Ulcerative colitis. Specimen from colectomy reveals diffusely hemorrhagic granular mucosa in a continuous distribution.
Ulcerative colitis (UC) is a disease characterized by remitting and relapsing inflammation of the large intestine. UC, Crohn disease (CD) and indeterminate colitis account for the disorders that represent the inflammatory bowel diseases (IBDs).
Many patterns of presentation are possible within the pediatric age group. The hallmark symptoms of UC include abdominal cramping, diarrhea, and bloody stools, but physical symptoms vary with extent, duration, and severity of the disease. UC affects the rectum, with contiguous involvement that can include the entire large intestine. The disease phenotype can be characterized according to the Paris Classification, which divides the disease into isolated proctitis, left-sided colitis, extended colitis, and pancolitis.[1] Extraintestinal manifestations of UC, such as joint pain, ophthalmic conditions, and hepatobiliary disease may occur in some patients. See Presentation.
In the United States, 2 of every 100,000 children (age's 10-19 y) are affected, and 20-25% of all cases UC occur in persons aged 20 years or younger and the disease is increasing among young children (< 5 y). See Epidemiology.
Colonoscopy with biopsy is the most valuable procedure in evaluating patients with inflammatory bowel disease. Typical findings in someone with UC are inflammation that is first evident in the rectum and that proximally extends in a contiguous fashion. See Workup.
The therapeutic goal is to gain clinical and laboratory control of the disease with minimal adverse effects while permitting the patient to function as normally as possible. Approximately 5-10% of patients with UC require acute surgical intervention because of fulminant colitis refractory to medical therapy. Total proctocolectomy is often curative in patients with UC and removes the risk of colonic adenocarcinoma. See Treatment.
The mainstay of outpatient management is anti-inflammatory therapy with 5-aminosalicylic acid (5-ASA) preparations, such as sulfasalazine and mesalamine. Acute flares of UC in the pediatric population tend to respond well to corticosteroids, but numerous adverse effects prevent long-term use. Immunomodulatory agents and tumor necrosis factor inhibitors are also used to alleviate exacerbations of disease and increase patient comfort, as are newer therapies (eg, vedolizumab), and they can be a viable treatment option when the patient is steroid-dependent or steroid-refractory. See Medication.
For information on the general pathophysiology, etiology, and prognosis in patients with ulcerative colitis, see Ulcerative Colitis.
The incidence of pediatric-onset ulcerative colitis (UC) appears to be on the rise, often with a more severe disease presentation.[2] In the United States, 2 of every 100,000 children (age's 10-19 y) develop UC, and 20-30% of all cases occur in persons aged 20 years or younger. In most studies, UC incidence peaks between adolescence and early adulthood (ie, in people aged 15-30 y). A smaller peak occurs in patients aged 60-80 years. The incidence of inflammatory bowel disease among young children (< 5 y) has increased. These children often have disease that is limited to the colon; however, the disease can later progress to involve other parts of the intestine.
Although many children with ulcerative colitis (UC) have a mild course and respond well to therapy, severe complications can arise in patients with UC during acute exacerbations of disease or as the disease progresses. Male sex and higher Pediatric Ulcerative Colitis Activity Index score at diagnosis appear to be independent risk factors for colectomy in children with UC.[3] Factors predictive for the development of chronic pouchitis in pediatric ulcerative colitis are use of immunomodulators and the early occurrence of the first episode of pouchitis within 15 months after IPAA.[4]
Toxic megacolon is the most serious acute complication of UC and is reported to occur in up to 5% of patients; it is rare in young patients. Toxic megacolon is considered a medical and surgical emergency.
The pathogenesis of toxic megacolon is related to severe inflammation resulting in disordered intestinal motility. Compromised mucosal integrity then may allow bacteria to enter the submucosal tissues, leading to necrosis and peritonitis. Absorptive function is also impaired, resulting in increased luminal fluid volume and electrolyte losses.
Toxic megacolon usually occurs in the presence of severe pancolitis. Concurrent infection, such as Clostridium difficile colitis can lead to toxic megacolon; use of antidiarrheal agents or recent barium enema study or colonoscopy have also been implicated as causes. In addition, metabolic abnormalities (eg, hypokalemia, hypomagnesemia, hypoproteinemia), impaired epithelial integrity of the colon, and altered motor function and are frequently found in patients with toxic megacolon.
Toxic megacolon is associated with fever, abdominal distention, and tenderness. Abdominal obstruction series reveals dilatation of the colon with loss of normal haustral markings and signs of edema. Toxic megacolon places the patient at risk for colonic perforation, gram-negative sepsis, and massive hemorrhage.
Colonic malignancy is a clinically significant complication in patients with UC. Disease duration and pancolitis are well-recognized risk factors for malignancy, with the cancer risk surpassing that of the general population after 10 years. Other less-characterized risk factors include sclerosing cholangitis, a bypassed and defunctionalized segment of bowel, and a low folate level.
Children who develop UC before age 14 years have a cumulative colorectal-cancer incidence of 5% at age 20 years and 40% at age 35 years. Patients aged 15-39 years who develop UC have a cumulative incidence of 5% at age 20 years and 30% at age 35 years. The risk for children with disease onset in the first decade of life is unknown, but these children should undergo colonoscopic screening for dysplasia beginning in adolescence.
Epithelial dysplasia generally precedes carcinoma; therefore, yearly screening with surveillance colonoscopy and biopsy should be performed. Dysplasia can be missed on surveillance biopsy; prophylactic colectomy should be considered for adults who developed UC during childhood. With this in mind, psychologically prepare adolescents and young adults by discussing surgical options before the need for surgery arises.
Extraintestinal manifestations are common in UC; approximately 25-35% of patients with inflammatory bowel disease (IBD) have at least one extraintestinal manifestation. Extraintestinal disease may be prognostically important because the rate of pouchitis increases after colectomy in patients with UC and extraintestinal manifestations.
Pyoderma gangrenosum occurs in 1% of UC patients. An indolent chronic ulcer may occur even when disease is in remission. Intralesional therapy with steroids is useful, and colectomy results in healing in approximately 50% of patients.
Ophthalmologic manifestations most frequently occur when the disease is active. The incidence in adults is 4% but is less in children. The most common findings are episcleritis and anterior uveitis. Uveitis is usually symptomatic, causing pain or decreased vision. Patients with IBD should likely undergo routine ophthalmologic examination.
Arthritis is the most common extraintestinal manifestation of IBD, occurring in 10-25% of adolescents. The arthritis is usually a transient, nondeforming synovitis that involves the large joints in an asymmetric distribution. In children, arthritis may precede gastrointestinal (GI) symptoms by years.
Hepatobiliary disease is another common extraintestinal manifestation of UC in children. Hepatobiliary complications may precede the onset of GI symptoms, they may accompany active disease, or they may develop after surgical resection. Chronic active hepatitis, granulomatous hepatitis, amyloidosis, fatty liver, and pericholangitis are some of the intrahepatic manifestations of IBD. Extrahepatic manifestations include cholelithiasis and primary sclerosing cholangitis (PSC).
Thromboembolic disease is considered to be the result of a hypercoagulable state that parallels disease activity and is manifested by thrombocytosis; elevated plasma fibrinogen, factor V, and factor VIII; and decreased plasma antithrombin III. The hypercoagulable state may lead to deep venous thrombosis, pulmonary emboli, and neurovascular disease.
Thorough education about the pathophysiology, medications, and short-term and long-term risks of ulcerative colitis (UC) is an essential part of any treatment program.
The Crohn's and Colitis Foundation of America and the Crohn's and Colitis Foundation of Canada are nonprofit organizations dedicated to the education and treatment of patients affected by Crohn disease and UC.
The North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition, in concert with the Children's Digestive Health and Nutrition Foundation, have developed educational resources for children and families affected by inflammatory bowel disease (IBD). These resources are available at GI Kids.
For patient education information, see the Digestive Disorders Center, as well as Crohn's Disease in Children and Teens, Crohn's Disease Diet (Trigger Foods), and Inflammatory Bowel Disease (IBD).
Ulcerative colitis (UC) is a diffuse mucosal inflammation limited to the colon that affects the rectum; it may extend proximally in a symmetric uninterrupted pattern involving only some of or the entire large intestine. The most common presenting symptoms are rectal bleeding, diarrhea, and abdominal pain. Many patterns of presentation occur in the pediatric age group.
The disease phenotype can be characterized according to the Paris Classification, which divides the disease into isolated proctitis, left sided colitis, extended colitis and pancolitis.[1] Meta-analyses have shown that at diagnosis, 28% of children have proctitis (E1), 35% had left-sided colitis (E2), and 37% had extensive colitis (E3). At follow up (median, 6.7 y), extension of disease was seen in 49% of cases, with 60% of patients demonstrating extensive colitis.
Mild disease is observed in 50-60% of patients. This presentation involves insidious onset of diarrhea, later associated with hematochezia. No systemic findings of fever, weight loss, or hypoalbuminemia are observed. Mild UC is typically confined to the distal colon and responds well to therapy.
Moderate disease is observed in 30% of patients and is characterized by bloody diarrhea, cramps, urgency to defecate, and abdominal tenderness. Associated systemic findings, such as anorexia, weight loss, low-grade fever, and mild anemia, are present.
Severe disease occurs in approximately 10% of patients. This presentation involves more than 6 bloody stools per day, abdominal tenderness, fever, anemia, leukocytosis, and hypoalbuminemia. Patients with severe colitis may experience life-threatening complications, including severe hemorrhage, toxic megacolon, or intestinal perforation.
Less than 5% of children with UC present with predominantly extraintestinal manifestations, such as growth failure, arthropathy, skin manifestations, or liver disease.
A clinical scoring system known as the Pediatric Ulcerative Colitis Activity Index (PUCAI) has been developed and validated.[5] The PUCAI may be used to determine when it is necessary to escalate therapy in fulminant colitis. It is also used to assess disease activity in clinical trials involving pediatric patients with UC.
For more information about the general clinical approach to UC, see Ulcerative Colitis.
The findings on physical examination in ulcerative colitis (UC) vary with extent, duration, and severity of the disease. In addition to abdominal signs, many extraintestinal manifestations of UC may become evident during physical examination.
Vital signs may indicate fever. Tachycardia may represent anemia or hypovolemia. Tachypnea may be present because of abdominal splinting or as a compensatory mechanism for acidosis in cases of severe dehydration.
Comparison with growth charts may reveal delayed growth. Cushingoid appearance is indicative of steroid use, usually over a long period. The patient may appear toxic in cases of fulminant disease. Long-standing and severe disease may cause signs of malnutrition, such as muscle wasting.
Abdominal examination findings may be normal, but abdominal tenderness is likely. Voluntary or involuntary guarding may be present. Bowel sounds may be normal, hyperactive, or hypoactive; rushes or high-pitched tinkling may be found in cases of obstruction.
Rebound tenderness indicates severe disease and possible perforation. A palpable mass may indicate obstruction or megacolon. An enlarged spleen may be indicative of portal hypertension from associated autoimmune hepatitis or primary sclerosing cholangitis. Long-standing disease can be associated with colonic stricture and evidence for bowel obstruction.
Skin examination may reveal pallor in cases of anemia, decreased skin turgor in cases of dehydration, and jaundice, caput medusae, or spider angiomata when associated liver involvement is present. Erythema nodosum may be evident on extensor surfaces (more common in Crohn disease [CD] than UC); pyoderma gangrenosum affects approximately 1% of UC patients.
Patients with episcleritis can present with a painful erythematous eye. Cataracts may occur in patients with significant steroid history. Scleral icterus may be indicative of liver disease.
Joint pain (arthralgia) is a common finding in inflammatory bowel disease, although swollen or red joints (arthritis) occur less frequently. The large peripheral joints, such as the knees, ankles, wrists, and elbows, are most commonly involved, but any joint can be involved. Approximately 1% of UC patients develop ankylosing spondylitis; most of these patients test positive for human leukocyte antigen (HLA) type B27.
Unlike what is seen in some CD patients, perianal examination in UC patients should not reveal any evidence of fistulae or abscesses; chronic diarrhea may lead to perianal erythema, fissuring, or hemorrhoids, however.
Sexual development may be delayed in patients with UC, but this finding is more common in patients with CD.
Endoscopy must be performed if ulcerative colitis (UC) is suspected. A full colonoscopy is always indicated. As a result, going directly to colonoscopy is more cost-effective in many cases.[6]
Antineutrophil cytoplasmic antibodies (ANCA) and anti–Saccharomyces cerevisiae antibodies (ASCA) have been the most intensely studied serologic markers for inflammatory disease.
Other studies include complete blood count, stool assays, comprehensive metabolic profile, an upper gastrointestinal series with small bowel follow through, and abdominal obstruction series.
See also the Guidelines section for recommendations by the American College of Gastroenterology and the American Gastroenterological Association.
An upper endoscopy and colonoscopy are performed. Wireless video capsule endoscopy, also known as the Pillcam, is an increasingly used imaging technology that may reveal small bowel involvement in inflammatory bowel disease that differentiates Crohn disease from ulcerative colitis.
Proceeding directly to full colonoscopy may be especially applicable in young children, in whom flexible sigmoidoscopy is likely to necessitate the same degree of sedation as is used with colonoscopy. A flexible sigmoidoscopy is never indicated in the pediatric population for diagnostic purposes unless severity of disease prevents passage to the terminal ileum. One must visualize the whole colon to determine the extent of disease.
Go to Rigid Sigmoidoscopy for more complete information on this topic.
Colonoscopy with biopsy is the most valuable procedure in the evaluation of the patient with inflammatory bowel disease. Typical findings in someone with ulcerative colitis (UC) are inflammation that is first evident in the rectum and that proximally extends in a contiguous fashion. The mucosa typically appears erythematous, friable, and granular and has lost the normally visible vascular markings. Findings more consistent with Crohn disease (CD) than with UC are sparing of the rectal mucosa, aphthous ulceration, and noncontiguous or skip lesions.
When possible, visualizing the entire colon and the last portion of the ileum (terminal ileum) is optimal, because the terminal ileum is not actively involved in UC but is commonly involved in CD. Nevertheless, patients with pancolitis occasionally have microscopic inflammation in the terminal ileum, which is thought to be secondary to reflux of colonic contents through an inflamed ileocecal valve (ie, backwash ileitis).[7]
Biopsy findings consistent with UC are polymorphonuclear leukocytes near the base of the crypts. Cryptitis describes aggregation of polyps in the crypt epithelium, and the term crypt abscess is used when polyps have accumulated in the lumen of the crypt.
Lymphocytes, eosinophils, and mast cells may also be observed in the lamina propria in acute UC. No pathognomonic biopsy findings have been described for UC, however. Noncaseating granulomas are diagnostic of CD.
Go to Colonoscopyfor more complete information on this topic.
Serologic markers can provide more information; however, these alone are not diagnostic of inflammatory bowel disease (IBD) and lack accuracy to direct clinical care.[8]
Antineutrophil cytoplasmic antibody (ANCA) test is most commonly associated with ulcerative colitis (UC). ANCA assay results are positive in 60-80% of UC patients. The finding of ANCA is roughly 50% sensitive and 94% specific, and it has a 76% positive predictive value for UC.[9, 10, 11] ANCA is present in only about 40% of patients with Crohn disease.
Specifically, perinuclear ANCA (pANCA), found on the inside of the nuclear membrane, is highly associated with UC. The presence of pANCA is associated with an earlier need for surgery.
For children with ambiguous and mild complaints and for whom UC is part of the differential diagnosis, algorithms have been proposed in which the presence of ANCA is used to identify those patients who require more invasive diagnostic tests.[12]
Anti-S cerevisiae antibody (ASCA) test is a serologic marker that is more highly associated with Crohn disease, being present in 60% of cases; ASCA is present in only 12% of UC patients.
ANCA and ASCA titers are not correlated with disease activity.[13]
Complete blood cell (CBC) count
A CBC count commonly reveals a mild anemia, which can be due to chronic blood loss (ie, microcytic, hypochromic) or may represent chronic disease (ie, normocytic). In cases of fulminant colitis, severe anemia may be present. The CBC discloses the hematocrit level, which may be decreased in children with chronic disease or acute bleeding.
Obtain a comprehensive metabolic panel. Serum albumin levels may be low in fulminant colitis.
Erythrocyte sedimentation rate (ESR) and C-reactive protein level are frequently elevated during active disease. Micronutrient and vitamin levels are typically low in Crohn disease but less commonly so in ulcerative colitis. Liver dysfunction may indicate sclerosing cholangitis or autoimmune hepatitis.
Obtain stool cultures to rule out infectious colitis. Obtain an assay for E coli H7:0157 if the patient's symptoms are consistent with hemolytic-uremic syndrome.
Obtain a stool assay for C difficile toxins A and B, because C difficile colitis can mimic ulcerative colitis, or it may be responsible for a flare. Evaluation for toxin A or toxin B alone is inadequate for an accurate diagnosis of C difficile infection.
The fecal calprotectin level may be elevated during times of active inflammation. Calprotectin is a calcium-binding S-100 protein found in the neutrophil cytosol that is released with cell activation or death. An assay for calprotectin is now commercially available and may be useful to differentiate a disease flare from other causes of abdominal pain or diarrhea.
In all children with ulcerative colitis (UC) except those with sepsis, imaging studies should be undertaken only if they are deemed necessary after endoscopic evaluation is complete.
Go to Ulcerative Colitis Imaging for more information on this topic.
An abdominal obstruction series (ie, supine and upright abdominal radiography) is useful to evaluate for air-fluid levels, dilated loops of bowel, evidence of obstruction, or possible toxic megacolon. No pathognomonic findings for UC with this type of study have been reported.
Barium enema study is useful to evaluate the colon for stricture and for mucosal abnormalities, especially when colonoscopy cannot be performed. Barium enema studies may also demonstrate a source of bleeding other than UC, such as a polyp.
An upper GI series with small-bowel follow-through is used to evaluate for small-bowel inflammation that would support a diagnosis of Crohn disease (CD) rather than UC.
CT scanning of the abdomen is useful to evaluate for bowel-wall thickening and obstruction. If present, abscesses and fistulae imply a diagnosis of CD rather than UC. Many children with a preliminary diagnosis of inflammatory bowel disease undergo CT scanning of the abdomen as part of the initial evaluation of abdominal pain.
Radionuclide-tagged white blood cell scanning can be used to demonstrate small-bowel inflammation that differentiates CD from UC.
MRI of the abdomen is increasingly used to evaluate the large and small bowel for inflammatory changes and to look for transmural versus mucosal inflammation.
Video capsule endoscopy is used as another modality to distinguish CD from UC. The sensitivity of video capsule in diagnosing small bowel lesions is greater than that of barium radiography.[14]
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.[15]
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.
For patients presenting with the symptoms of ulcerative colitis, consultations are indicated with a pediatric gastroenterologist and, in more severe cases, a pediatric surgeon.
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.[16]
Mild ulcerative colitis (UC) in the pediatric population can be treated with pharmacotherapy, most commonly anti-inflammatory agents.
The mainstay of outpatient management is anti-inflammatory therapy with 5-aminosalicylic acid (5-ASA) preparations.[17] 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.[18]
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%.
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%).[19]
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.
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 (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.
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.
Treatments for fulminant ulcerative colitis (UC) include cyclosporine, tacrolimus, and infliximab.
Cyclosporine (cyclosporin A) is a potent inhibitor of the inflammatory cascade that primarily acts by inhibiting interleukin-2 production, though it also decreases the recruitment of cytotoxic T cells and blocks other inflammatory cytokines.
In refractory fulminant UC, cyclosporine has effectively induced remission, obviating immediate surgery. Because cyclosporine is such a potent immunosuppressive agent, the physician must be absolutely certain that an infection is not contributing to the colitis. The patient must also be considered susceptible to opportunistic infections, such as those due to cytomegalovirus and Pneumocystis carinii.
Cyclosporine is nephrotoxic and may cause irreversible renal insufficiency. In addition, cyclosporine is epileptogenic and may precipitate seizures in patients, especially those with low cholesterol or magnesium levels.
Because of its many potential toxicities, cyclosporine should be used only by physicians who are experienced in its administration. In addition, for UC patients, strongly consider surgical colectomy to treat fulminant disease because of the long-term risk of cancer and the curative nature of the surgery.
Tacrolimus is a potent inhibitor of T-lymphocyte function, although the exact mechanism is poorly understood. Tacrolimus is primarily used to prolong the survival of transplant grafts. Tacrolimus has shown some anecdotal success in inducing remission and preventing colectomy among UC patients. A review of 18 pediatric patients with UC reported that 17 had a response to tacrolimus, although 11 patients still ultimately required colectomy.[20]
Toxicities such as nephrotoxicity, bone marrow suppression, and neurologic symptoms make tacrolimus use for UC patients controversial. It should only be considered for select patients in whom other options are not possible or not effective.
In September 2011, the US Food and Drug Administration (FDA) approved infliximab for the treatment of UC in children.
Infliximab is a monoclonal antibody against tumor necrosis factor (TNF)-alpha, a proinflammatory cytokine that occurs early in the inflammatory cascade. Infliximab is effective in treating Crohn disease (CD) and has received attention and indications for use in UC patients.[21, 22] The drug is given as an intravenous infusion, typically in an induction regimen of two infusions over 2 weeks. In several reports, refractory UC responded to infliximab, and emergency colectomy was avoided.
In a retrospective series of pediatric patients with UC, 100% of patients were short-term responders to infliximab, with 75% showing complete resolution of symptoms and the remaining 25% showing partial improvement after a median of 6 infusions; 67% were long-term responders after a median of 10.4 months.[23] A better response was noted in patients who were considered steroid-dependent rather than steroid-refractory.
A better response to infliximab infusions was also observed among patients concurrently taking 6-mercaptopurine; the concurrent use of 6-mercaptopurine and infliximab has become more controversial, however, following reports of hepatosplenic T-cell lymphoma in patients with inflammatory bowel disease receiving both medications. Dual therapy has not been proven to be better. Higher levels of infliximab are seen, but dual therapy is not necessarily better.
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.[9, 24] 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.[25, 26]
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).[27] 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.
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.
The ACG released their guideline on preventive care in inflammatory bowel disease (IBD) in 2017.[28] Some of their preventive health maintenance recommendations are outlined below.
Strong recommendations
Conditional recommendations
The AGA released new guidelines on the management of mild-to-moderate ulcerative colitis (UC) in February 2019,[31] with a focus on the use of oral (PO) and topical 5-aminosalicylates (5-ASA) agents, rectal (PR) corticosteroids, and PO budesonide.[31, 32]
Strong recommendations
Patients with extensive mild-moderate UC: The AGA recommends using either standard-dose mesalamine (2-3 g/d) or diazo-bonded 5-ASA rather than low-dose mesalamine, sulfasalazine, or no treatment. (Patients already on sulfasalazine in remission or patients with prominent arthritic symptoms may reasonably choose sulfasalazine 2-4 g/d if alternatives are cost-prohibitive, albeit with higher rate of intolerance.)
Patients with mild-moderate ulcerative proctitis who choose rectal therapy over oral therapy: The AGA recommends using mesalamine suppositories.
Conditional recommendations
Patients with extensive or left-sided mild-moderate UC: The AGA suggests adding rectal mesalamine to oral 5-ASA.
Patients with mild-moderate UC with a suboptimal response to standard-dose mesalamine or diazo-bonded 5-ASA or with moderate disease activity: The AGA suggests using high-dose mesalamine (>3 g/d) with rectal mesalamine.
Patients with mild-moderate UC being treated with oral mesalamine: The AGA suggests using once-daily dosing rather than multiple times per day dosing.
Patients with mild-moderate UC: The AGA suggests using standard-dose oral mesalamine or diazo-bonded 5-ASA, rather than budesonide MMX (Multi-Matrix System) or controlled ileal release budesonide for induction of remission.
Patients with left-sided mild-moderate ulcerative proctosigmoiditis or proctitis: The AGA suggests using mesalamine enemas (or suppositories) rather than oral mesalamine. (Patients who have a higher value for convenience of oral medication administration and a lower value on effectiveness could reasonably choose oral mesalamine.)
Patients with mild-moderate ulcerative proctosigmoiditis who choose rectal therapy over oral therapy: The AGA suggests using mesalamine enemas rather than rectal corticosteroids. (Patients who place a higher value on avoiding difficulties associated with mesalamine enemas and a lower value on effectiveness may reasonably select rectal corticosteroid foam preparations.)
Patients with mild-moderate ulcerative proctosigmoiditis or proctitis being treated with rectal therapy who are intolerant of or refractory to mesalamine suppositories: The AGA suggests using rectal corticosteroid therapy rather than no therapy for induction of remission.
Patients with mild-moderate UC refractory to optimized oral and rectal 5-ASA, regardless of disease extent: The AGA suggests adding either oral prednisone or budesonide MMX.
No recommendations
The AGA makes no recommendations for the use of probiotics in those with mild-moderate UC, nor for the use of curcumin in patients with mild-moderate UC despite 5-ASA therapy.
In patients with mild–moderate UC without Clostridium difficile infection, the AGA recommends fecal microbiota transplantation be performed only in the context of a clinical trial.
Clinical Context: Sulfasalazine was the first 5-aminosalicylic acid preparation available for the treatment of ulcerative colitis (UC). It is useful in the management of ulcerative colitis and acts locally in the colon to decrease the inflammatory response and systemically inhibits prostaglandin synthesis
Clinical Context: Mesalamine is DOC to maintain remission. Mesalamine is provided as a controlled-release capsule (Pentasa) or enteric-coated tablet (Asacol). Begin with a low dose, and increase the dose if adverse effects (eg, headache, diarrhea) do not develop. It is also available as an enema or suppository for rectal administration. Asacol is the only oral product approved for use in children aged 5 years or older. The dose of Asacol in children is dependent on weight.
The currently approved PO mesalamine products in the United States differ only in the mechanism of drug delivery. Asacol has mesalamine within a Eudragit-S coating that dissolves and releases the mesalamine at pH 7, which typically occurs in the terminal ileum. Pentasa is 5-ASA in ethylcellulose and has a time-release coating. Its release begins at the pylorus. Rectal dosage forms deliver high concentrations of mesalamine to the left colon as high as the splenic flexure (enema with 30 min retention) or to the rectum for use in proctitis (supp). Although effective, mesalamine is associated with a relatively high relapse rate upon discontinuation.
Clinical Context: Balsalazide is a prodrug that is converted into 5-aminosalicyclic acid through bacterial azoreduction. Metabolites of the drug may decrease inflammation by blocking production of arachidonic acid metabolites in the colon mucosa.
These drugs are used to maintain remission and to induce remission of mild flares of disease. The mainstay of outpatient management is anti-inflammatory therapy with 5-aminosalicylic acid (5-ASA) preparations.
Clinical Context: 6-Mercaptopurine is a purine analog that inhibits purine ribonucleotide synthesis and cell proliferation. It alters immune response through effects on natural killer cells and cytotoxic T cells.
Clinical Context: Azathioprine is rapidly converted to 6-mercaptopurine in vivo. It antagonizes purine metabolism and inhibits synthesis of DNA, RNA, and proteins. It may decrease proliferation of immune cells, which lowers autoimmune activity.
Clinical Context: Cyclosporine, also called cyclosporin A, is used to treat severe colitis refractory to corticosteroids. One must strongly consider surgical colectomy. It may cause irreversible nephrotoxicity, seizures, and opportunistic infections.
Clinical Context: Used for short-term exacerbations. It has a direct effect on inflammation, including decreased release of inflammatory cytokines; inhibition of phospholipase, which, in turn, inhibits arachidonic acid liberation from membranes; and inhibition of neurofibromatosis (NF)–kappa-beta function.
Clinical Context: Methylprednisolone decreases inflammation by suppressing migration of polymorphonuclear leukocytes and reversing increased capillary permeability. This agent is administered intravenously in severe cases.
These drugs are used to induce the remission of acute exacerbations. Acute flares of moderate-to-severe ulcerative colitis in the pediatric population tend to respond well to corticosteroids, but numerous adverse effects limit long-term use.
Clinical Context: Infliximab neutralizes cytokine TNF-alpha and inhibits its binding to TNF-alpha receptor. Mix in 250 mL 0.9% NaCl and infuse IV over 2 hours. A low-protein-binding filter (1.2 µm or smaller) must be used. It is indicated for reducing signs and symptoms and inducing and maintaining clinical remission in children aged 6 years and older with moderate-to-severe active UC who have had an inadequate response to conventional therapy.
Tumor necrosis factor (TNF) is a cytokine; 2 forms with similar biologic properties have been identified. TNF-alpha, or cachectin, is produced predominantly by macrophages. TNF-beta, or lymphotoxin, is produced by lymphocytes. TNF is but one of many cytokines involved in the inflammatory cascade that may contribute to symptoms.
Ulcerative colitis. Specimen from colectomy reveals diffusely hemorrhagic granular mucosa in a continuous distribution.
Histological section: diffuse inflammatory process, limited to mucosa and superficial portion of the submucosa (full thickness biopsy,staining, magnification).
Histological section: diffuse inflammatory process, limited to mucosa and superficial portion of the submucosa (full thickness biopsy,staining, magnification).
