest tightness, shortness of breath, rash, vomiting, and/or blood pressure instability) or delayed symptoms (fever, arthritis, and rash occurring 2 to 14 days after an infusion). Some infusion reactions are caused by antibodies to infliximab. One study suggested that the probability of developing antibodies is reduced if patients are premedicated with intravenous hydrocortisone [71]. Other strategies for reducing antibody formation include the use of scheduled infusions rather than "on-demand" infusions and concomitant treatment with thiopurines or MTX [71-73].

Many infusion reactions are mild and can be managed by intravenous glucocorticoids, diphenhydramine, and a decrease in infusion rate. In a patient with a history of infusion reactions, subsequent infusions are typically managed by giving glucocorticoids orally for three to five days and/or an intravenous dose of hydrocortisone immediately prior to the infusion. Test doses of infliximab (usually 0.1 mg over 15 minutes, followed by 1 mg) are given and, if tolerated, the treatment infusion is performed. Alternatively, a patient with a history of a reaction can be converted from infliximab to adalimumab (a humanized anti-TNF antibody that is effective in adult patients who are intolerant of infliximab).

Serious infections – Like other biologic agents or immunomodulators, treatment with infliximab increases a patient's susceptibility to bacterial, fungal, and viral infections [74-78]. Before initiating treatment with any of these agents, we suggest that all patients undergo immunodiagnostic screening for tuberculosis, as well as baseline evaluation for vaccine-preventable infections, including measurement of titers for measles and hepatitis B virus (HBV) serologies and documentation of immunity to varicella (table 4) [75]. Tests for latent tuberculosis are unreliable once the patient is on an anti-TNF agent or other strong immunosuppressant [78]. Special considerations for immunizations are discussed in a separate topic review. (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'.)

Serious infections reported in patients during treatment with these agents include bacterial sepsis, tuberculosis, nontuberculous mycobacterial infection, Listeria and disseminated varicella or cytomegalovirus infection, and Legionella pneumophila [75,77,79,80]. Advice for patients to help avoid infections is summarized in the table (table 5). (See "Tumor necrosis factor-alpha inhibitors: Bacterial, viral, and fungal infections".)

The risk for invasive fungal infection has raised particular concern [77,81]. In 2008, the FDA issued a warning about the risk for pulmonary and disseminated histoplasmosis, coccidiomycosis, blastomycosis, aspergillosis, and other invasive fungal infections in patients undergoing treatment with infliximab or other anti-TNF antibodies [82]. The warning is based on case reports of patients in whom histoplasmosis infection was not promptly recognized, and some of these patients died. Typical signs and symptoms of histoplasmosis and other invasive fungal infections include fever, malaise, weight loss, sweats, cough, dyspnea, pulmonary infiltrates on radiographs, or serious systemic illness including shock. Infection is acquired through inhalation of contaminated soil (eg, in chicken coops) in an endemic area, which includes parts of the midwestern United States (eg, the Ohio and Mississippi river valleys), Mexico, Central and South America, Africa, and Asia [75]. (See "Tumor necrosis factor-alpha inhibitors: Bacterial, viral, and fungal infections", section on 'Fungal infections'.)

Malignancy – Most available data suggest a mildly increased risk of lymphoma and hepatosplenic T cell lymphoma (HSTCL) in patients receiving immunosuppressive therapy for CD, although the absolute risk remains low. The risk from monotherapy with infliximab or other anti-TNF antibodies appears to be very small and probably less than for thiopurine monotherapy, although causality cannot be definitively determined, because the disease is extremely rare. In patients on combination therapy, the majority of the risk appears to be attributable to the thiopurine component [83] (see 'Safety and monitoring' below). However, lymphoma may also occur in patients receiving infliximab monotherapy [84]. Very limited data suggest that anti-TNF antibodies may increase the risk for melanoma. (See "Tumor necrosis factor-alpha inhibitors: Risk of malignancy".)

Citing concerns about possible increased risks for lymphoma and other malignancies, the FDA performed a Safety Review of TNF inhibitors and strengthened the warnings in the prescribing information. The FDA specifically recommended that discussions with patients and families include the risks and potential benefits of anti-TNF antibodies, as well as the risks and benefits of alternative treatments [85].

The malignancy concerns are central to decisions about use of immunomodulators in combination with an anti-TNF antibody. (See 'Anti-TNF monotherapy versus combination therapy with an immunomodulator' below.)

Other – Other serious complications with infliximab therapy have been reported, including miliary tuberculosis, other opportunistic infections [86], immune-mediated hepatitis [87], liver failure, autoimmune disease, demyelinating disease or other neurologic disorders [88], and one pediatric case of a fatal fulminant central nervous system process of unclear etiology [89]. Infliximab or other TNF inhibitors may also induce psoriasis in approximately 10 percent of patients, with average latency of approximately 1 year after starting the medication [90-94]. They probably also contribute to skin cancer risk in individuals with IBD [95,96]. (See "Important health maintenance issues for children and adolescents with inflammatory bowel disease", section on 'Skin monitoring and care'.)

Infliximab biosimilars — Almost all studies of infliximab in pediatric patients utilized the originator (aka "reference") product of infliximab. However, other pharmaceutical companies subsequently developed anti-TNF molecules with a similar chemical structure to infliximab, called infliximab biosimilars. Clinical trials in adults have demonstrated comparable efficacy and safety of infliximab biosimilars in patients with rheumatoid arthritis as well as IBD. However, pediatric data remain limited, though the few published studies again suggest comparable efficacy and safety [97]. The European Society for Paediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN) suggested that "a switch from the originator infliximab (to a biosimilar) may be considered in children with IBD in clinical remission, following at least 3 induction infusions" [98]. However, ESPGHAN also recommends against multiple medication switches, as might be attempted in a patient with loss of efficacy, because it may be difficult to determine whether a specific product results in worse outcomes of disease. They also recommend keeping careful records of medications so that a hospital can ascertain whether a patient is receiving a reference product or biosimilar. Increasingly, switches from originator to biosimilar are being mandated by insurance due to cost savings [99,100]. (See "Overview of medical management of high-risk, adult patients with moderate to severe Crohn disease", section on 'Biosimilars'.)

Adalimumab — Adalimumab is an antibody directed against TNF and is approved by the FDA for the treatment of moderate to severe CD in children. Adalimumab is a humanized antibody, whereas infliximab is a chimeric antibody. The development of a new citrate-free formulation has resulted in reduced patient discomfort during injection, which was one of the main impediments to use. Either infliximab or adalimumab may be used as "first-line" anti-TNF therapy in children.

Indications – Most experts consider adalimumab to be a reasonable first-line alternative to infliximab when anti-TNF antibody medication is indicated, for either induction (see 'Anti-tumor necrosis factor antibody medications' above) or maintenance therapy [3]. Adalimumab is also used as a second-line treatment for patients who lose response to or are intolerant of infliximab.

Dose and administrationAdalimumab is administered by subcutaneous injection every two weeks. For adults and children ≥40 kg body weight, the manufacturer's label recommends a loading dose of 160 mg, followed by 80 mg two weeks later, and 40 mg every two weeks for maintenance. For children 17 to 40 kg body weight, the loading dose is 80 mg, followed by 40 mg two weeks later, and 20 mg every two weeks for maintenance. Escalation to weekly dosing is often necessary, guided by therapeutic drug monitoring and/or the clinical response. (See "Treatment of Crohn disease in adults: Dosing and monitoring of tumor necrosis factor-alpha inhibitors".)

EfficacyAdalimumab appears to have similar efficacy to infliximab, based on indirect evidence from separate trials and clinical experience, but the drugs have not been directly compared in randomized trials. Advantages of infliximab include more extensive experience and less frequent dosing in the maintenance phase (every eight weeks in contrast with every two weeks). Advantages of adalimumab are reduced cost (because no infusion center is needed) and the convenience of administering the medication at home or school. In the past, injections of adalimumab were quite painful due to the low pH of the medium, but a newer citrate-free formulation has a higher pH and is far less painful.

Most efficacy studies of adalimumab have been as a second-line therapy in patients who failed infliximab therapy due to lack of response, infusion reaction, or development of anti-infliximab antibodies [101-105]. In one such study that included 115 children and adolescents treated with adalimumab, 70 percent had a clinical response at one year [106]. Most of these subjects had failed a prior trial of infliximab because of loss of response, infusion reaction, or intolerance. The IMAgINE 1 trial evaluated two maintenance dosing regimens of adalimumab in 188 pediatric patients with moderate to severe CD [107]. Subjects were enrolled only if they had failed treatment with oral glucocorticoids or an immunomodulator (thiopurine or MTX) and had responded to an open-label induction with adalimumab. Approximately 40 percent of patients had been previously treated with infliximab but had become unresponsive or had adverse reactions to that drug. The trial focused on the maintenance phase of adalimumab. A standard-dose group received 40 mg for body weight ≥40 kg or 20 mg for body weight <40 kg, and a low-dose group received 20 mg for body weight ≥40 kg or 10 mg for body weight <40 kg. After 26 weeks of maintenance therapy, during which these doses of adalimumab were given every two weeks, 33.5 percent of patients remained in clinical remission and there was no significant difference between the two dosing regimens. Most importantly, the patients who were infliximab-naïve had comparable remission rates to the REACH trial [56] (approximately 50 percent), while those who had previously been treated with infliximab and lost response had significantly lower remission rates (approximately 20 percent).

Adalimumab is also efficacious as a first-line therapy for children with moderate to severe CD who have not been previously treated with infliximab or other biologic agents. In a trial in this population, sustained corticosteroid-free remission was achieved in 80 percent of children managed with proactive monitoring and dose adjustment and in 48 percent of those managed with reactive dose adjustment [108]. Adalimumab also significantly improved linear growth and weight gain [109,110].

Adverse effects – Adverse effects of adalimumab are similar to infliximab (see 'Adverse effects' above and "Tumor necrosis factor-alpha inhibitors: An overview of adverse effects"). Some patients have injection site reactions such as swelling or itching, which can be treated with premedication with an antihistamine.

Anti-TNF monotherapy versus combination therapy with an immunomodulator — Decisions about use of combination therapy (anti-tumor necrosis factor [anti-TNF] antibody with an immunomodulator) are complex because of uncertainties about the relative risks and benefits of combination versus monotherapy. As a result, there is considerable variation in clinical practice among IBD specialists. Practice ranges from avoiding combination therapy altogether, to using combination therapy for a limited period of time, to continuing combination therapy indefinitely, and/or substituting MTX rather than thiopurines for the combination therapy [3]. Given the equipoise regarding the use of combination therapy, patient and family values and preferences are important when deciding between combination therapy or biologic monotherapy. A plain-language summary to guide this discussion is outlined in the table (table 6).

Combination therapy (anti-TNF antibody with an immunomodulator) – Important considerations are:

Potential risks – The main concern about combination therapy is that it might increase the risk of lymphoma as compared with monotherapy. Since large studies of IBD patients suggest that thiopurines confer a slight increase in lymphoma risk, it is logical to infer that thiopurine discontinuation might reduce that risk [83,111,112]. However, because the overall risk of lymphoma in this population is small, any increased risk conferred by combination therapy is probably also very small, albeit poorly defined. There is insufficient information to determine whether MTX in combination with infliximab or other biologic agent is associated with lymphoma risk in IBD patients [113,114]. (See 'Safety and monitoring' below.)

Another concern is that combination therapy might increase the risk of opportunistic infection compared with monotherapy [83]. Although use of multiple immunosuppressive medications generally increases risks for infections, this is balanced by a reduction in infection risk achieved by improving disease remission rates and minimizing steroid use, based primarily on studies in adults [83,115].

Potential benefits – Combination therapy reduces the rate of antibody formation (which can cause loss of response to infliximab) [116]. It also improves remission rates as compared with monotherapy, based on evidence from large studies in adults with moderate or severe CD [47]. Similarly, in a study in children, patients treated with combination therapy for at least six months postinduction were substantially more likely to remain in remission compared with those treated with infliximab monotherapy (78 versus 54 percent at one year and 68 versus 46 percent at two years, respectively) [117]. Combination therapy is most likely to be beneficial for patients with risk factors for debilitating CD, such as those with fistulizing disease, perianal involvement, growth failure, or corticoid dependence [83]. The optimal duration and type of combination therapy remains uncertain [118,119].

Implementation – For a patient who is not responding to immunomodulators (thiopurines, MTX), one approach is to add infliximab or adalimumab to the immunomodulator and leave a patient on combination therapy for 6 to 12 months [118]. Then, if the patient is in remission, the patient may either continue on combination therapy or change to monotherapy with infliximab alone. This decision should be made collaboratively with the patient and family, after a detailed discussion about the risks and benefits of combination therapy versus monotherapy, acknowledging the limited information available (table 6).

After the immunomodulator is stopped, the disease relapses in some patients (approximately 10 percent in one case series [120]). In such cases, we suggest restarting combination therapy. For such patients, we usually use low-dose oral MTX with infliximab. However, if high titers of antibodies to infliximab are present, we generally switch to adalimumab or another biologic agent. We try to avoid long-term use of thiopurine with infliximab due to the rare risk of lymphoma.

If combination therapy with infliximab is planned, use of MTX rather than a thiopurine has the potential benefit of providing a protective effect against antibody formation, while reducing lymphoma risk. In particular, we prefer MTX rather than thiopurines in young males because young males seem to be at increased risk for HSTCL. However, the benefits of using MTX as an adjunct to anti-TNF therapy have not been established, since the only study that demonstrates that MTX reduces antibodies to infliximab utilized higher-dose subcutaneous MTX [121]. Additional data are required to see if low-dose oral MTX is effective. (See 'Methotrexate' below.)

Anti-TNF monotherapy – Monotherapy with an anti-TNF antibody is a reasonable alternative to combination therapy. For this strategy, the patient may advance directly to an anti-TNF antibody (without ever using an immunomodulator). Alternatively, for patients who are already on an immunomodulator, this is discontinued as soon as the anti-TNF agent is started. Monotherapy may be safer than combination therapy, as outlined above, and some data suggest that "optimized monotherapy" (where infliximab interval and dose are adjusted based on drug levels rather than using the standard dose) may improve efficacy and reduce loss of response, thus avoiding the need for combination therapy [122].

Data from adult studies and other considerations regarding concomitant immunosuppressive agents are discussed in more detail in a separate topic review. (See "Treatment of Crohn disease in adults: Dosing and monitoring of tumor necrosis factor-alpha inhibitors".)

Second-line biologic agents

Candidates and rationale – Candidates for second-line biologic agents are individuals with nonresponse despite therapeutic anti-TNF antibody drug levels (ie, trough infliximab levels ≥10 micrograms/mL):

Primary nonresponse – Up to one-third of patients treated with infliximab or adalimumab do not respond [123].

Secondary loss of response – Among patients who had an initial response to infliximab or adalimumab, approximately 13 percent develop secondary loss of response each year [124].

For these groups of patients, further treatment with adalimumab or infliximab has relatively low success rates [123]. Therefore, treatment with ustekinumab or vedolizumab is used by some experts, based on good outcomes with clinical experience, indirect evidence from studies in adults, and observational studies in children, as outlined below. This evidence supports the medical necessity of these drugs in selected patients. (See 'Medical necessity of off-label use of medications in pediatrics' below.)

UstekinumabUstekinumab is a monoclonal antibody that binds to the p40 subunit of interleukin (IL)-12 and IL-23. It has received FDA approval to be utilized in adults with CD but is used off-label in children. Limited data have been reported in children with plaque psoriasis, rheumatoid arthritis, and CD. Observational studies suggest that ustekinumab is efficacious in children with CD unresponsive to anti-TNF [125-128]. In adults, ustekinumab is given with an induction dose based on body weight (260 mg for <55 kg, 390 mg for 55 to 85 kg, 520 mg for >85 kg), followed by 90 mg given subcutaneously every two months.

One retrospective case series described outcomes of ustekinumab treatment of 52 pediatric patients with IBD (80 percent with CD), 81 percent of whom had failed other biologic agents [127]. After 52 weeks of therapy, 75 percent of patients were still on ustekinumab therapy, the majority of whom required dose escalation. Steroid-free remission was achieved in 50 percent of patients who had failed other biologic agents and 90 percent of those who had not been exposed to other biologic agents. A second multicenter retrospective study of 44 patients demonstrated similar results, with 77 percent of patients remaining on ustekinumab for one year and 39 percent of those achieving clinical remission. (See "Overview of medical management of high-risk, adult patients with moderate to severe Crohn disease", section on 'Ustekinumab'.)

VedolizumabVedolizumab is a humanized anti-alpha-4-beta-7 integrin monoclonal antibody that inhibits T-lymphocyte migration into the gastrointestinal tract. It is administered intravenously at weeks 0, 2, and 6 for induction and then maintenance with every four to eight weeks depending on disease severity, with more severe disease requiring four-week dosing [129,130]. Pediatric weight-based dosing is 6 mg/kg, to a maximum dose of 300 mg [129,130].

All pediatric studies are retrospective cohort studies, which show lower response rates compared with other biologic agents [129-131]. Therefore, it is generally used as a second- or third-line therapy for patients with primary nonresponse or secondary loss of response to infliximab (or biosimilar) or adalimumab. In patients who had failed one or more TNF-alpha antagonists, week 14 and 22 remission rates range between 30 to 45 percent [129,130]. Steroid-free remission at week 22 ranges from 20 to 30 percent [129-131]. Vedolizumab has been shown to have efficacy in adults with CD, either as first-line therapy [132] or after loss of response to an anti-TNF agent [133-135]. Its use in pediatric patients is often limited to those with loss of response to an anti-TNF, in part due to insurance denials of this and other off-label uses of drugs. (See 'Medical necessity of off-label use of medications in pediatrics' below.)

Notably, vedolizumab has a delayed onset of action compared with other biologic agents, particularly in individuals with severe refractory disease with loss of response to TNF-alpha antagonists. Little significant clinical response is appreciated until weeks 14 to 22 [131,133,136]. This delayed onset suggests that vedolizumab may not target preexisting inflammation but instead may inhibit propagation of further inflammation by inhibiting T-lymphocyte trafficking to the gut. Furthermore, treating the transmural inflammation seen in CD may require longer therapy than with ulcerative colitis, which may be why response rates in ulcerative colitis are faster and higher [136]. Additionally, TNF-alpha antagonists downregulate MAdCAM-1 expression; thus, patients with anti-TNF administered before vedolizumab may require more time to respond to this drug [133,136].

A significant benefit of vedolizumab use is its milder side effect profile in comparison with other biologics. The actions and immunosuppressive effects of vedolizumab are limited to the gastrointestinal tract, in contrast with many other therapies for CD that are systemically immunosuppressive, including TNF-alpha antagonists, immunomodulators, and ustekinumab. Furthermore, vedolizumab does not increase the risk of malignancy, which has been reported with these other CD therapies. The main potential side effect of vedolizumab is infusion reactions.

Medical necessity of off-label use of medications in pediatrics — Use of second-line biologic agents and/or escalation of doses beyond those approved by the FDA may be appropriate and medically necessary for selected children with CD. 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" [137].

Substantial evidence supports a role for dose escalation, therapeutic drug monitoring, and utilization of drugs that are approved for adults in the management of pediatric CD. 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 under each of the drugs. 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 [138,139]. (See 'Second-line biologic agents' above and 'Dose and administration' above.)

Immunomodulators — Thiopurines and MTX are immunomodulatory drugs that are sometimes used for maintenance therapy in CD. When used as monotherapy, they are generally considered second-line options because biologic agents (eg, infliximab or adalimumab) have somewhat better risk/benefit profile for most patients. Immunomodulators can also be used in combination with a biologic agent, either to reduce antibody formation or for refractory cases (see 'Anti-TNF monotherapy versus combination therapy with an immunomodulator' above). Specific considerations are outlined below.

Mercaptopurine and azathioprine — The thiopurine drugs azathioprine (AZA) and mercaptopurine (also known as 6-mercaptopurine [6-MP]) are one of several options for maintenance treatment of moderate or severe CD (algorithm 1). They can be used in combination with a biologic agent (eg, infliximab or adalimumab) but are sometimes used as monotherapy. Their use has declined since the early 2000s because they have limited efficacy as monotherapy and because of concerns about the small risk of lymphoma associated with thiopurines. These concerns have prompted a trend toward other maintenance regimens, including a biologic agent alone or in combination with MTX or, possibly, MTX monotherapy. Nevertheless, thiopurines warrant consideration in some cases because of their long history of use and efficacy in CD. (See 'Safety and monitoring' below.)

In the liver, 6-MP and AZA are converted to 6-thioguanine (6-TG) nucleotides, which inhibit lymphocyte proliferation by impairing DNA synthesis. 6-MP or AZA may require two to four months of treatment to achieve their maximal effect. Thus, they are not useful as induction agents.

Dose — Because AZA is metabolized into 6-MP, the drugs are equally effective and differ only in their dosing. In children, standard doses for AZA are 1.5 to 2.5 mg/kg/day orally (maximum dose 200 mg/day). 6-MP is generally given at doses between 1 to 1.5 mg/kg/day orally (maximum 150 mg/day). Some patients may benefit from doses above this range (eg, 6-MP 2 mg/kg/day), if appropriately monitored for toxicity. As an example, one observational report suggests that younger children (<6 years) may require doses at the higher end of this range or above (median AZA equivalent 3.1 mg/kg/day) to achieve clinical remission [140]. All children treated with these drugs should be monitored closely for signs of toxicity, as discussed below.

Because of genetic variation in metabolism of thiopurines, the optimal dose of these drugs varies. To determine a safe starting dose, we suggest evaluating patients for the thiopurine methyltransferase genotype (TPMT genotype) or phenotype (TPMT activity) prior to beginning treatment with 6-MP or AZA. TPMT is an enzyme that is essential in the metabolism of thiopurines. Approximately 90 percent of patients are homozygous for the allele TPMT 1 (ie, TPMT 1/1 genotype) and have normal or rapid metabolism of thiopurines. In contrast, 10 percent of patients have reduced TPMT activity (eg, TPMT 1/3a genotype) and metabolize thiopurines more slowly. These patients typically respond to much lower doses of the medication (eg, 0.5 mg/kg/day of 6-MP). Approximately 1 in 300 patients has absent TPMT activity (eg, TPMT 3a/3a genotype) and does not metabolize the medication. These patients are at high risk for pancytopenia and should not be treated with thiopurines. A second genetic polymorphism, in the NUDT15 gene (nudix hydrolase 15), has also been shown to correlate with neutropenia, particularly in Asian patients. Since not all genetic panels incorporate assessing for this genotype, monitoring of leukocyte counts remains important in IBD patients on thiopurines [141].

Efficacy — Clinical remission rates in patients treated with 6-MP and AZA monotherapy vary in clinical trials but are probably around 30 percent, as suggested by a large registry study in the United States [142]. Similar remission rates were reported for the SONIC trial in adults [47]. A considerably higher remission rate (90 percent at 18 months) was suggested by a smaller earlier trial in children with new-onset CD [143]. Overall, it is generally accepted that the remission rate for patients treated with 6-MP or AZA is lower than the remission rate for patients treated with anti-tumor necrosis factor (anti-TNF) antibodies, such as infliximab. (See "Overview of medical management of high-risk, adult patients with moderate to severe Crohn disease".)

Safety and monitoring — 6-MP and AZA are generally well tolerated by children. Toxicities of these drugs include some that are dose dependent (bone marrow suppression and hepatotoxicity) and others that are dose independent (eg, nausea, pancreatitis, infection, malignancy) [144]. Because of these issues, patients treated with 6-MP or AZA require frequent monitoring.

Monitoring and bone marrow suppression – Routine monitoring during thiopurine treatment can help to optimize dosing and reduce the risk of bone marrow suppression and hepatotoxicity, which are dose-dependent side effects. Mild leukopenia occurs in approximately 10 percent of children during treatment with thiopurines and responds to dose reduction [144]. Severe bone marrow suppression is a rare but potentially life-threatening side effect, usually associated with absent TPMT activity.

In our practice, we monitor patients by performing a complete blood count (CBC) and aminotransferase levels (alanine aminotransferase [ALT] and aspartate aminotransferase [AST]) before treatment and again at 2, 4, 8, and 12 weeks after initiating therapy. If the results are normal, we monitor every three months thereafter and two to three weeks after a change in dose. If significant leukopenia (white blood cell [WBC] count <3000) is detected, thiopurine treatment should be interrupted and/or the dose reduced.

If TPMT testing is not available, then a thiopurine may be started at a low dose, followed by close monitoring of CBC. Our protocol is to check the CBC biweekly for two months, then monthly for four more months; if the WBC count falls to between 2000 and 4000/mm3, we reduce the thiopurine dose by 50 percent [145]. If the WBC falls below 2000/mm3, we stop the thiopurine and check the CBC every 10 days until the WBC returns to normal, at which time a lower dose of thiopurine can be tried, if necessary.

Monitoring of blood levels of 6-TG (the active metabolite) and 6-methylmercaptopurine (6-MMP; the hepatotoxic metabolite) also can be helpful in assessing drug metabolism and compliance and in optimizing drug dosing [146,147]. However, there is a wide range of response (and toxicity) across a range of erythrocyte 6-TG levels. Therefore, genotyping and metabolite testing does not substitute for conventional laboratory monitoring for toxicity, with periodic measurements of a CBC and aminotransferases.

The target range for 6-TG is between 235 to 450 pmol/8 x 10(8) erythrocytes [146]. Patients with 6-TG above this range are at risk for bone marrow suppression, so the CBC should be monitored and consideration should be given to decreasing the dose.

Some patients who are rapid metabolizers will have high levels of 6-MMP (above 5000 pmol/8 x 10(8) erythrocytes). High 6-MMP levels are associated with an increased risk of elevated aminotransferases. For these patients, the addition of allopurinol in combination with a reduced 6-MP dose (decreased by at least 50 percent) can shunt metabolism away from the 6-MMP metabolite and toward increased 6-TG production by inhibiting the enzyme xanthine oxidase [148]. Thus, combination therapy of a lower dose of 6-MP with allopurinol can improve therapeutic effects and decrease hepatotoxicity. This approach has been shown to be effective in pediatrics, improving remission rates, decreasing corticosteroid use, and allowing patients to maintain on an oral therapy rather than escalating to an anti-TNF medication [149]. However, because combination treatment with allopurinol can raise the 6-TG level and lead to potentially life-threatening bone marrow suppression, it is important to monitor patients closely with CBC at 2, 4, 8, and 12 weeks until it is clear that there are no adverse effects on a stable dose of allopurinol and 6-MP. We do not recommend using an allopurinol and thiopurine combination unless monitoring of 6-TG and 6-MMP levels is readily available, due to the risk of high levels and myelosuppression. In our practice, we rarely utilize combination allopurinol and mercaptopurine due to the availability of other options to treat IBD.

The use of 6-MP and AZA in adults and details about metabolite monitoring are discussed in separate topic reviews. (See "Overview of azathioprine and mercaptopurine use in inflammatory bowel disease" and "Thiopurines: Pretreatment testing and approach to therapeutic drug monitoring for adults with inflammatory bowel disease".)

Infection – 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 a separate topic review. Acute Epstein-Barr virus (EBV) infection warrants temporary discontinuation of the thiopurine because mononucleosis in a patient on thiopurines may be associated with malignancy, as described below. (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'.)

Malignancy – 6-MP and AZA are also associated with a small increased risk of developing lymphoma, some of which are associated with infection with EBV [3,144,150-154]. The risk of lymphoproliferative disease is substantially increased in patients who develop primary EBV disease while on immunosuppressive therapy, particularly thiopurines [56]. As a result, some experts have suggested screening for EBV seropositivity prior to thiopurine treatment [155]. This is particularly relevant for adolescents since a majority will experience primary EBV infection in late adolescence or early adulthood [156]. However, there is no consensus about whether thiopurines should be avoided in patients who have not had primary EBV infection. The absolute risk of lymphoproliferative disease associated with thiopurines is probably very low (<1 per 1000 patient-years in one adult cohort [157]), but the risks in children and the relative risks for lymphoproliferative disease associated with thiopurines versus other immunosuppressive therapies have not been established. Some reassurance comes from a study in 192 pediatric patients who were seronegative for EBV when they began thiopurine treatment [158]. Seven patients (4 percent) experienced seroconversion to EBV, and most were symptomatic, but none developed EBV-associated lymphoproliferative disease.

In patients who are receiving thiopurines who develop active EBV infection (as documented by clinical symptoms, elevated EBV immunoglobulin M [IgM], and positive polymerase chain reaction [PCR]), immunosuppressive therapy should be stopped until the infection resolves, if possible. It is unclear if other immune-suppressive treatments (MTX, infliximab) should also be held in active EBV infection. The risk of lymphoma related to treatment with 6-MP/AZA in patients with CD is discussed separately. (See "Overview of azathioprine and mercaptopurine use in inflammatory bowel disease", section on 'Malignancy'.)

A small number of cases of HSTCL have been reported in adolescents and young adults during treatment with a combination of medicines known to suppress the immune system, including anti-TNF antibodies, AZA, and/or 6-MP; a few cases were in patients receiving AZA or 6-MP alone [83,85,159-163]. Most reported cases are in young males. Because HSTCL is otherwise extremely rare (approximately 100 cases have been reported in the literature), it is unlikely that these cases are due to chance alone. The thiopurine is thought to be the primary risk factor for HSTCL, both because some cases occurred on thiopurine monotherapy and because thiopurines are known to raise the risk of lymphoma; anti-TNF monotherapy is less likely to be associated with lymphoma, although data are limited [83]. The small risk of lymphoma must be weighed against the benefits of combination treatment, including better disease control and decreased rate of antibody formation, as discussed below [164]. (See "Overview of azathioprine and mercaptopurine use in inflammatory bowel disease", section on 'Malignancy' and 'Anti-TNF monotherapy versus combination therapy with an immunomodulator' above.)

Patients with IBD have an increased risk for melanoma and nonmelanoma skin cancer. Limited data suggest that nonmelanoma skin cancer may be most closely related to the use of thiopurines, while melanoma skin cancer may be more associated with anti-TNF therapy [83]. (See "Important health maintenance issues for children and adolescents with inflammatory bowel disease", section on 'Surveillance for cancer'.)

The true long-term risks of lymphoma and other malignancies in children receiving immunosuppressive therapies are unknown. Most available data suggest a mildly increased risk of malignancy in patients receiving these medications, but the actual risk remains low (eg, approximately 7 cases per 10,000 patient years) [74,111,165,166]. In addition, there is some uncertainty about which medications or combinations are associated with these malignancies. We and most other experts believe that in children with moderate to severe CD that is refractory to conventional treatment, the established benefit of these therapies generally exceeds the risk of a slight increase in chance of developing lymphoma. However, these potential benefits and risks should be explained in detail to the patient and family before selecting a therapy or combination therapy. (See 'Anti-TNF monotherapy versus combination therapy with an immunomodulator' above.)

Pancreatitis – Acute pancreatitis is an uncommon side effect of 6-MP and AZA, reported in approximately 5 percent of adults and 1 percent of pediatric patients using these drugs for IBD, representing a sixfold increase in risk compared with a relevant control group [144,167,168]. The risk appears to be limited to the first 90 days of treatment, is not dose dependent, and typically resolves when the drug is withdrawn [167].

Early use of thiopurines — Treatment with thiopurines early in the course of CD has been shown to reduce the likelihood of relapse. This was shown in a trial in children with newly diagnosed CD, in which children treated with 6-MP had reduced steroid use and fewer relapses compared with those treated with placebo [1,143]. However, this strategy is being used less frequently due to concerns about complications of thiopurines. Such complications include leukopenia, opportunistic infections, and an increased risk of lymphoma, as discussed above. Instead, use of thiopurines is typically limited to patients with a demonstrated need for maintenance therapy, such as those with moderate or severe CD or those who relapse when steroids are withdrawn. Even for this group of patients, there is a trend to select alternate immunosuppressive agents, including anti-TNF antibodies or MTX. (See 'Anti-tumor necrosis factor antibody medications' above.)

Methotrexate

Combination therapy – Intramuscular or subcutaneous MTX given once a week is a second-line therapy for maintenance of remission and is primarily used in combination with a biologic agent. Indeed, some clinicians prefer to use MTX rather than thiopurines for combination therapy because of concerns that combination treatment with thiopurines and anti-TNF antibodies may increase risk for lymphoma. A randomized controlled trial found that the combination of MTX and infliximab did not improve remission rates compared with infliximab alone, but the combination was associated with a reduced prevalence of antibodies to infliximab, raising the possibility that combination therapy may reduce loss of response to infliximab [121].

Monotherapy – MTX monotherapy is moderately effective in maintaining remission in children. A meta-analysis of 14 observational studies including 886 children reported a clinical remission rate of 58 percent at three to six months (95% CI 48-67 percent) and 37 percent at 12 months (95% CI 30-46 percent) [169]. In a retrospective review of 65 pediatric patients who initiated MTX maintenance monotherapy, 21 percent had mucosal healing, 49 percent of patients were in clinical remission, and 45 percent had changed to alternate therapies after one year [170]. Similar findings were seen in a meta-analysis of studies in adults, which concluded that patients receiving MTX had lower rates of disease relapse compared with those receiving placebo (65 percent versus 39 percent) [171]. (See "Overview of medical management of high-risk, adult patients with moderate to severe Crohn disease", section on 'Methotrexate'.)

MTX monotherapy probably has very limited benefit for inducing (as distinct from maintaining) remission, based primarily on studies in adults [172,173].

Dose and administration – MTX typically is given in children at a dose of 15 mg/m2 per week (up to a maximum of 25 mg per week, which is the dose used for adults) [2,174,175]. On occasion, slightly higher doses are used [176]. We suggest giving the drug subcutaneously for three to six months to ensure absorption. Patients who successfully enter remission may be switched to oral MTX, although no randomized trials are available to establish the efficacy of oral MTX [175,177-179]. The best available information comes from a multicenter retrospective study of subcutaneous versus oral MTX that demonstrated comparable one-year steroid-free clinical remission rates (overall steroid-free remission rate 34 percent) [179]. This study utilized propensity score modeling to adjust for the variables such as disease severity and MTX drug dose that might bias treatment selection (eg, less sick patients were treated with oral MTX, while sicker patients were treated with subcutaneous MTX, or higher doses given via the subcutaneous route). Interestingly, in this study, patients who were initially given subcutaneous MTX and converted to oral MTX had the highest remission rate (45 percent steroid-free remission), but this may reflect a center-specific effect because most such patients were treated at one hospital.

Adverse effects – Use of MTX is limited by its side effects, which include nausea, myelosuppression, oral ulcers, infection, pulmonary abnormalities, and hepatitis. Therefore, we recommend monitoring of the CBC and aminotransferases, as with thiopurine therapy. To minimize the nausea, MTX is given at bedtime; if nausea persists, it may be treated with medications such as ondansetron. We routinely give folic acid 1 mg daily because folic acid supplementation may reduce the likelihood of gastrointestinal symptoms, liver enzyme abnormalities, and oral ulcers [180].

MTX is strictly contraindicated in pregnancy and should be discontinued in both females and males at least three months prior to conception. (See "Major side effects of low-dose methotrexate", section on 'Prevention of side effects with folate'.)

Aminosalicylates — 5-aminosalicylate (5-ASA) medications may be used as maintenance therapy in children with mild CD (algorithm 1). They are generally well tolerated, but their efficacy in CD is unclear. There are no good randomized controlled trials of aminosalicylate treatment for mild CD in children, and it is unclear if these medications have any efficacy in moderate to severe CD.

The family of 5-ASA medications includes sulfasalazine, mesalamine, olsalazine, balsalazide, and mesalamine-Multi-Matrix (MMX), each of which has a 5-ASA moiety. The 5-ASA is readily absorbed throughout the small intestine; therefore, the parent compound generally must be modified for site-specific use in CD. Most of the studies of mesalamine preparations in CD are more than two decades old, did not utilize mucosal healing as an endpoint, and showed only mild efficacy over placebo. (See "Sulfasalazine and 5-aminosalicylates in the treatment of inflammatory bowel disease".)

All of these medications are designed to deliver the 5-ASA moiety to the colon, where the 5-ASA inhibits synthesis of proinflammatory prostaglandins and leukotrienes. The timed-release formulation (Pentasa) and pH-sensitive release formulation (Asacol) have enteric coatings that help to deliver medication to the proximal and distal small intestine, respectively, making these 5-ASA preparations potentially useful in the treatment of diffuse small bowel CD and Crohn ileocolitis [181]. (See "Sulfasalazine and 5-aminosalicylates in the treatment of inflammatory bowel disease".)

In adults, at least two 5-ASA agents (Pentasa and Asacol) were slightly superior to placebo (remission rate 40 percent for ASA versus 30 percent for placebo) in inducing remission in active CD. High doses of Pentasa (4 g/day, 16 pills a day) or Asacol (at least 3.2 g/day, 8 pills a day) must be used to achieve these modest effects [182]. Similarly, mesalamine has a slight benefit (risk difference for relapse 5 to 10 percent over placebo) in preventing relapses of CD in adults [183]. No pediatric studies have evaluated the efficacy of these medications in children with CD. (See "Overview of the medical management of mild (low risk) Crohn disease in adults".)

Most aminosalicylates other than sulfasalazine can be started in their full doses. Sulfasalazine should be started at a low dose (eg, 25 mg/kg/day) and increased gradually, according to the patient's tolerance, up to 50 to 75 mg/kg/day (maximum dose of 4 to 6 g/day). Because sulfasalazine competitively inhibits folate absorption, patients should be treated simultaneously with folate (1 mg/day) [184,185]. Sulfasalazine and olsalazine can be compounded into a suspension for young children to drink. It is recommended that other aminosalicylates be swallowed whole; however, capsules of Pentasa containing granules or balsalazide containing powder may be opened and administered by sprinkling the contents on soft food.

Aminosalicylates generally are well tolerated. Approximately 20 percent of patients will have dose-limiting side effects with sulfasalazine, with the most common adverse reactions being headaches, photosensitivity, and skin rash. Studies in adults have highlighted concerns about an association with renal disease, including interstitial nephritis [186]. Other side effects seen with sulfasalazine include a hypersensitivity reaction (manifested by fever, skin rash, and adenopathy), hepatitis, pancreatitis, leukopenia, and decreased sperm count. Other aminosalicylates also may have side effects (eg, rash, pancreatitis, proteinuria, interstitial nephritis, pneumonitis, pericarditis), but these are infrequent. Nevertheless, monitoring of patients on aminosalicylates should include CBCs (suggested frequency at least twice a year), creatinine, and urinalysis (suggested frequency at least annually to screen for interstitial nephritis). (See "Sulfasalazine and 5-aminosalicylates in the treatment of inflammatory bowel disease".)

Antibiotics — Antibiotics are important components of treatment for patients with abdominal abscess and are used in conjunction with percutaneous drainage [187]. (See "Overview of the management of Crohn disease in children and adolescents", section on 'Abdominal abscess'.)

Antibiotics also have a limited role in the treatment of mild active CD, both for patients with perianal disease [3] and also for those with colonic disease [2]. Agents such as ciprofloxacin or metronidazole have efficacy comparable to aminosalicylates in the treatment of mild active CD [188]. Combination therapy with azithromycin and metronidazole was explored in a randomized trial in children with mild or moderate CD, in which 66 percent of patients treated with combination therapy achieved remission at eight weeks compared with 39 percent for those on metronidazole monotherapy [189]. This response to antibiotics in children appears to be better than that for adults. Limitations of this study include the absence of a maintenance arm and lack of data on endoscopic remission. Nevertheless, this remains a potential option for patients in whom the clinician wishes to avoid immunosuppression or who do not respond to other therapies.

Limited evidence suggests that antibiotics may have a role as "salvage" therapy in patients with refractory colonic disease. This was shown in a case series of 63 patients with ileocolonic or colonic disease (43 percent CD, 36 percent ulcerative colitis, 21 percent IBD-unclassified) who were failing anti-TNF treatment and were refractory to or dependent on glucocorticoids, in whom a combination antibiotic regimen achieved a clinical response in more than 60 percent and remission in 40 percent [190]. Among the subset of patients with acute severe colitis, 27 percent (7 of 26 patients) achieved remission. These findings suggest that combination antibiotics may be useful to induce remission during transition to a maintenance medication with delayed onset of efficacy, such as vedolizumab.

The primary side effects of metronidazole are metallic taste, nausea, a disulfiram reaction if taken with alcohol, peripheral neuropathy with long-term use, and a possible risk for fetal effects if taken during early pregnancy (see "Metronidazole: An overview", section on 'Toxicity'). Ciprofloxacin is generally reserved for more resistant organisms because resistance can develop during therapy [187]. Ciprofloxacin is generally well tolerated; reported side effects include stomach upset, allergic reactions, increased risk for Clostridioides difficile infection, and tendonitis or tendon rupture. Treatment with rifaximin has been associated with modest improvement in preliminary studies in adults [191]. Adverse effects of azithromycin include gastrointestinal side effects, hepatotoxicity, and QT prolongation. (See "Overview of the management of Crohn disease in children and adolescents", section on 'Perianal disease' and "Overview of the medical management of mild (low risk) Crohn disease in adults", section on 'Antibiotics' and "Azithromycin and clarithromycin", section on 'Adverse reactions'.)

Other medications — A variety of therapies have been used for patients not responding to any of the above agents [3,50]. Most of the available information about these therapies comes from studies in adults, and treatment decisions in pediatric patients are made on a case-by-case basis. Given the potential toxicities of these potent immunosuppressive agents and/or limited evidence of benefit, we suggest they be reserved either for patients enrolled in a clinical trial or for patients who have not responded to immunomodulators or to the biologic agents described above. (See 'First-line biologic agents' above and 'Second-line biologic agents' above.)

CertolizumabCertolizumab pegol consists of the antigen-binding (Fab) fragment of a humanized anti-TNF monoclonal antibody, which is covalently attached to a polyethylene glycol moiety to increase the half-life. It is a second- or third-line anti-TNF agent for CD in adults, typically used for those who responded to infliximab or adalimumab, then lost response due to development of antibodies, or became intolerant to these drugs (eg, infusion reactions or lupus-like reactions). One relatively rare instance where certolizumab is particularly helpful is as rescue therapy in patients who develop infliximab-induced lupus (symmetric large joint arthralgias, high-titer antinuclear antibodies [ANA] and anti-double-stranded DNA antibodies). Discontinuing infliximab and switching to certolizumab or adalimumab has been shown to manage CD symptoms without leading to recurrence of the infliximab-induced lupus [192]. Certolizumab is administered subcutaneously. Induction dosing for adults is 400 mg at weeks 0, 2, and 4, followed by 400 mg every four weeks for maintenance of remission. (See "Overview of medical management of high-risk, adult patients with moderate to severe Crohn disease", section on 'Choice of anti-TNF agent'.)

There are no pediatric studies of certolizumab to date. When studied in adults with moderate to severe luminal CD, remission (defined by a Crohn disease activity index [CDAI] <150) by week 6 was 22 percent for certolizumab and 17 percent for placebo, and response (defined as a decrease in CDAI of 100 points) by week 6 was 35 percent to certolizumab and 27 percent to placebo [193]. Response rates are somewhat lower for patients previously exposed to anti-TNF therapies [193,194].

GolimumabGolimumab is a recombinant human monoclonal antibody that neutralizes TNF-alpha activity. It is currently approved for adults with rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis and has been approved for adults with ulcerative colitis but not CD. (See "Overview of dosing and monitoring of biologic agents and small molecules for treating ulcerative colitis in adults", section on 'Golimumab'.)

ThalidomideThalidomide, an inhibitor of both TNF and angiogenesis, has been used off-label to treat refractory IBD for more than a decade. Published case series, our own clinical experience, and a randomized trial suggest that it is an effective agent [195-197]. Toxicities include neuropathy, leukopenia, and profound congenital anomalies in the offspring of women who took thalidomide during pregnancy. For this reason, thalidomide is tightly monitored and regulated.

TacrolimusTacrolimus was effective in randomized trials in adults with refractory CD and observational studies in children but generally does not yield long-term remission, and the renal toxicity of this agent limits its long-term use [198-200].

CyclosporineCyclosporine has been effective in the acute treatment of fistulizing disease in adults, but the effect is highly variable, and it is probably not helpful in maintaining remission [201].

Complementary and alternative therapies — Patients often seek advice from practitioners of alternative medicine. In surveys of children with CD from six different IBD centers in the United States, 40 to 50 percent were using therapies not prescribed by their clinician [202-204]. The clinician should inquire about the use of herbs and dietary supplements since some of these complementary therapies may have gastrointestinal side effects [202]. The National Institutes of Health's National Center for Complementary and Integrative Health provides reliable information on complementary and alternative medicine practices. (See "Complementary and integrative health in pediatrics".)

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: Crohn disease in children (The Basics)")

Beyond the Basics topic (see "Patient education: Crohn disease (Beyond the Basics)")

SUMMARY AND RECOMMENDATIONS

Overview – For Crohn disease (CD) affecting the ileum and/or colon, a variety of medications are available (table 1). The choice of medication typically depends on disease location, severity, and response.

These therapies can be grouped as induction therapies, which have relatively rapid onset of action, and maintenance therapies, which are appropriate for long-term use. Some of these therapies are appropriate for both induction and maintenance. An approach to selecting among these medications is summarized in the algorithms (algorithm 1 and algorithm 2) and discussed in more detail in a separate topic review. (See "Overview of the management of Crohn disease in children and adolescents", section on 'Selection of medical treatment'.)

Induction therapy – The main options are:

Glucocorticoids – Systemic glucocorticoids are appropriate for induction in moderate to severe CD [1]. In the United States, glucocorticoids are a common initial treatment for the acute therapy. (See 'Glucocorticoids' above.)

Exclusive or partial enteral nutrition – Exclusive enteral nutrition (EEN) is an appropriate approach for induction in patients with moderate to severe CD, especially for those with extensive small bowel involvement or growth failure. This approach is common in Canada, the United Kingdom, and Europe and less widely used in the United States. Partial enteral nutrition combined with a specific exclusion diet (CD exclusion diet) is an emerging strategy that may be more easily accepted by patients. (See 'Exclusive or partial enteral nutrition' above and "Overview of the management of Crohn disease in children and adolescents", section on 'Nutritional therapy'.)

Infliximab or adalimumabInfliximab or adalimumab can be used for induction or maintenance therapy. They are sometimes used for initial medical treatment of high-risk patients with severe disease or for those with moderate disease, due to patient preference and other patient-specific considerations. (See 'Anti-tumor necrosis factor antibody medications' above.)

Aminosalicylates – Aminosalicylates may be appropriate for induction and maintenance in mild ileocolonic CD, but data about their efficacy for treating this phenotype are limited. (See 'Aminosalicylates' above.)

Maintenance therapy – The main options are:

Infliximab or adalimumab – The main biologic agents used for CD in children are infliximab or adalimumab (or their biosimilars), which are anti-tumor necrosis factor (anti-TNF) antibodies and can be used for both induction and maintenance. (See 'First-line biologic agents' above.)

The relative risks and benefits of monotherapy with an anti-TNF antibody versus combination therapy with an immunomodulator (eg, 6-MP) remain unclear. In adults, combination therapy with an immunomodulator and biologic is more effective than use of either agent individually. A plain-language summary to guide discussions about treatment decisions is outlined in the table (table 6). (See 'Anti-TNF monotherapy versus combination therapy with an immunomodulator' above.)

Immunomodulators – Immunomodulators used for CD are thiopurines (6-mercaptopurine [6-MP] or azathioprine [AZA]) and methotrexate (MTX). These are appropriate only for maintenance because of delayed onset of action. (See 'Mercaptopurine and azathioprine' above and 'Methotrexate' above.)

Aminosalicylates – These have low efficacy and low toxicity, are used primarily for mild CD, and are appropriate for induction and maintenance. The choice of agent depends on disease location. (See 'Aminosalicylates' above.)

Antibiotics – Antibiotics are important components of treatment for patients with abdominal abscess and are used in conjunction with percutaneous drainage. Oral antibiotics such as ciprofloxacin and metronidazole also have a limited role in the treatment of mild active CD, especially for patients with perianal disease but also for those with colonic disease. (See 'Antibiotics' above.)

Other medicationsVedolizumab and ustekinumab are newer biologics with different mechanisms of action. Because of limited pediatric data, these drugs are used for nonresponders to immunomodulators and anti-TNF antibodies. A variety of other therapies, including certolizumab, golimumab, thalidomide, and tacrolimus, have been used for patients not responding to any of the above agents. Of note, use of second-line biologic agents and/or escalation of doses beyond those approved by the US Food and Drug Administration (FDA) may be appropriate and medically necessary for selected children with CD. (See 'Second-line biologic agents' above and 'Other medications' above and 'Medical necessity of off-label use of medications in pediatrics' above.)

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Topic 120380 Version 18.0

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