Pediatrics

Inflammatory bowel disease - Crohns Disease

OVERVIEW: What every practitioner needs to know

Are you sure your patient has Crohn disease? What are the typical findings for this disease?

Crohn disease, along with ulcerative colitis, are the two most common chronic intestinal conditions collectively known as inflammatory bowel disease (IBD). The inflammation associated with Crohn disease can affect any part of the gastrointestinal tract from the mouth to the anus; however the ileum and colon are the two areas most frequently involved. Crohn disease is associated with inflammation, fistula formation and structural changes within the bowel. It is likely that Crohn disease represents a heterogenous group of disorders with common clinical features mediated by multiple genetic defects.

The most common presenting symptom in children is recurrent or chronic abdominal pain. Other presenting symptoms can include decreased appetite, nausea, vomiting, diarrhea (with or without blood noted in stool), weight loss or poor weight gain, and poor growth. Crohn disease is characterized by symptomatic bouts of disease flare-ups interspersed with asymptomatic periods (remissions). Most children with Crohn disease lead normal active lives with no limitations except during acute flares of the disease.

One of the most important factors in correctly diagnosing Crohn disease is realizing that this condition can develop in children, and a detailed medical history can lead to a high index of suspicion. Information to obtain before conducting laboratory studies include the duration, frequency, and location of abdominal pain; the frequency and consistency of bowel movements; the presence or absence of blood or mucus; a decrease or change in appetite and/or unexpected weight loss; decreasing growth percentiles, and pubertal delay. A family history of Crohn disease or ulcerative colitis (as many as 30% of children with IBD will have a family member with the diagnosis of IBD) is also suggestive of Crohn disease.

Clues on physical examination that may suggest a diagnosis of Crohn disease include short stature, low body mass index, clubbing, abdominal tenderness, perinanal lesions (e.g., skin tags, abscess, fissures, fistulas), and evidence of pubertal delay for patient age (Tanner staging).

A definitive diagnosis of Crohn disease is established by a combination of endoscopic, histologic, and radiographic findings.

Extraintestinal manifestations of Crohn Disease

Up to 30% of patients with IBD will exhibit some extraintestinal manifestation during their lifetimes. These can cause varying degrees of morbidity. Some correlate with gastrointestinal symptoms but others can remain even when the patient's intestinal disease is in remission.

Growth failure manifested by impairment in linear growth is common in Crohn disease. Growth failure may be the only presenting sign of Crohn disease, and it may not be accompanied by any gastrointestinal symptoms. The pathogenesis of growth failure is multifactorial and includes suboptimal intake, malabsorption, increased caloric needs, and effects from proinflammatory cytokines. After growth failure, arthralgias/arthritis are the most common extraintestinal manifestations associated with IBD.

Joint manifestations can be peripheral (e.g., knees, ankles, wrists) or axial (e.g., ankylosing spondylitis, sacroileitis).

Liver involvement can occur in the form of autoimmune hepatitis and primary sclerosing cholangitis (PSC).

Common skin manifestations include erythema nodosum and pyoderma gangrenosum.

Ocular inflammation can occur and includes episcleritis and uveitis. Care should be taken not to confuse this for conjunctivitis.

Recurrent oral aphthous lesions are common in Crohn disease. Oral granulomatous inflammation may also occur, presenting as lip swelling, oral ulcers, and buccal mucosal irregularities.

Other extraintestinal manifestations include unexplained recurrent low-grade fevers, osteopenia/osteoporosis, and very rare occurrences of pulmonary, vascular, neurologic, and renal findings.

What other disease/condition shares some of these symptoms?

Several infectious diseases of the intestine share the presenting symptoms of IBD and Crohn disease. They include viral infections with agents such as Salmonella, S higella, Yersinia, Campylobacter, Escherichia coli,Amebae, and Mycoplasmatuberculosis.

Other noninfectious conditions that also share these symptoms include the following: ulcerative colitis, eosinophilic gastroenteritis, appendicitis, pelvic inflammatory disease, celiac disease, ischemic bowel disease, vasculitides (e.g., Henoch-Schönlein purpura), polyps, intussusception, ovarian cysts, Behçet's disease, immunodeficiencies (e.g., common variable immunodeficiency), and chronic granulomatous disease.

Malignancies such as non-Hodgkin lymphoma, adenocarcinoma, and carcinoid tumors are also known to present with similar symptoms.

What caused this disease to develop at this time?

The actual etiology of Crohn's disease remains unknown. Current evidence suggests that both genes and the environment play significant roles. The intestinal tract is exposed to numerous dietary and bacterial antigens and normally exists in a state of controlled inflammation known as tolerance.

Environmental triggers such as infections can lead to increased intestinal inflammation. In normal individuals, this activates the immune system, which eventually returns to its homeostasis. It is speculated that some variable of an environmental trigger makes individuals with a certain genetic profile more susceptible to Crohn disease and thus enacts it on exposure to the trigger. Dysregulation of the individual's immune system contributes to the chronicity of the inflammatory response.

What laboratory studies should you request to help confirm the diagnosis? How should you interpret the results?

Laboratory studies may provide helpful clues indicating that an inflammatory process is occurring in the gastrointestinal tract. Laboratory abnormalities that may be associated with Crohn disease include anemia, thrombocytosis, leukocytosis, elevated erythrocyte sedimentation rate, elevated C-reactive protein level, hemoccult-positive stool, increased stool lactoferrin or calprotectin levels, and hypoalbuminemia. Stools should be checked for bacteria, ova and parasites, and Clostridium difficile toxin if diarrhea is present.

Testing for tuberculosis should be considered in the appropriate patient with a history of contact with patients with tuberculosis, travel to endemic areas, or other suggestive symptoms.

Serologic markers have recently been identified and may be helpful in diagnosing IBD or differentiating between Crohn disease and ulcerative colitis. These markers detect antibodies in the serum of patients with IBD and include atypical perinuclear anticytoplasmic antibodies, antibodies to Saccharomyces cerevisiae, anti-E. coli outer membrane porin C antibodies, and antibodies to bacterial flagellin.

Evaluation of liver enzymes including aspartate aminotransaminase, alananine aminotransaminase, alkaline phosphatase, and gamma-glutamyl transpeptidase (GGT) can be helpful laboratory screens. These tests have limitations, especially in children, and their higher specificity than sensitivity makes them less useful as general screening tools.

It should be noted that laboratory tests in patients with Crohn disease may be completely normal, especially if the intestinal inflammation is mild or limited.

What endoscopic studies should be performed to confirm the diagnosis of Crohn disease?

Endoscopic studies should be performed to definitively diagnose Crohn disease and to determine extent, location, and severity of disease. Endoscopy with biopsy is the most sensitive test available to evaluate the upper gastrointestinal tract, colon, and ileum. Esophagogastroduodenoscopy provides evaluation of the esophagus, stomach, and duodenum. Enteroscopy can be used to evaluate the small intestine more extensively. Colonoscopy evaluates the colon and, if terminal ileal intubation can be achieved, would enable evaluation of the most distal part of the ileum - an area frequently affected in Crohn disease.

Endoscopic findings can include erythema, friability, mucopurulent exudates, ulcerations, cobblestoning, and pseudopolyps (See Figure 1, Figure 2, Figure 3). Histopathologic findings include the presence of acute and chronic inflammation. Noncaseating granulomas are considered pathognomonic for Crohn disease; however the majority of biopsy specimens will not show granulomas.

Figure 1.

Colonic ulcer in Crohn disease.

Figure 2.

Colonic pseudopolyps in Crohn disease.

Figure 3.

Active Crohn disease with cobblestoned mucosa.

Wireless video capsule endoscopy may provide adjunct information regarding small intestine inflammation.

Would imaging studies be helpful? If so, which ones?

Findings on radiographic studies may suggest Crohn disease but do not necessarily confirm the diagnosis. Radiography is helpful in determining extent, location, and severity of disease. Abdominal radiography should be performed as an initial study if there is concern for perforation or surgical abdomen to evaluate for free peritoneal air. An upper gastrointestinal series with a small bowel follow-through has been the most commonly obtained radiographic study.

With newer technologies, other modalities such as computed tomography (CT), magnetic resonance imaging (MRI), and ultrasonography are being increasingly used. These studies may indicate evidence of intestinal mucosal irregularity, luminal narrowing, bowel wall thickening, or fistulas.

If you are able to confirm that the patient has Crohn disease, what treatment should be initiated?

Crohn disease is a chronic condition. Therapies are used to induce and maintain clinical remission (i.e., to ameliorate symptoms and maintain the patient in an asymptomatic state). Therapeutic options include medications and dietary and surgical interventions. Treatment goals for children with Crohn disease are directed toward the patient's physical and psychosocial well-being so that the patient has the best possible quality of life.

Short-term goals include relief of immediate symptoms such as abdominal pain, diarrhea, and gastrointestinal bleeding. Long-term goals include minimizing long-term complications such as growth failure and the need for hospitalizations and surgery. Therapies are chosen so that they provide the greatest efficacy while minimizing adverse effects. Keeping therapeutic regimens simple may help maximze adherence.

Medications for inducing remission

Medical therapies include the following general drug classes: corticosteroids, aminosalicylates, antibiotics, immunomodulators, and biological agents.

Corticosteroids remain the most frequently used medications to induce remission for moderate to severe Crohn disease; however they are rarely used as monotherapy. Typical starting prednisone doses range from 1-2 mg/kg/d administered once daily. Usually doses do not exceed the equivalent of prednisone 40-60 mg daily, as greater doses have not shown increased efficacy. If oral dosing fails to treat symptoms, intravenous corticosteroids should be considered.

Studies suggest that nearly 60% of patients who receive corticosteroids will have have complete remission of symptoms and approximately 25% of patients will have partial remission in the acute phase. If a clinical response occurs, corticosteroids are ideally tapered over an 8 to 12-week period.

Corticosteroids can also be administered rectally. Budesonide is an oral form of corticosteroid that undergoes a high rate of first-pass hepatic metabolism, thus minimizing corticosteroid side effects. An enteric-coated budesonide that is designed to deliver the active drug to the terminal ileum and ascending colon is commerically available.

Aminosalicylates (5-aminosalicylic acid [5-ASA]) are locally active anti-inflammatory agents. These medications have proven efficacy in the induction of mild to moderate ulcerative colitis, but there is much less medical evidence regarding their efficacy to treat active Crohn disease. Nonetheless, they are often used as adjunct therapy in pediatric Crohn disease. 5-ASA medications come in a variety of formulations that are meant to protect the drug from gastric degradation and disperse the active agent in various areas of the intestinal tract - from the small intestine to the colon. They can be administered orally or rectally.

Thiopurine immunomodulators are also frequently used in pediatric Crohn disease to induce remission in moderate to severe disease, fistulous disease, and perianal disease. Medications include 6-mercaptopurine (1-1.5 mg/kg/d) and azathioprine (2-2.5 mg/kg/d). The medications have a slow onset of action and may take up to 3 months or more to reach maximal effect. They are frequently started in conjunction with corticosteroids in moderate to severe disease.

Methotrexate, a folic acid antagonist, has been shown to induce clinical remission in adults using intramuscular or subcutaneous doses of 25 mg weekly. Traditionally, it is typically used for patients who are intolerant or refractory to thiopurine immunomodulators. Recently, methotrexate has been receiving increased attention in the medication armentarium for the treatment of pediatric Crohn disease. Dosing based on common pediatric practice is typically 15 mg/m2 weekly administered subcutaneously. Alternative dosing for children is weekly subcutanous dosing of 10 mg (20-29 kg), 15 mg (30-39 kg), 20 mg (40-49 kg), or 25 mg (=50 kg).

Anti -tumor necrosis factor (TNF)-a agents include infliximab, adalimumab, and certolizumab. TNF-a is a potent mediator of inflammation in a number of inflammatory and autoimmune disorders including Crohn disease. These medications are administered either intravenously or subcutaneously. When initiating treatment, several doses are typically given within a period of weeks, and if the patient has a clinical response, they can be continued from weekly to every 8 weeks depending on the agent that is being used.

Infliximab is the anti-TNF-a agent with the most adult and pediatric data because it has been on the market longest. Induction dosing to see if clinical remission can be achieved is typically 5 mg/kg/dose intravenously (IV) given at weeks 0, 2, and 6. An induction course for adalimumab can range from 40-160 mg/dose given at week 0 and 2 depending on the child's weight.

Antibiotics (e.g., metronidazole, ciprofloxacin, rifaximin) are widely used in the treatment of IBD, although there are relatively few studies that have suggested efficacy in treating active Crohn disease for perianal and colonic involvement, fistulization, and postoperative recurrence. Treatment of a specific pathogen is not thought to be the key reason why antibiotics have efficacy. Rather the answers may lie in decreasing luminal bacterial concentrations or the selective elimination of certain bacterial species and decreasing tissue invasion, microabscess formation, or bacterial translocation, with a downregulation of the local inflammatory response.

Medications for maintaining remission

Corticosteroids are not efficacious in maintaining remission, and prolonged courses even at lower doses (e.g., <10 mg daily) should be avoided whenever possible in the pediatric patient. Studies suggest that only about a third of patients may have a prolonged response after corticosteroid induction; thus corticosteroids are typically used as a bridge to an effective maintenance agent.

Thiopurine immunomodulators have been shown to be efficacious in maintaining disease remission and minimizing chronic corticosteroid exposure. Methotrexate doses for maintenance of remission are typically reduced 20%-40% from initial doses if a patient responds clinically and continues to do well after initial dosing. Administration of methotrexate can be given either subcutaneously or orally.

Using aminosalicylates (5-ASA) to maintain remission in Crohn disease remains controversial, with some trials demonstrating efficacy and others none.

Anti-TNF-a agents (infliximab, adalimumab, certolizumab) have shown efficacy in maintenance of remission. Dosing, route (intravenous versus subcutaneous), and frequency of administration varies depending on the agent. Infliximab has the largest amount of medical evidence in both children and adults, as it is the option that has been on the market the longest. Dosing begins at 5 mg/kg/dose IV every 8 weeks for maintenance of remission and, depending on clinical response, may be escalated to 10 mg/kg/dose and given more frequently. For children, adalimumab maintenance dosing typically ranges from 20-40 mg given subcutaenously every other week and can be escalated to weekly if need be.

Nutritional evaluation and interventions

Nutritional rehabilitation is important for patients with weight loss, growth failure, or biochemical abnormalities. Obtaining input from a dietician, when available, in patient management is beneficial. Frequently patients may not be able to consume the required 100%-150% caloric intake of the recommended daily allowance through a regular oral diet. Knowing pre-illness weight and/or recent weight changes is useful in assessing the impact of chronic intestinal inflammation. Tricep skin fold thickness and midarm circumference may be helpful to estimate fat mass and lean mass.

Assessment of nutritional difficiencies is essential. Consider evaluating concentrations of albumin, prealbumin, hemoglobin, iron/ferritin, zinc, calcium, phosphorous, copper, magnesium, selenium, and vitamins A, D, E, B12 using coagulation studies. Supplementation should be prescribed if results indicate necessity.

After diagnosis, routine monitoring of weight, height, and body mass index is recommended. Whenever possible the gastrointestinal tract should be used and patients should be encouraged to eat a well-balanced diet. Some patients can take supplements orally but often will not be able to consume the necessary volume needed for nutritional rehabilitation. In these patients, the administration of nutrition through a nasogastric tube should be considered.

Dietary modifications such as routine use of low-residue, lactose-free, or other elimination diets have insufficient medical evidence to suggest they be recommended to the general Crohn disease population. Parenteral nutrition is typically reserved for hospitalized patients with severe gastrointestinal symptoms that prevent them from tolerating oral or enteral feedings.

Enteral nutrition is beneficial for providing additional caloric intake. Medical evidence suggests that it can be used as primary therapy to decrease inflammatory cytokine levels, reverse intestinal inflammation, and induce and maintain clinical remission. It appears that elemental formulas do not provide additional benefit over polymeric formulas.

Surgical interventions for Crohn disease

Medical management remains the first-line treatment for Crohn disease. Indications for surgery in Crohn disease include failure of medical therapy, corticosteroid dependency, stricture, perforation, intraabdominal abscess, fistula, intractable gastrointestinal bleeding, growth failure, pubertal delay, and dysplasia.

It is estimated that more than 70% of patients with Crohn disease will require intestinal surgery 20 years after diagnosis. Many patients will experience disease recurrence and require a second operation about 10 years later. The goal of surgery is to remove as little bowel as possible. Prevention of postoperative recurrence is important for patients who have undergone surgical resection such as ileocectomy. Identification of individuals at high risk for recurrence remains an important area of study.

Evidence for the use of postoperative pharmacologic maintenance is limited. Some benefit has been shown with thiopurine immunomodulators, antibiotics, 5-ASA agents, and anti–TNF-a medications. Endoscopic evaluation of the surgical anastomosis within 3-6 months after surgical resection may help predict risk of postoperative clinical recurrence.

What are the adverse effects associated with each treatment option?

Use of corticosteroids as treatment may cause moon facies, acne, weight gain, hirsutism, skin striae, mood changes, psychoses, cataracts, osteopenia, osteoporosis, growth retardation, or infection. Studies suggest that the use of corticosteroids and narcotics impose the largest risk for the development of serious infection and mortality.

Aminosalicylates may cause side effects such as rash, headache, hair loss, renal insufficiency, colitis, hepatitis, pancreatitis, or decreased sperm counts in adult male patients.

Thiopurine immunomodulators have idiosyncratic and dose-related side effects. Idiosyncratic effects include pancreatitis and myalgias. Dose-related effects include bone marrow suppression, elevated liver enzyme levels, infections, gastrointestinal intolerance (nausea, vomiting, diarrhea), and malignancy (e.g., non-Hodgkin lymphoma, hepatosplenic T-cell lymphoma). Patients with decreased thiopurine methyl transferase (TPMT) activity (an enzyme that metabolizes these drugs) may be at risk for the development of adverse events such as myelosuppression. Commercially available testing of TPMT genotype or enzyme activity is available and can help guide dosing.

Methotrexate complications include nausea, vomiting, and elevated levels of liver enzymes. Methotrexate is an abortifacient and teratogen; thus pregnancy counseling is strongly recommended for female patients of childbearing age who are started on this medication.

Anti-TNF-α medications may cause infusion reactions, bone marrow suppression, infection, reactivation of latent tuberculosis, malignancy (e.g., non-Hodgkin lymphoma or hepatosplenic T-cell lymphoma). It is recommended that patients have a documented negative result on purified protein derivative testing before starting treatment.

What are the possible outcomes of Crohn disease?

Crohn disease is a chronic disorder that currently does not have a known cure. Crohn disease is categorized by periods of symptoms (flares) with periods of no symptoms (remission). Approximately 10% of patients may have a chronic, continuous disease course. If left untreated, Crohn disease can lead to a number of complications such as chronic pain, growth failure, malnutrition, anemia, and the need for surgical intervention.

The treatments that are offered to the patient are those that will ameliorate symptoms and achieve remission but minimize adverse events. A recent goal of medical treatment has been achieving mucosal healing, as this has been associated with sustained clinical remission and reduced rates of hospitalization and surgical resection.

What causes this disease and how frequent is it?

Population-based studies indicate that the highest incidence of IBD is found in northern Europe, the United Kingdom, and North America. However, IBD is now being seen with increasing frequency in Asia, South America, and Africa. Pediatric IBD accounts for 7%-20% of all IBD cases. In the United States it is estimated that there are approximately 1.5 million individuals with IBD. Over the past 5 decades the incidence of Crohn disease appears to be increasing in children, whereas the incidence of ulcerative colitis has slightly increased or remained stable.

There appears to be a predominance of Crohn disease among boys; however, by the older teen years and into adulthood it occurs more frequently in female individuals, particularly in areas of high incidence.

Familial occurrence of IBD and studies indicating high concordance of Crohn disease in monozygotic twins suggests a strong link between genetics and IBD development. In adults with IBD, a positive family history is found in approximately 10%-15% of patients; for children with IBD, a positive family history may be noted in as many as 30% of patients. Population-based studies have shown an 8 to 10-fold risk of IBD among relatives of patients with IBD.

It is currently believed that IBD is a polygenic disease with a pattern of complex genetic traits, and in the past decade several dozen gene mutations have been associated with Crohn disease. However, genetic mutations are not sufficient or necessary for the development of Crohn disease. Among the more than 100 IBD genes that have been identified to date, the first reported susceptibility gene for Crohn's disease (NOD2) remains the one with the most meaningful contribution (~20-fold risk) to Crohn disease risk alone.

The NOD2 gene is involved in the innate immune system and mutations along it may involve impaired response to commensal or pathogenic bacteria. Genotype-phenotype studies suggest that NOD2 mutations are associated with the development of ileal disease and a phenotype that favors strictures.

Epidemiologic studies have clearly shown that smoking increases the risk for Crohn disease. Although a number of other enivronmental factors have been studied - including various dietary constituents, infections, perinatal events, use of oral contraceptives and antibiotics - the data have led to weak associations at best.

What complications might you expect from the disease?

Growth failure is commonly see in Crohn disease (see section on "extraintestinal manifestations of Crohn disease"). Additionally corticosteroids can have a negative impact on linear growth in children with Crohn disease. Bone mineral density is often reduced in children with Crohn disease and can lead to osteoporosis/osteopenia. The pathogenesis is multifactorial, including effects of the disease inflammation and treatment effects (e.g., corticosteroids).

Dual-energy x-ray absorptiometry can help identify patients in need of aggressive management. Therapeutic management for decreased bone density includes controlling the intestinal inflammation; optimizing nutrition, calcium, and vitamin D intake; and promoting physical activity. For significant cases, consultation with a pediatric endocrinologist may be beneficial.

Malnutrition and nutritional deficiencies can occur (e.g., protein and mineral vitamin deficiencies). Development of anatomic lesions can occur and include strictures, fistulas, and perianal disease (e.g., abscess, fistula, fissures). These children can experience psychosocial problems, including poor school functioning, anxiety, depression, and psychological distress.

How can Crohn disease be prevented?

Currently there is no ability to identify with certainty who is at risk for the development of Crohn disease. Additionally, medical evidence is not available to suggest that any factors can be modified to prevent this condition, even if it is able to be identified. Individuals with the highest risk of development of IBD (10% risk) are siblings of individuals with IBD. Being homozygous for NOD2 mutations increases the risk of the development of Crohn disease approximately 20-fold.

What is the evidence?

Burger, D, Travis, S. "Conventional medical management of inflammatory bowel disease". Gastroenterology. vol. 140. 2011. pp. 1827-37.

(Review of conventional therapies used in the treatment of adults with IBD, with suggested algorithms based on medical evidence and expert consensus.)

Cho, JH, Brant, SR. "Recent insights into the genetics of inflammatory bowel disease". Gastroenterology. vol. 140. 2011. pp. 1704-12.

(Comprehensive review of the state of the art in IBD genetics.)

Conklin, LS, Oliva-Hemker, M. "Nutritional considerations in pediatric inflammatory bowel disease". Expert Rev Gastroenterol Hepatol. vol. 4. 2010. pp. 305-17.

(General review of nutritional evaluation, complications, and interventions in children with IBD.)

Cosnes, J, Gower-Rousseau, C, Sekski, P. "Epidemiology and natural history of inflammatory bowel disease". Gastroenterology. vol. 140. 2011. pp. 1785-94.

(Review of incidence, prevalence, and evolution of IBD over time.)

Fichera, A, Michelassi, F. "Surgical treatment of Crohn's disease". J Gastrointest Surg. vol. 11. 2007. pp. 791-803.

(Review of indications for surgical treatment and options available (including minimally invasive approaches) to Crohn disease.)

Grossman, AB, Baldassano, RN. "Specific considerations in the treatment of pediatric inflammatory bowel disease". Expert Rev Gastroneterol Hepatol. vol. 2. 2008. pp. 105-24.

(General review outlining unique manifestations of pediatric IBD, current trends in pharmacologic therapies.)

Heyman, MB, Kirschner, BS, Gold, BD. "Children with early-onset inflammatory bowel disease (IBD): analysis of a pediatric IBD consortium". J Pediatr. vol. 146. 2005. pp. 35-40.

(Presents data from a large pediatric registry discussing age-related differences in presentation, clinical complications and anatomic involvement.)

Hyams, J, Crandall, W, Kugathasan, S. "Induction and maintenance infliximab therapy for the treatment of moderate-to-severe Crohn's disease in children". Gastroenterology. vol. 132. 2007. pp. 863-73.

(Prospective, multicenter trial evaluating efficacy of infliximab for induction and maintenance of remission in pediatric Crohn's disease.)

Kugathasan, S, Judd, RH, Hoffmann, RG. "Epidemiologic and clinical characteristics of children with newly diagnosed inflammatory bowel disease in Wisconsin: statewide population-based study". J Pediatr. vol. 143. 2003. pp. 525-31.

(Population-based study describing epidemiology of pediatric IBD in the United States.)

Loftus, CG, Loftus, EV, Harmsen, WS. "Update on the incidence and prevalence of Crohn's disease and ulcerative colitis in Olmstead County, Minnesota 1940-2000". Inflamm Bowel Dis. vol. 13. 2007. pp. 254-61.

(Epidemiologic study of IBD in the United States.)

Markowitz, J, Grancher, K, Kohn, N. "A multicenter trial of 6-mercaptopurine and prednisone in children with newly diagnosed Crohn's disease". Gastroenterology. vol. 119. 2000. pp. 895-902.

(Study demonstrating efficacy and steroid-sparing properties of immunomodulators in pediatric IBD.)

Rosh, JR, Lerer, T, Markowitz, J. "Retrospective evaluation of the safety and effect of adalimumab therapy (RESEAT) in pediatric Crohn's disease". Am J Gastroenterol. vol. 104. 2009. pp. 3042-9.

(Retrospective study evaluating indications, safety, tolerability, and clinical response in a large multicenter patient cohort.)

Siegel, CA, Marden, SM, Persing, SM. "Risk of lymphoma associated with combination anti-tumor necrosis factor and immunomodulator therapy for the treatment of Crohn's disease: a meta-analysis". Clin Gastroenterol Hepatol. vol. 7. 2009. pp. 874-81.

(Meta-analysis presenting calculated risk of developing non-Hodgkin lymphoma in patients with Crohn disease treated with thiopurine immunomodulators and anti-TNF-α agents.)

Talley, NJ, Abreu, MT, Achkar, JP. "An evidence-based systematic review on medical therapies for inflammatory bowel disease". Am J Gastroenterol. vol. 106. 2011. pp. S2-25.

(Evidence-based statements on IBD therapies developed by the American College of Gastroenterology IBD Task Force.)

Tracey, D, Klareskog, L, Sasso, EH. "Tumor necrosis factor antagonist mechanisms of action: a comprehensive review". Pharmacol Ther. vol. 117. 2008. pp. 244-79.

(Extensive review of the possible mechanisms of action for the use of anti-TNF-α agents in the treatment of IBD and other immune-mediated disorders.)

Ongoing controversies regarding etiology, diagnosis, treatment

Development of biomarkers that will enable the identification of patients with Crohn disease at high risk for the development of aggressive disease is currently being researched. Ultimately the development of genetic/biomarker panels that identify individuals at high risk for the development of Crohn disease would also be beneficial.

Step-up versus top-down therapy is another controversial topic. Top-down therapy may benefit early promotion of mucosal healing, which may prevent long-term complications; however, this needs to be weighed against potentially serious adverse effects (e.g., serious infection, malignancy) and cost. Additionally there is a substantial group of patients whose disease would not require more potent treatments initially.

Postmarketing surveillance of patients with IBD who are receiving concomitant treatment with thiopurine immunomodulators (6-mercaptopurine, azathioprine) and an anti-TNF-α medication revealed a possible increase in the incidence of hepatosplenic T-cell lymphoma. Most have been male patients with a median age in young adulthood. Although the number of cases remain relatively small (several dozen), given that this malignancy has a very high mortality rate it has brought into question whether these two types of therapies should routinely be used in combination.

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