Peak inflammatory bowel disease (IBD) onset typically occurs during adolescence. An estimated 3 million patients are affected by IBD in the United States, with approximately 25% of those patients diagnosed before age 20 years.1 Because of the potential for malnutrition and delayed growth, early diagnosis, followed by appropriate treatment, is critical in children and adolescents with the disease.1
“Clinicians, gastroenterologists, and pediatricians need to screen for, prevent, and treat [the] unique medical and psychosocial comorbidities associated with IBD in this unique age group,” wrote Joshua M. Steinberg, MD, of the department of gastroenterology, MedStar Georgetown University Hospital, and Aline Charabaty, MD, of the department of gastroenterology at the Johns Hopkins School of Medicine and Sibley Memorial Hospital.1 “Special considerations need to be taken in the choice of therapy and monitoring in adolescents and encouraging compliance… is critical to treatment success.”1
In a review published in Current Gastroenterology Reports,1 Drs Steinberg and Charabaty conducted a review of specific IBD manifestations, health maintenance issues, and treatment considerations for an adolescent patient population.
Health Maintenance Considerations
Health maintenance domains span a range of systems and include growth, pubertal development, cancer screening, and psychosocial health. A review of each domain is outlined below.
Linear Growth and Pubertal Development
One of the most common issues faced by children and adolescents with IBD is growth failure associated with delayed puberty.2 Causes of this delay are multifactorial and are inclusive of malnutrition, malabsorption, increased gastrointestinal losses, increased caloric needs, proinflammatory cytokines-induced growth hormone resistance, and the use of corticosteroids.1 Growth failure can be insidious, according to Drs Steinberg and Charabaty, and can precede gastrointestinal symptoms by several years.1 These symptoms are more common in patients with Crohn disease compared with ulcerative colitis (40% vs 10%).1
To address this issue, treatment must be appropriate and multidisciplinary in nature. Targeting active disease, limiting steroid use, and referring the patient to a pediatric endocrinologist and a dietitian are all considered essential.1 Height, weight, and body mass index (BMI) should be recorded at every office visit because changes in these measures might be indicative of relapse.1
Peak bone mass in healthy boys and girls is reached at 16 and 18 years of age, respectively; however, bone metabolism in IBD is frequently complicated by delayed puberty, malnutrition, decreased intake of vitamin D-rich foods, malabsorption, low BMI, active inflammation, and corticosteroid use.1,3
According to International Society of Clinical Densitometry recommendations, pediatric patients with IBD should undergo a total body and lumbar spine dual-energy X-ray absorptiometry scan.1 This is particularly valuable for patients with low BMI, severe disease, and evidence of malnutrition. The z score can be a helpful measure of bone mineral density deviation by further identifying patients who would benefit from a referral to a pediatric endocrinologist. If further bone health-targeted interventions are necessary, clinicians can consider targeted improvement of nutrition, calcium, and vitamin D supplemental intake and the use of weight-bearing exercises as tolerated.1
Diet and Vitamin Deficiencies
Active disease, chronic blood loss, malabsorption, associated lactose intolerance, and poor oral intake are all associated with an elevated risk for mineral and vitamin deficiencies. Providers should implement early vitamin and mineral level assessments and should encourage consumption of foods that are both nutrient-dense and rich in calcium, vitamin D, iron, folate, and vitamin B12.1
Patients with Crohn disease with ileal or small bowel disease or a history of intestinal resection should have levels of vitamin B12, folate, and zinc checked yearly because, as Drs Steinberg and Charabaty noted, low alkaline phosphate can be an indicator of zinc deficiency.1 A consultation with an IBD-registered dietitian can be “extremely valuable” in helping adolescents discover healthy dietary choices that are both tolerable and enjoyable.1
“Despite widespread vaccination awareness among patients and clinicians, many adolescents with IBD do not receive appropriate immunizations in a timely fashion,” wrote Drs Steinberg and Charabaty.1,4
Adolescents with IBD should receive all inactivated vaccines. These vaccines include tetanus toxoid-reduced diphtheria toxoid-acellular pertussis adsorbed, human papillomavirus (HPV), meningococcal conjugate vaccine, hepatitis A and B, and inactivated polio.
“Immunization against hepatitis B is particularly important when considering the initiation of an [anti-tumor necrosis factor (TNF)] agent or other advanced therapies,” Drs Steinberg and Charabaty noted.1
In addition, yearly influenza and regular pneumococcal vaccines are recommended in adolescents being treated with immunosuppressive therapies that may increase the patient’s risk for pneumonia or upper respiratory infections.1,4
Live vaccines, including varicella and MMR, should be administered and brought up to date before the initiation of any immunosuppressive therapy; immunosuppressive therapies are defined as “≥ prednisone, 2 mg/kg/day or equivalent, or prednisone 20 mg/day or equivalent, for ≥ 14 days, cyclosporine, tacrolimus, thiopurines, methotrexate, or advanced therapies (biologics and synthetic small molecules)”1; however, no immunosuppressive therapy should be administered either 3 months before or 6 weeks after live virus vaccine administration.1
Adolescents with IBD should be encouraged to avoid smoking, and adolescents who are already smokers should be encouraged to enroll in a smoking cessation program because smoking increases flare risk, complications, and disease recurrence, particularly in patients with Crohn disease.1 In light of their current popularity, use of electronic cigarettes should also be discouraged.1
Within this patient population, adolescents commonly turn to their gastroenterologists for contraceptive advice and guidance.1
Although oral contraceptive pills have been associated with an increased risk for IBD development, the use of these pills in patients with current IBD has not been associated with an increased risk for flare1; however, Drs Steinberg and Charabaty noted that estrogen-based contraceptives, including hormonal combination oral contraceptive pills, the patch, or the ring may increase the risk for venous thromboembolism (VTE) by 2-fold.1 No increased risk has been noted with progestin-only methods, including the pill, implants, or an intrauterine device (IUD), or with a copper IUD.
“The choice of contraceptive methods should be a shared decision with input from the patient, the gynecologist, and the treating gastroenterologist, taking into account efficacy, tolerability, and risk of VTE,” Drs Steinberg and Charabaty noted.1,5
In terms of fertility, adolescent girls who undergo total colectomy and ileal pouch anal anastomosis for ulcerative colitis are at an increased risk for infertility in the future, which should be discussed when considering surgery.1
Cancer Screening and Cancer Prevention
After 7 to 10 years of disease, patients with either ulcerative colitis or Crohn colitis that involves more than one-third of the colon have an increased risk for colon cancer development.1 Surveillance colonoscopy should be implemented, particularly in patients who were diagnosed with IBD as children. Persons with IBD and primary sclerosing cholangitis should undergo surveillance colonoscopy at diagnosis and should be screened for cholangiocarcinoma, hepatocellular carcinoma, and gallbladder cancer.1
Both anti-TNF therapies and thiopurines have been associated with an increased risk for melanoma and nonmelanoma skin cancers, respectively. Annual skin checks and appropriate sun protection practices should be encouraged.1
Adolescent girls treated with thiopurines are at an increased risk for cervical dysplasia. The HPV vaccine is strongly recommended for both boys and girls, and routine pap smears should be conducted in patients who are sexually active.1
“At a time of life transition and self-discovery… IBD can have a deeply profound impact on the psychosocial development of adolescents,” wrote Drs Steinberg and Charabaty. “Multiple factors including the chronic nature of the disease, the unpredictability of flares and complications and fatigue… and the effect on physical appearance can all negatively impact the adolescent’s athletic, social, and emotional life.”1
Clinical visits, diagnostic tests, and infusion therapies represent particular challenges for adolescents, who often feel they are expected to perform and excel across academic and extracurricular spheres and also to portray positive experiences on social media. These considerations should be taken into account when addressing adolescents’ psychosocial health overall.
Depression, anxiety, and social isolation occur in up to 25% of adolescents with IBD.6 Left untreated, anxiety and depression can lead to poor compliance with prescribed therapies and subsequent recurrence of IBD symptoms.1
“Encouraging adolescents to connect with other teenagers with IBD… and to get involved in IBD advocacy work can help create a support network, as well as empower adolescents into making positive changes in… and overall improve their quality of life,” Drs Charabaty and Steinberg noted.1
Medical therapy goals have shifted in recent years, from focusing on symptom reduction to now include inducing and maintaining steroid-free remission, disease and therapeutic complication progression, restoration of growth and pubertal development, and overall improvement of quality of life and psychosocial wellness; however, during periods of wellness, compliance with prescribed medications and follow-up can be especially challenging.1
During periods of disease flare, corticosteroids are typically used to induce remission; rates of complete remission have reached 58% after 1 month of therapy1,7; however, steroid therapy is not appropriate for maintenance therapy because of significant adverse event risks and limited efficacy in inducing mucosal healing or maintaining remission. Among adolescents in particular, limiting steroid use is important because of the inhibitory effects on both linear growth and bone density, among other physical and emotional disruptions.
Sulfasalazine can be an effective and cheap therapy but is often poorly tolerated.1 Adverse effects — inclusive of fevers, rash, headache, gastrointestinal distress, and nausea — may lead to poor compliance in adolescents. Newer sulfasalazine and aminosalicylate drugs are sulfa-free and are generally well tolerated, safe, and effective for inducing and maintaining remission in ulcerative colitis; however, these drugs are not efficacious in Crohn disease.1,8
Exclusive enteric nutrition (EEN) involves the exclusive use of “specific elemental, semi-elemental, or polymeric formulas” to provide 120% to 150% of the total daily recommended energy intake. EEN has been found to induce clinical remission and mucosal healing in a significant proportion of patients with newly diagnosed pediatric Crohn disease.1,9 In contrast to steroids, EEN has a positive effect on linear growth and is not associated with any serious systemic adverse effects.1
Partial enteric nutrition (PEN) involves the use of liquid formula to cover 25% to 50% of a patient’s total daily requirements in conjunction with normal daytime diet.1 PEN can be effective maintenance therapy when used alone or in combination with other medical therapies.1
Thiopurines, which include azathioprine and mercaptopurine, are immunomodulators used to maintain steroid-induced remission in Crohn disease and ulcerative colitis. Azathioprine is slow acting and not appropriate for remission induction.1 Before initiating a thiopurine therapy, the thiopurine methyltransferase genotype or phenotype should be checked for relative risk for myelosuppression.1 After initiating therapy, frequent blood count and liver enzyme monitoring should be performed; it should be repeated after dose escalation and regularly thereafter.1
Previously, methotrexate was underused in IBD management; however, it is now more frequently used because of the small increased lymphoma risk associated with thiopurine therapy. Methotrexate is prescribed either as monotherapy or in combination with anti-TNF therapies to prevent antidrug antibody formation. Methotrexate dosage in pediatric populations generally ranges from 10 to 17.5 mg/m2 once per week, with a maximum dose of 25 mg/m2/wk administered either subcutaneously or orally. After 3 to 6 months of remission, the maintenance dose can be decreased to 10 mg/m2/wk. Daily folic acid 1 mg should be taken to minimize gastrointestinal adverse effects and leukopenia.1
Advanced therapies include anti-TNF treatments, vedolizumab, ustekinumab, tofacitinib, and tacrolimus. Monoclonal anti-TNF therapies have “revolutionized” care and treatment strategies in IBD.1 Infliximab and adalimumab specifically have been approved by the US Food and Drug Administration for the treatment of moderate to severe Crohn disease and ulcerative colitis in pediatric populations.1
Anti-TNF agents should be considered first-line therapies in patients with severe disease, perianal disease, associated extra-intestinal manifestations, and significant growth failure in disease refractory to induction with steroids.1
No particular medical preference exists for specific anti-TNF therapy; as such, adolescent choice for delivery method — intravenous or subcutaneous — should be taken into account, as well as lifestyle, comfort level with injections, and therapeutic compliance.1
“Positive effects of anti-TNF agents can translate into less sick days away from school, friends, and extracurricular activities, which is particularly important to adolescents craving to have a ‘normal teenage life’ and complete scholarly and extracurricular activities,” Dr Charabaty wrote.1
Vedolizumab is an α4β7 anti-integrin monoclonal antibody that prevents the binding of circulating leukocytes to the endothelial surface and migration into the inflamed gut mucosa. Vedolizumab received approval in 2014 to treat moderate to severe Crohn disease and ulcerative colitis in adult patients who are biologic-naïve or who have failed anti-TNF therapies.1 Limited data are available in pediatric populations, although 1 European retrospective multicenter study found that vedolizumab was safe and effective in 64 children with IBD refractory to anti-TNF therapies.10
Ustekinumab inhibits the activity of interleukins 12 and 23 through binding to the common subunit p40. Ustekinumab received approval in 2016 and 2019 for Crohn disease and ulcerative colitis, respectively, in patients who are either anti-TNF-naïve or who failed anti-TNF therapies.1 Current literature is limited to case reports across pediatric populations. One study of 52 children and adolescents highlighted a positive safety profile, a patient-friendly dosing schedule, and efficacy in treating associated conditions, including arthritis and psoriasis.11
Tofacitinib blocks the JAK-STAT inflammatory pathway and was recently approved to treat adults with moderate to severe ulcerative colitis.1 There is only limited experience with tofacitinib use for ulcerative colitis treatment in pediatric and adolescent populations. Similarly, limited data exist on the use of tacrolimus, an immunosuppressive agent, in pediatric refractory Crohn disease or ulcerative colitis.1
Conclusions and Looking Forward
Despite positive forward movement, IBD care in adolescent populations still poses particular challenges. The recognition of unique IBD manifestations and health maintenance issues specific to adolescent patients, as well as the use of a multidisciplinary approach, are crucial for success.1
“A strong patient-physician relationship and adequate familial and social support are crucial to promote compliance and help the adolescent to progressively take ownership of the disease and acquire self-management skills prior to transitioning to adult care,” Drs Steinberg and Charabaty concluded.1
Disclosure: Several study authors declared affiliations with the pharmaceutical industry. Please see the original reference for a full list of authors’ disclosures.
1. Steinberg JM, Charabaty A. The management approach to the adolescent IBD patient: Health maintenance and medication considerations. Curr Gastroentreol Rep. 2020;22(1):5.
2. Sanderson, IR. Growth problems in children with IBD. Nat Rev Gastroenterol Hepatol. 2014;11(10):601-610.
3. Laakso S, Valta H, Verkasalo M, Toiviainen-Salo S, Viljakainen H, Mäkitie O. Impaired bone health in inflammatory bowel disease: a case-control study in 80 pediatric patients. Calcif Tissue Int. 2012;91(2):121-130.
4. Bousvaros A, Lu Y. Immunizations in the child with inflammatory bowel disease. In: Mamula P, Grossman AB, Baldassano RN, Kelsen JR, Markowitz JE, eds. Pediatric Inflammatory Bowel Disease. Basel, Switzerland: Springer International Publishing AG; 2017.
5. Limdi JK, Farraye J, Cannon R, Woodhams E, Farraye FA. Contraception, venous thromboembolism, and inflammatory bowel disease: What clinicians (and patients) should know. Inflamm Bowel Dis. 2019;25(10):1602-1612.
6. Mackner LM, Whitaker BN, Maddux MH, et al. Depression screening in pediatric inflammatory bowel disease: recommendations and a toolkit for implementation. J Pediatr Gastroenterol Nutr. 2020;70(1):42-47.
7. Faubion WA Jr, Loftus EV Jr, Harmsen WS, Zinsmeister AR, Sandborn WJ. The natural history of corticosteroid therapy for inflammatory bowel disease: a population-based study. Gastroenterology. 2001;121(2):255-260.
8. Lim WC, Wang Y, MacDonald JK, Hanauer S. Aminosalicylates for induction of remission or response in Crohn’s disease. Cochrane Database Syst Rev. 2016;7:CD008870.
9. Borrelli O, Cordischi L, Cirulli M, et al. Polymeric diet alone versus corticosteroids in the treatment of active pediatric Crohn’s disease: a randomized controlled open-label trial. Clin Gastroenterol Hepatol. 2006;(6):744-753.
10. Ledder O, Assa A, Levine A, et al. Vedolizumab in paediatric inflammatory bowel disease: a retrospective multi-centre experience from the Paediatric IBD Porto Group of ESPGHAN. J Crohns Colitis. 2017;11(10):1230-1237.
11. Dayan JR, Dolinger M, Benkov K, et al. Real world experience with ustekinumab in children and young adults at a tertiary care pediatric inflammatory bowel disease center. J Pediatr Gastroenterol Nutr. 2019;69(1):61-67.