Ulcerative Colitis in Children Treatment & Management: Approach Considerations, Treatment of Mild Disease, Treatment of Moderate-to-Severe Disease (original) (raw)

Treatment

Approach Considerations

The general goals for managing inflammatory bowel disease (IBD) in children are to achieve the best possible clinical and laboratory control of the disease with minimal adverse effects while permitting the patient to function as normally as possible. [20]

Most patients with ulcerative colitis (UC) can be treated on an outpatient basis. Nevertheless, hospitalization is necessary when maximal outpatient therapy is unsuccessful or when patients develop severe disease.

For more information on the general treatment of ulcerative colitis, see Ulcerative Colitis.

See also the Guidelines section for recommendations by the American College of Gastroenterology and the American Gastroenterological Association.

Consultations

For patients presenting with the symptoms of ulcerative colitis, consultations are indicated with a pediatric gastroenterologist and, in more severe cases, a pediatric surgeon.

Long-term monitoring

In children who have chronic inflammatory changes in the pouch reservoir, annual screening endoscopy should be performed. If no inflammation is present, screening endoscopy may be performed every 2 years. [21]

Treatment of Mild Disease

Mild ulcerative colitis (UC) in the pediatric population can be treated with pharmacotherapy, most commonly anti-inflammatory agents.

5-Aminosalicylic acid

The mainstay of outpatient management is anti-inflammatory therapy with 5-aminosalicylic acid (5-ASA) preparations. [22] Sulfasalazine (Azulfidine) was the first such preparation available for the treatment of UC. More recently, mesalamine (Pentasa, Asacol, Lialda) was introduced. Mesalamine may have fewer adverse effects than sulfasalazine because the sulfa component has been removed; it is not available in a pediatric preparation, however.

Asacol tablets must be swallowed whole, which limits its use in young children. However, Asacol is the only oral product that is approved for children aged 5 years or older.

Asacol's efficacy was evaluated in a 6-week treatment study of two dose levels in 82 pediatric patients aged 5-17 years with mildly to moderately active ulcerative colitis. All patients were divided by weight category (17 to < 33 kg, 33 to < 54 kg, and 54 to 90 kg) and randomly assigned to receive a low dose (1.2, 2.0, and 2.4 g/day for the respective weight category) or a high dose (2.0, 3.6, and 4.8 g/day). Baseline and screening visits were followed by a treatment period of 6 weeks. The high dose was not more effective than the low dose and is not an approved dosage. At week 6, 73.2% of the patients in the low dose group, and 70.0% of the patients in the high dose group achieved success based on the TM-Mayo; 34.1% of the patients in the low dose group and 42.5% of the patients in the high dose group achieved complete response. [23]

Pentasa capsules may be opened so that the granules can be swallowed from a spoon (eg, mixed with applesauce), but this exposes the medicine to degradation high in the gastrointestinal tract—an area that is not affected in UC. Balsalazide (Colazal) is another form of 5-ASA that is active in only the colon.

Lialda uses a multimatrix (MMX) release system, is pH dependent, and includes an expedient that further slows the release of 5-ASA throughout the entire colon.

Rectal therapy may be helpful. Many symptoms of UC, such as urgency and tenesmus, are secondary to rectal disease or left-sided colitis. 5-ASA suppositories alone for ulcerative proctitis and distal proctosigmoiditis are useful in inducing remission, with reported rates as high as 70-80%.

A statement from the European Society for Paediatric Gastroenterology Hepatology and Nutrition (ESPGHAN) recommends the following [7] :

• Mild-moderate UC: Use oral 5-ASA compounds as first-line induction and maintenance therapy.
• Combined oral and rectal 5-ASA therapy are more effective than oral 5-ASA monotherapy.
• Reserve rectal monotherapy for mild-to-moderate ulcerative proctitis (uncommon pediatric phenotype).
• 5-ASA is preferred over steroids when rectal therapy is used.

Probiotics as potential treatment

Probiotics are defined as live microbial food products that have beneficial effects on the host. Probiotics have been suggested as potential treatments for numerous digestive disorders; whether they are effective treatments remains controversial, however.

In an investigation of a specific probiotic preparation, subjects in the treatment group achieved a 93% remission rate versus 36% in the control group, with a lower relapse rate at 1 year seen in the treatment group as well (21% vs 73%). [24]

Probiotics may represent an appealing adjunct to other treatments, given their low propensity for side effects.

Probiotics may have a more important role with pouchitis in patients with ulcerative colitis.

Treatment of Moderate-to-Severe Disease

Acute flares of moderate to severe ulcerative colitis (UC) in the pediatric population tend to respond well to corticosteroids, but numerous adverse effects limit long-term use. Immunomodulatory agents, such as 6-mercaptopurine, are useful in patients who are steroid-dependent or who have disease that is refractory to steroid treatment. These drugs can take up to 3-months to take effect, however, severely limiting their usefulness in acute exacerbations of disease.

Corticosteroids

Corticosteroids (eg, prednisone) are effective in controlling acute flares of disease but long-term use is not desirable owing to numerous adverse effects.

Corticosteroids are known to cause linear growth failure, which may already be a clinically significant problem in the young patient with inflammatory bowel disease. Corticosteroids also cause osteoporosis, which leads to compression fractures of the spine. The many undesirable cosmetic effects of corticosteroids include weight gain, acne, and cushingoid appearance. Steroids may cause agitation and restlessness, as well as personality changes, such as irritability or emotional lability.

Despite the undesirable adverse effects, some patients depend on steroids to keep their disease under control. In other patients, the disease does not respond well to steroids. When a UC patient demonstrates signs of steroid dependence, other treatments should be used to limit the patient's steroid exposure.

Intravenous corticosteroids (eg, methylprednisolone) may be effective in inducing remission when oral steroids are ineffective. Significantly increased efficacy does not appear to occur with doses above 2 mg/kg/d (not to exceed 48 mg/d). High-dose intravenous steroids have the adverse effects of oral steroids and increase the likelihood of hyperglycemia and hypertension.

The ESPGHAN recommendations for corticosteroids include the following [7] :

• Oral steroids: Use as second-line treatment for mild-moderate UC not responding to 5-ASA (oral/ rectal); may be considered as first line in the higher end of the moderate disease range
• Severe UC: Treat with intravenous steroids
• Mild disease refractory to 5-ASA before oral prednisolone: Consider second-generation oral steroids with lower systemic effect (eg, beclomethasone dipropionate (BDP) and budesonide-MMX; evidence for budesonide-MMX supportive only for left-sided colitis)
• For maintaining remission, apply steroid-sparing strategies rather than using steroids

Immunomodulatory agents

Immunomodulatory agents are purine analogs that inhibit purine ribonucleotide synthesis and cell proliferation. Immunosuppressive agents also inhibit the immune response of natural killer cells and cytotoxic T cells.

Use immunomodulatory agents, such as 6-mercaptopurine (Purinethol) and azathioprine (Imuran), in patients with inflammatory bowel disorder who are steroid-dependent or whose disease is refractory to steroid treatment. These medications take approximately 3 months to take full effect and, therefore, are not useful in acute exacerbations of disease.

Although immunomodulatory agents are usually well tolerated, they do have the potential adverse effects of pancreatitis, hepatitis, and bone marrow suppression. The pancreatitis is usually an idiosyncratic reaction that is not dose related and that resolves on removal of the drug. The hepatitis appears to be related to the buildup of a metabolite of the medication and may resolve when the dose is adjusted. Bone-marrow suppression is dose related and may have delayed onset.

Monitor patients for leukopenia on a frequent basis early in the course of therapy and then less frequently in the months that follow.

The ESPGHAN recommendation for immunomodulators include the following [7] :

• Thiopurines: Use to maintain remission in children who are corticosteroid-dependent or who relapse frequently (≥2 relapses per year) despite optimal 5-ASA treatment, as well as in patients intolerant to 5-ASA; consider thiopurines after discharge from an episode of acute severe colitis
• Do not use thiopurines for induction of remission in pediatric UC patients
• Measure thiopurine metabolites in patients with incomplete response on a stable thiopurine dosage, in those who present with leukopenia or elevated transaminases, or if poor compliance is suspected

Biological treatment

ESPGHAN recommendations on biologic treatment include the following [7] :

• Consider infliximab (IFX) in the setting of chronically active or steroid-dependent UC, uncontrolled by 5-ASA and thiopurines, for both induction and maintenance of remission
• Consider adalimumab or golimumab in those with an initial response but who then lose response or are intolerant to IFX, based on serum levels and antibodies
• There is no role for adalimumab and golimumab in patients with primary nonresponse to IFX
• After anti-TNF failure, consider vedolizumab in chronically active or steroid-dependent patients as second-line biologic therapy

Other interventions

ESPGHAN recommendations on other interventions include the following [7] :

• Do not routinely use granulocyte/monocyte apheresis nor fecal microbiota transplantation (FMT) in pediatric UC
• Do not routinely use antibiotics for induction or maintenance of remission of pediatric UC
• Clinicians may consider probiotic agents (eg, VSL#3, E coli Nissle 917) in mild UC as adjuvant therapy or in those intolerant to 5-ASA
• Clinicians may consider curcumin as add-on therapy for inducing and maintaining clinical remission of mild-to-moderate UC
• The following are not recommended as primary treatment: Germinated barley foodstuff, omega-3, aloe vera, herbal medicine, and intravenous immunoglobulin

Treatment of Fulminant Disease

An evidence-based consensus guideline from the European Crohn’s and Colitis Organisation (ECCO) and the European Society of Paediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN) for the management of pediatric ulcerative colitis includes the following recommendations for the treatment of fulminant disease. [25]

Recommendations

Initial management: infectious screening

Use a stool culture to exclude bacterial causes for acute severe ulcerative colitis (ASC) (eg, Clostridium difficile toxins A and B).

Consider oral vancomycin as first-line therapy for C difficile infection in severe ulcerative colitis (UC).

Rule out cytomegalovirus (CMV) colitis in children not responding to 3 days of intravenous (IV) steroid.

Consider other infections when relevant, including viral and parasitic (eg, cryptosporidiosis, amoebiasis), such as in the presence of fever, other affected household members, or nonbloody diarrhea; perform stool testing for Entamoeba histolytica in endemic areas or in the setting of recent travel to endemic areas.

Corticosteroids

Initial treatment at admission: IV methylprednisolone (IVCS) 1 mg/k/day (≤40 mg/day) once daily in the morning. Reserve a higher dose of 1.5 mg/k/day (up to 60 mg/day) in 1 or 2 divided daily doses for disease on the more severe end of the spectrum and for children in whom oral steroids received prior to admission failed.

Disease monitoring and when to start second-line therapy

Patients with a Pediatric UC Activity Index (PUCAI) above 45 points on the third day of IVCS treatment undergo planning for second-line therapy between days 3 to 5.

In children with a PUCAI above 65 points, initiate second-line therapy on day 5 of IVCS treatment.

In children with a PUCAI of 35 to 65 on day 5, continue IVCS for an additional 2 to 5 days; monitor daily to confirm a gradual response before deciding on second-line therapy in most cases within a total of 7 to 10 days of treatment.

Medical second-line therapies when steroids fail

Use infliximab as the second-line medical therapy in the setting of IVCS-refractory disease in anti-tumor necrosis factor (TNF)–naïve children.

Consider calcineurin inhibitors (tacrolimus, cyclosporine) as an alternative second-line medical therapy.

When introducing second-line therapy, always discuss the possibility of treatment failure and, therefore, the need for colectomy.

Monitoring for toxic megacolon

Perform abdominal x-ray at admission using a low threshold, particularly in the presence of abdominal tenderness or distention, significant pain, and in those with systemic toxicity.

Prompt surgical evaluation of children with toxic megacolon is recommended; only consider conservative management in the setting of stable clinical conditions and in highly specialized centers under close monitoring. Perform urgent colectomy if there is no apparent improvement within 24 to 72 hours.

Suggested pediatric criteria for toxic megacolon include radiographic evidence of transverse colon diameter of at least 56 mm (or >40 mm in those < 10 years) plus evidence of systemic toxicity, such as the following:

• Fever >38ºC
• Tachycardia (heart rate >2 standard deviations above the mean for age)
• Dehydration
• Electrolyte disturbance (sodium, potassium, or chloride)
• Altered level of consciousness or coma
• Hypotension or shock

Total Proctocolectomy

Historically, surgery has been viewed as definitive therapy for ulcerative colitis (UC). Ileo-pouch anal anastomosis, which is performed in one, two, or three stages, is often curative in patients with UC, alleviating symptoms and removing the risk of colonic adenocarcinoma, whereas surgery is palliative in patients with Crohn disease and pancolitis.

Prior to 1980, total proctocolectomy with end ileostomy or continent (or Koch) ileostomy was the mainstay of therapy. Yet, in the late 1970s, reports of continence-preserving procedures involving ileal pouch–anal anastomosis (IPAA) began to surface. [12, 26] As experience amassed, the procedure was refined, and the IPAA has become the most common operation for UC patients who choose to maintain anal continence.

If colectomy is not performed to control symptoms, the risk of death from colon cancer is about 8% at 10-25 years after colitis is diagnosed. Therefore, surgical removal of the colon is a virtual necessity for most patients with UC. Because the disease is limited to the colon, colectomy is considered a curative procedure. [27, 28]

Approximately 5-10% of patients with UC require acute surgical intervention because of fulminant colitis refractory to medical therapy. In addition, the presence of pancolitis is the strongest predictor of the need for surgery in children.

In a study of 41 children with medically refractory UC who underwent two-stage laparoscopic IPAA between 2004 and 2017 at a single institution, investigators found similar outcomes whether the patients were treated with the traditional approach (an initial total proctocolectomy and creation of an IPAA and diverting stoma, followed by ileostomy closure several weeks later) (TIPPA) or with an alternative approach in which a subtotal colectomy and end ileostomy is performed (NIPAA). [29] However, children in NIPAA treatment group required significantly fewer prescriptions for antidiarrheal agents.

Contraindications to ileal pouch–anal procedures in children with UC are few. The only absolute contraindication is anal sphincter dysfunction. Preexisting incontinence due to neurologic impairment or other causes makes reservoir construction unnecessary, and it makes ileoanal pull-through inadvisable.

In children, elective colectomy is indicated when refractory disease significantly interferes with their growth and nutrition or with their ability to maintain a normal lifestyle (ie, attend school) or when dysplasia or malignancy is detected.

Diet

Patients with ulcerative colitis should avoid poorly digested foods, such as uncooked vegetables, seeds, nuts, and high roughage, especially patients with stricture or narrowing. Patients with fulminant disease, possible obstruction, or possible toxic megacolon should ingest nothing by mouth until their condition is stable.

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• Ulcerative Colitis in Children. Ulcerative colitis. This specimen from a colectomy reveals diffusely hemorrhagic granular mucosa in a continuous distribution.
• Ulcerative Colitis in Children. Histologic section: Note the diffuse inflammatory process, limited to mucosa and superficial portion of the submucosa (full thickness biopsy, staining, magnification).
• Ulcerative Colitis in Children. Histologic section: Note the diffuse inflammatory process, limited to mucosa and superficial portion of the submucosa (full thickness biopsy, staining, magnification).

Author

Mutaz I Sultan, MD, MBChB Assistant Professor and Chief of Pediatrics, Al-Quds University Medical College; Pediatric Gastroenterologist and Hepatologist, Division of Pediatrics, Makassed Hospital, Palestine

Mutaz I Sultan, MD, MBChB is a member of the following medical societies: European Society for Paediatric Gastroenterology, Hepatology and Nutrition, Palestine Medical Council

Disclosure: Nothing to disclose.

Chief Editor

Carmen Cuffari, MD Associate Professor, Department of Pediatrics, Division of Gastroenterology/Nutrition, Johns Hopkins University School of Medicine

Carmen Cuffari, MD is a member of the following medical societies: American College of Gastroenterology, American Gastroenterological Association, North American Society for Pediatric Gastroenterology, Hepatology and Nutrition, Royal College of Physicians and Surgeons of Canada

Disclosure: Received honoraria from Prometheus Laboratories for speaking and teaching; Received honoraria from Abbott Nutritionals for speaking and teaching. for: Abbott Nutritional, Abbvie, speakers' bureau.

Additional Contributors

Petar Mamula, MD Professor, Department of Pediatrics, Division of Gastroenterology and Nutrition, The Children's Hospital of Philadelphia, University of Pennsylvania Perelman School of Medicine

Petar Mamula, MD is a member of the following medical societies: American Academy of Pediatrics, American Gastroenterological Association, American Society for Gastrointestinal Endoscopy, North American Society for Pediatric Gastroenterology, Hepatology and Nutrition

Disclosure: Nothing to disclose.

Judith R Kelsen, MD Ann and Richard Frankel Chair in Gastroenterology Research, Director, Very Early-Onset Inflammatory Bowel Disease Program, Associate Professor of Pediatrics, Division of GI, Hepatology, and Nutrition, The Children's Hospital of Philadelphia, Perelman School of Medicine at the University of Pennsylvania

Judith R Kelsen, MD is a member of the following medical societies: American Academy of Pediatrics, American Association for the Study of Liver Diseases, American Gastroenterological Association, North American Society for Pediatric Gastroenterology, Hepatology and Nutrition

Disclosure: Nothing to disclose.

Acknowledgements

Robert Baldassano, MD, Director, Center for Pediatric Inflammatory Bowel Disease, Children's Hospital of Philadelphia; Professor, Department of Pediatrics, Division of Gastroenterology and Nutrition, University of Pennsylvania School of Medicine

Robert Baldassano, MD is a member of the following medical societies:Alpha Omega Alpha, American Academy of Pediatrics, American Gastroenterological Association, and North American Society for Pediatric Gastroenterology and Nutrition

Disclosure: Abbott Inc, Consulting fee, Consulting

Liz D Dancel, MD Intern, Department of Pediatrics, Greenville Hospital System University Medical Center

Disclosure: Nothing to disclose.

Jonathan Markowitz, MD Assistant Professor, Department of Pediatrics, Inpatient Gastroenterology, Division of Gastroenterology and Nutrition, University of Pennsylvania School of Medicine; Director, The Children's Hospital of Philadelphia.

Jonathan Markowitz is a member of the following medical societies: American College of Gastroenterology, American Gastroenterological Association, and North American Society for Pediatric Gastroenterology and Nutrition

Disclosure: Nothing to disclose.

David A Piccoli, MD Chief of Pediatric Gastroenterology, Hepatology and Nutrition, The Children's Hospital of Philadelphia; Professor, University of Pennsylvania School of Medicine

David A Piccoli, MD is a member of the following medical societies: American Association for the Study of Liver Diseases, American Gastroenterological Association, and North American Society for Pediatric Gastroenterology and Nutrition

Disclosure: Nothing to disclose.

Jorge H Vargas, MD Professor of Pediatrics and Clinical Professor of Pediatric Gastroenterology, University of California, Los Angeles, David Geffen School of Medicine; Consulting Physician, Department of Pediatrics, University of California at Los Angeles Health System

Jorge H Vargas, MD is a member of the following medical societies: American Liver Foundation, American Society for Gastrointestinal Endoscopy, American Society for Parenteral and Enteral Nutrition, Latin American Society of Pediatric Gastroenterology, Hepatology & Nutrition, and North American Society for Pediatric Gastroenterology and Nutrition

Disclosure: Nothing to disclose.

Mary L Windle, PharmD Adjunct Associate Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Nothing to disclose.