Continuing Education Activity

Crohn disease and ulcerative colitis are distinct clinical entities collectively referred to as "inflammatory bowel disease" (IBD). These gastrointestinal conditions have an unclear etiology, although genetic, environmental, and immunologic influences have been implicated. Crohn disease can affect any part of the digestive tract but most commonly involves the small intestine and proximal colon. Gastrointestinal symptoms are prominent, though extraintestinal pathology and systemic inflammation can also arise. Patients may initially present with nonspecific symptoms, and some may not have a clear family history. Thus, diagnostic and treatment delays are not uncommon. Understanding the condition's pathophysiology and evidenced-based management strategies can improve patient outcomes.

This activity for healthcare workers is designed to enhance learners' competence in evaluating and managing Crohn disease. This activity is also designed to equip learners with valuable insights to collaborate effectively with an interprofessional team caring for individuals with this condition.

Objectives:

• Identify the signs and symptoms indicative of Crohn disease.

• Create a clinically sound diagnostic strategy to evaluate a patient suspected to have Crohn disease.

• Differentiate the various Crohn disease treatment options to develop a personalized management plan for an individual diagnosed with this condition.

• Collaborate effectively with an interprofessional team to formulate short- and long-term care plans for patients with Crohn disease.

Introduction

Crohn disease is a form of inflammatory bowel disease (IBD) like ulcerative colitis, though Crohn disease often presents more subtly. Crohn disease is an immunologically mediated inflammatory gastrointestinal condition, with pathology involving the entire thickness of the bowel wall.

The condition may involve any part of the gastrointestinal tract. Minnesota data show that 19% of patients present with stricturing or fistulizing disease within 90 days of diagnosis. About half of all patients experience an intestinal complication, such as fistulae, phlegmons, strictures, and abscesses, within 20 years of diagnosis. Population-based studies from Northern Europe and Minnesota suggest that Crohn disease presents with ileal, ileocolonic, or colonic involvement each third of the time, with disease migration occurring in only 6% to 14% of patients.[1] Pathology in the upper gastrointestinal tract, ileal, or ileocolonic region portends a greater stricturing and fistulizing risk compared to colonic involvement.[2] Crohn disease may also have extraintestinal manifestations, which often involve the eyes, skin, liver, and joints. 

The disease runs a chronic and often progressive course. Frequent symptoms include diarrhea, abdominal pain, nausea, or vomiting. Weight loss, fever, and fatigue are systemic manifestations of this condition. Without treatment, longstanding inflammation can produce debilitating complications. Early diagnosis and management can help optimize quality of life and outcomes for patients with Crohn disease.[3][4][5][6][7]

Etiology

IBD's exact etiology is unknown. However, substantial evidence suggests that the condition may result from an inappropriate immune response to environmental antigens like drugs, toxins, infections, or intestinal microbes in a genetically susceptible host. Large-scale genome studies have identified over 200 IBD-associated genes and more than 71 Crohn disease–susceptibility loci.[8][9][10]

Genetic variants are associated with certain Crohn disease phenotypes. For example, NOD2/CARD15 mutations have been detected in patients with Crohn disease presenting with ileal involvement and increased severity at a younger age. These individuals often require surgical intervention. Genotyping is expected to provide prognostic information on disease severity in the future. Currently, genetic testing remains mostly a research tool.[11]

Epidemiology

Crohn disease is most commonly seen in North America, Northern Europe, and New Zealand. The condition has a bimodal distribution, with the onset occurring most frequently between ages 15 and 30 and 40 and 60. Crohn disease is more prominent in urban than rural areas. The condition has a high incidence in Northern Europeans and people of Jewish descent (incidence 3.2 per 1000 individuals). Prevalence in Asians, Africans, and South Americans is low.[12] However, recent studies have shown a significant increase in incidence in rapidly industrializing areas of Asia, Africa, and Australasia.[13]

Pathophysiology

Crohn disease is multifactorial. Genetic, infectious, immunological, environmental, and dietary factors contribute to the condition's development. The excessive immune response arises from innate and acquired mechanisms involving intestinal macrophages, neutrophils, and helper T-cells (T_h), promoting proinflammatory mediators like tumor necrosis factor-α (TNF-α). T_h1 and T_h17 are crucial mediators in the Crohn disease inflammatory cascade. Colonic Crohn lesions were found to have high levels of cytokines like interferon-γ and interleukins (ILs) 2, 12, and 18.[14][15][16] 

Inflammation in the initial stages of the illness gives rise to nonspecific symptoms such as fever and malaise. Diarrhea and abdominal pain arise from intestinal injury. Right lower quadrant (RLQ) pain may manifest due to ileocecal involvement. Terminal ileal damage can give rise to malabsorption and vitamin deficiencies. Anemia can arise from either vitamin B12 insufficiency or fecal blood loss, depending on which intestinal area is most involved. Extraction of inflammation can cause dysfunction of the surrounding organs due to fistulae formation.

Extraintestinal manifestations of Crohn disease are mostly due to systemic inflammation and include arthritis, uveitis, pericholangitis, and renal disorders. These conditions may appear before the intestinal manifestations. Systemic amyloidosis is a rare, late sequela.

Anatomy of the Small and Large Intestines

The small and large intestines comprise most of the gastrointestinal tract. The mucosal surfaces in these gut regions are designed for maximal absorption—of nutrients in the small bowel and water in the large bowel. Thus, more environmental antigens can enter the bloodstream through the gut than the skin and pulmonary tract.

The small intestine is typically 6 meters long and divided into the duodenum, jejunum, and ileum. The duodenum is retroperitoneal, while the jejunum and ileum are intraperitoneal. The ileum terminates in the ileocecal valve.

The mucosal surface of the small bowel consists of columnar absorptive epithelium and goblet, endocrine, and Paneth cells. Columnar cells occupying most of the small intestinal mucosa have numerous villi for absorbing nutrients. Under the microscope, these villi resemble a brush. Thus, this part of the small bowel luminal surface is called the "brush border." Each villus' core houses a portion of the lamina propria, which contains blood and lymph vessels, leukocytes, fibroblasts, and smooth muscle cells. The crypts of Lieberkuhn (or simply "crypts") are the furrows between the villi's bases extending as deep as the muscularis mucosa. The normal villus-to-crypt height is 4 to 5.1:1. 

Goblet, endocrine, and Paneth cells are scattered between the columnar cells and may be found in the crypts. Goblet cells secrete mucin for gut protection and lubrication. Gut endocrine cells secrete various peptides that regulate the digestive process. Paneth cells produce antimicrobial proteins like defensins. The crypts also contain stem cells, which replace damaged or sloughing luminal cells. 

In the duodenum, the submucosa contains Brenner glands. These glands secrete mucus, bicarbonate, glycoproteins, and pepsinogen II. Microscopically, Brenner glands resemble pyloric mucous glands.

The muscularis mucosa contains smooth muscle sheets anchoring the absorptive villi and crypts. The smooth muscle cells in this area facilitate villous folding and unfolding to maximize the gut absorptive surface. 

The large intestine (colon) is normally about 1.5 meters long and comprises the cecum and the ascending, transverse, and descending colon. The sigmoid colon extends from the pelvic brim, traverses within the peritoneum, and becomes the rectum at the S3 vertebral level. The distal rectum is extraperitoneal.

The colon's mucosal surface is lined mainly by columnar absorptive cells with shorter villi than small intestinal epithelial cells. The colonic crypts also contain goblet, endocrine, Paneth, and stem cells.

Both small and large intestinal mucosae have great regenerative capacities, with complete cell turnover occurring within a week. Thus, these gut segments have remarkable reparative abilities but are also prone to cytotoxic damage from cancer therapies.

Bacteria colonize the small and large bowel mucosae. Colonization is highest at the ileum. Nonpathogenic gram-negative bacterial strains, eg, nonpathogenic E coli, typically comprise the intestinal flora.

Mucosal and submucosal lymphoid tissue nodules are scattered throughout the intestines. In the ileum, these nodules form the Peyer patches. M cells in the surface epithelium covering the lymph nodules can engulf antigens intact from the intestinal lumen to the antigen-presenting cells beneath the mucosal surface. Antigen-presenting cells consist of macrophages and dendritic cells. T lymphocytes, activated B cells, and plasma cells are scattered in the lamina propria. Immunoglobulins are also scattered in the lamina propria, but the most abundant is immunoglobulin A. 

The outer muscular layers of the intestines are responsible for peristalsis. The myenteric plexus regulates movements in these layers. The serosal layer consists primarily of collagen and elastic fibers. A layer of mesothelial cells covers the serosa, secreting a serous fluid that lubricates the outer intestinal surfaces (see Image. Large Intestine Transverse Section).

Histopathology

Crohn disease's characteristic transmural inflammation can occur in the entire gastrointestinal tract from the mouth to the perianal area. However, the condition most frequently affects the terminal ileum and right colon.

The initial lesion starts as an infiltrate around an intestinal crypt. Ulceration then develops, initially involving only the superficial mucosa but later growing into the deeper layers. Noncaseating granulomas develop with continuing inflammation, spreading toward the intestinal wall. Granuloma formation is seen in up to 33% of patients with Crohn disease, but their absence does not exclude the diagnosis.

The classic mucosal cobblestone appearance with skip lesions develops along the length of the bowel and intervening areas of normal mucosa. Resolution of acute episodes results in scarring in previously inflamed intestinal areas.[17] Repeated inflammation-and-scarring cycles can lead to stricture formation and bowel obstruction. Inflammation can spread to adjacent organs, which may manifest as enterovesicular, enteroenteral, enterocutaneous, and enterovaginal fistulae.

History and Physical

History

Crohn disease manifests variably, depending on the area involved. Patients initially report recurrent episodes of mild abdominal pain, diarrhea, flatulence, and fever with intervening asymptomatic periods lasting weeks to months. Emotional or physical stress often precipitates the "flare" or "flare-up" symptoms. More serious, localizing signs start to appear after repeated flare-ups. A family history of IBD may or may not be reported.

Ileocolic involvement

Patients with ileocolitis typically report recurrent RLQ pain and diarrhea. The pain may be described as colicky and relieved by defecation. Crohn disease may present similarly to acute appendicitis, which also typically has fever, diarrhea, and RLQ pain as symptoms. An inflammatory RLQ mass may also be palpated in patients with CD.

A low-grade fever is more typical of Crohn disease. A different pathology, such as an intraabdominal abscess, must be suspected in the presence of a high-grade fever. Weight loss often develops due to diarrhea and fear of eating.

Years of recurrent inflammation typically lead to fibrostenosis and stricture formation in the ileocecal area. Diarrhea is later replaced by chronic bowel obstruction. Ileocecal wall thinning eventually occurs, leading to microperforation and fistula formation into nearby organs. Dysuria, pneumaturia, and recurrent urinary tract infections are often due to enterovesical fistulae. Enterocutaneous fistulae may manifest as surgical scar drainage, as surgical scars are relatively weaker areas than intact skin. Dyspareunia and feculent vaginal discharge may signify an enterovaginal fistula.

Jejunoileal disease

Involvement of these small bowel regions often causes malabsorption and steatorrhea. Nutritional deficiencies consequently arise, compounded by poor eating. Nutrients that may be lost to chronic diarrhea include iron, albumin, calcium, magnesium, fat-soluble vitamins (A, D, E, and K), niacin, folic acid, vitamin B₁₂, and trace minerals like zinc, selenium, and copper. Patients may present with symptoms attributable to insufficient levels of specific nutrients. Individuals with jejunoileal pathology may also develop fistulae and electrolyte imbalance.

Colitis with perianal involvement

More characteristic of this condition are manifestations like hematochezia, pain on defecation, reduced rectal wall elasticity, incontinence, anorectal pain and fistulae, perirectal abscesses, anal strictures, and hemorrhoidal tags. Bowel obstruction may result from colonic stricturing, which may warrant surgery. Fistulization into the stomach may cause feculent emesis. Fistulization into the small bowel may manifest as bacterial overgrowth and malabsorption. Rectovaginal fistula can also develop in women with this condition.

Gastroduodenal pathology

Upper gastrointestinal tract symptoms are more common in patients with this condition than in the other forms of Crohn disease. Such symptoms include emesis, nausea, and epigastric pain. Gastric ulcer diagnostic workups are likely to reveal the absence of H pylori. Upper gastrointestinal obstruction is common. Children may develop esophageal involvement.

Extraintestinal manifestations

Crohn disease is associated with extraintestinal manifestations involving various organs. These conditions include the following:[18]

• Eyes: episcleritis, scleritis, uveitis
• Mouth: stomatitis, aphthous ulcers
• Liver: gallstones, cholangitis, primary sclerosing cholangitis
• Kidneys: nephrolithiasis, hydronephrosis, urinary tract infections
• Joints: axial (ankylosing spondylitis) or peripheral (knees, ankles, wrists, elbows) arthritis
• Skin: erythema nodosum and pyoderma gangrenosum

Crohn disease also induces a hypercoagulable state, increasing the risk of thromboembolic disease.[19] Decreased mobility in hospitalized patients may result in deep vein thrombosis, stroke, or pulmonary embolism.

Physical Examination

A thorough physical examination with a detailed abdominal assessment is crucial for patients with abdominal complaints. General assessment in individuals with Crohn disease may reveal signs of malnutrition like pallor and low weight. Vital signs assessment of these patients may reveal fever, tachycardia, and hypotension. 

Abdominal inspection may reveal enterocutaneous fistulae in patients with advanced disease. Hyperactive bowel sounds may indicate inflammation or obstruction, while absent bowel sounds may suggest ileus or severe inflammation. Palpation may reveal tenderness localizing to the intestinal area involved. Guarding is a sign of peritonitis in individuals with intraabdominal perforation or abscess. Individuals with advanced perianal disease may have perianal fistulae or hemorrhoids, necessitating a digital rectal examination. 

The skin, eyes, oral cavity, and joints must be examined for extraintestinal manifestations of Crohn disease. Liver involvement may manifest with right upper quadrant tenderness and jaundice. Renal damage must be suspected in the presence of flank tenderness and genitourinary abnormalities like genital fistulae and perineal skin tags. Female patients with gynecological complaints must undergo a pelvic examination.

Neurologic deficits may be elicited in patients with vitamin deficiencies. Diminished sensation, muscle atrophy, and gait abnormalities may be observed. 

Overall, a thorough physical examination of patients with Crohn disease can help identify active inflammation, assess disease severity, detect complications, and guide further diagnostic evaluation and management.

Evaluation

Laboratory Tests

Stool tests to rule out infections include culture and sensitivities, ovum and parasites, and C. difficile toxins. Stool calprotectin can detect active Crohn disease and is used for monitoring disease activity.[20][21][22][23]

Blood tests, including a complete blood count and a metabolic panel, may reveal anemia (due to vitamin B12 or iron deficiency) and liver disease. Electrolytes may be deranged due to diarrhea. Increased creatinine, blood urea nitrogen, and liver enzymes may indicate renal and liver involvement, respectively. Urinalysis may reveal bacteriuria and leukocyturia. Specific nutrient deficiencies, eg, iron and calcium, may be documented by taking serum levels if the test results can be used to correct the problem.

Special serologic tests, such as antineutrophil cytoplasmic and anti-Saccharomyces cerevisiae antibodies, are not routinely indicated to distinguish Crohn disease from ulcerative colitis. C-reactive protein (CRP) or erythrocyte sedimentary rate elevation may reflect inflammation severity.[24][25]

Imaging

Plain x-rays should be ordered if bowel obstruction is suspected. Small bowel follow-through is often used to assess terminal ileal involvement. This modality can also detect fistulas. The classic string sign due to stricture formation or spasm is often seen.

Gastroenterologists may perform a quick abdominal ultrasound during flare-ups or monitoring of treatment response (see Image. Periumbilical Fistula Ultrasonography). Ultrasound does not pose a radiation risk and is widely available, though the image may not have good resolution. Features that may be appreciated using this modality include fistulae, free intraperitoneal fluid, abscess formation, and increased superior mesenteric artery flow. The superior mesenteric artery often has increased flow volume during active disease that may be documented by Doppler ultrasound. 

Abdominal and pelvic computed tomography (CT), magnetic resonance imaging (MRI), or enterography (MRE) can detect abscesses, strictures, and fistulization (see Image. Crohn Disease on Computed Tomography). Both give clearer images of the diseased intestine. However, MRI can provide more detail when investigating fistulizing disease. Additionally, MRI is preferable over CT in pediatric populations, as it emanates little ionizing radiation.

The bowel mucosa may be visualized by upper endoscopy and colonoscopy. Additionally, these modalities permit the assessment of the extent of bowel inflammation and tissue sample collection for disease confirmation. Endoscopic evaluation is also useful for assessing treatment response.

Video capsule endoscopy (VCE) can visualize the small bowel in patients with Crohn disease when regular endoscopy or colonoscopy cannot reach these areas. However, caution is advised in using VCE in the setting of known stricturing disease due to the potential for capsule retention within the strictured segment. Capsule endoscopy can only detect mucosal changes. In contrast, MRI can detect transmural inflammation and other complications.

Miscellaneous Tests

Crohn disease treatments suppress the immune system. The patient's vaccination history should thus be known before initiating the regimen. Vaccines to inquire about include tetanus, diphtheria, pertussis, human papillomavirus, influenza, pneumococcal, hepatitis A, hepatitis B, measles, mumps, rubella, varicella-zoster virus, and severe acute respiratory syndrome coronavirus 2.

Obtain a baseline tuberculosis screen, particularly in patients initiating anti-TNF biologics. Screening for latent tuberculosis may include a combination of history, tuberculin skin test, interferon-γ release assay, and chest radiography.[26] 

Baseline thiopurine methyltransferase (TPMT) levels should be checked before deciding on treatment options. Low TPMT levels may increase the risk of side effects, while very high levels may decrease the effectiveness of prescribed treatment.

Treatment / Management

Medical Management

Medical treatment of Crohn disease is typically divided into the induction and maintenance phases. During induction, inflammation control is ideally achieved within 3 months. The maintenance phase aims to prolong the asymptomatic phase.

The choice of medical therapy is based on the patient's risk profile and disease severity.

• Mild-to-moderate disease can be treated by oral mesalamine, immunomodulators like thiopurines (6-mercaptopurine, azathioprine), methotrexate, and steroids.
• Mesalamines (5-ASAs) and sulfasalazine (5-ASA with a sulfapyridine moiety) exert an anti-inflammatory effect. The use of 5-ASAs is not as well-established in Crohn disease as in ulcerative colitis. While these medications may be tried in mild colonic Crohn disease, use in small bowel disease is not effective.[27]
• Corticosteroids are primarily used to induce Crohn disease flare remission and stabilize the condition until immunomodulator or biologic therapy takes effect, particularly in moderate-to-severe Crohn disease. However, prolonged corticosteroid use, eg, for maintenance, is avoided due to chronic side effects like osteoporosis, osteonecrosis, and adrenal insufficiency.
• Immunomodulators are steroid-sparing drugs effective in the maintenance therapy of moderate Crohn disease. These medications have a relatively slow action onset—between 8 to 12 weeks—and are thus not used for active Crohn disease induction remission. However, immunomodulators may be initially combined with steroids.[28][29][30][31] Dosages for Crohn disease are azathioprine 1.5 to 2.5 mg/kg/day, 6-mercaptopurine 0.75 to 1.5 mg/kg day, and methotrexate (MTX) 15 to 25 mg once weekly. TPMT is the main enzyme that inactivates toxic thiopurine metabolites. A low TPMT level can increase the risk of side effects, while a high level can reduce treatment potency.[32] MTX is teratogenic and may affect spermatogenesis. Thus, women of childbearing age and men should be counseled to use contraception within 3 months of MTX use.
• Moderate-to-severe disease (including fistulizing disease) is best treated with combined immunomodulators and biologics or biologics alone.
• Corticosteroids are primarily used to induce remission in moderate-to-severe Crohn disease and should be used sparingly to avoid side effects.
• Immunomodulators serve as adjuncts that reduce immunogenicity against biologics. Notably, combination therapy with an immunomodulator and anti-TNF is more effective than monotherapy with either medication.[33]
• Anti-TNF agents (infliximab, adalimumab, and certolizumab pegol) block the downstream effects of the TNF inflammatory cascade. These agents are efficacious in steroid-resistant or immunomodulator-refractory Crohn disease. The effect onset is relatively rapid, with clinical benefit seen within 2 weeks of initiation. Anti-TNF drugs are effective in treating fistulizing disease and reducing the risk of postsurgical endoscopic recurrence.[34] However, caution is advised when using these agents in patients with a history of demyelinating disease, congestive heart failure, and malignancies like lymphoma.[35] Recent data demonstrate no associated increase in adverse maternal-fetal outcomes in pregnant patients exposed to anti-TNF therapy.[36] 
• Leukocyte trafficking agents selectively inhibit an adhesion protein (integrin α4β7) on a memory T cell subset, preventing the T cells' binding to gut mucosal cells. This action mechanism produces gut-specific anti-inflammatory effects. Vedolizumab is the agent in this class used in Crohn disease. This drug was found to be more effective than placebo in inducing and maintaining remission in Crohn disease, with or without immunomodulators.[37] However, the time to clinical effect may be slower (around 10 weeks) than anti-TNF agents, particularly in patients previously on anti-TNF therapy.[38] Gut-specific actions limit vedolizumab's toxicity. Thus, this drug's side effect profile is relatively favorable.
• IL-12/23 agents (ustekinumab, risankizumab) are efficacious in patients who failed prior corticosteroid, immunomodulator, or anti-TNF treatment.[39][40][41] Ustekinumab is a nonselective IL-12/23 inhibitor, while risankizumab is a selective IL-23 inhibitor. The side effect profile of these agents is relatively favorable according to safety surveillance data in psoriasis patients.[42]
• JAK inhibitors target Janus kinases that contribute to abnormal immune responses. Upadacitinib is the first FDA-approved oral selective JAK inhibitor therapy for Crohn disease. This medication is efficacious in patients who previously failed conventional and biologic Crohn disease therapies.[43] The onset of clinical effects is relatively rapid at 2 weeks. However, this drug increases Herpes Zoster risk. Thus, the shingles vaccine is recommended before treatment initiation. Use of upadacitinib during pregnancy is not advised due to findings of teratogenicity in animal studies.[44]

In 2021, the American Gastroenterology Association (AGA) published perianal and fistulizing Crohn disease management guidelines strongly recommending infliximab over no treatment for inducing and maintaining disease remission. This biologic is the only medication with dedicated randomized controlled trial (RCT) data demonstrating efficacy.[45] The AGA also strongly recommended combining biologic agents with an antibiotic instead of using biologic monotherapy for inducing fistula healing. This recommendation was based on 2 RCTs showing that anti-TNF agents combined with ciprofloxacin were more efficacious in inducing fistula remission than anti-TNF monotherapy. 

Surgical Management

Surgery is warranted when Crohn disease complications arise, such as bowel obstruction from fibrostenotic strictures, fistulization despite appropriate medical therapy, recurrent abscesses, perforated bowel, dysplasia, cancer, or medically refractory disease. Surgical resection and stricturoplasty are options for managing fibrostenotic disease, the most common surgical indication (see Image. Subtotal Colectomy in Severe Crohn Colitis). Short segment strictures may be considered for endoscopic dilation.

Fistulotomy may be performed for simple fistulas, defined as superficial or low transsphincteric fistulas without associated proctitis. Complex fistulas may warrant chronic seton placement. Mesenchymal stem cell injection into the fistula pathway to reduce inflammation shows promise and is undergoing investigation.[46]

The American Society of Colon and Rectal Surgeons recommends total colectomy with ileorectal anastomosis or total proctocolectomy for patients with Crohn colitis with dysplasia not amenable to endoscopic resection. Other recommended indications are multifocal dysplasia and colorectal cancer. The recommendation is based on the increased metachronous colorectal cancer risk (14-40%) and high multifocal dysplasia rates in patients with Crohn's colitis who underwent colectomy for low- or high-grade dysplasia.[47][48][49]

A diverting ileostomy rather than primary anastomosis is usually considered when performing ileocolectomy in Crohn disease patients with multiple risk factors for an anastomotic leak. Such risk factors include smoking, steroid use, and weight loss.[47] 

Residual postsurgical disease or high postsurgical recurrence risk warrants postoperative biologic therapy, eg, with an anti-TNF agent, 2 to 4 weeks after surgery if postoperative infections have been ruled out.[47] 

Treatment Monitoring

The AGA recommended in 2023 that monitoring Crohn disease treatment response should be based on the presence of clinical symptoms and biomarker levels.[50] Biomarkers may be taken every 6 to 12 months in patients in remission and more frequently in those requiring therapy titration.

Suggested biomarkers are fecal calprotectin and serum CRP. Targets should be less than 150 μg/g for calprotectin and less than 5 mg/L for CRP to rule out active inflammation and avoid routine endoscopic evaluation of disease activity.

The AGA further recommended the following:

• Endoscopic or radiologic confirmation of disease remission within 3 years of symptomatic remission
• Biomarkers every 2 to 4 months to assess therapeutic response during active disease

A follow-up endoscopy should be performed 6 to 12 months after symptom resolution to document mucosal healing.

A fecal calprotectin of less than 50 μg/g is sufficient to rule out disease recurrence in patients who have remained asymptomatic 12 months after surgical remission. Routine endoscopic assessment is not required in these patients. The same biomarker and target may be used in asymptomatic individuals with low postoperative recurrence risk or higher postoperative recurrence risk but already on prophylactic medication. High-risk patients not on prophylactic medication should undergo endoscopic evaluation for disease activity assessment.

Dietary Management

Diet remains an adjunctive therapy. Dietitian input and nutritional supplementation are highly recommended during Crohn disease treatment, as symptomatic patients are at risk for malnutrition and micronutrient deficiencies. For example, individuals with a history of terminal ileum inflammation or resection are at higher risk for vitamin B12 deficiency.[51][52][53][54]

Data predominantly from the pediatric population show that certain dietary therapies, such as elemental and semielemental diets, effectively reduce mucosal inflammation.[55] However, these diets have been largely unsuccessful in adults due to poor adherence. Benefits are also not durable due to inflammation recurrence after resuming a nonrestrictive diet.

Differential Diagnosis

The differential diagnoses to consider when assessing patients with possible Crohn disease are listed below. Documentation of travel and exposure history and judicious use of laboratory, imaging, and histologic tests help differentiate the above diagnoses.

• Infectious enteritis and terminal ileitis
  • Coccidioides
  • Histoplasma
  • Salmonella
  • Tuberculosis
  • Yersinia
• Infectious colitis
  • Amebiasis
  • Campylobacter
  • C.difficile
  • Cytomegalovirus 
  • E.coli
  • Salmonella
  • Shigella
• Noninfectious
  • Behcet disease
  • Common variable immunodeficiency
  • Diverticulitis
  • Drug-induced colitis, eg, from nonsteroidal anti-inflammatory drugs and immunotherapy
  • Ischemic colitis
  • Sarcoidosis
  • Segmental colitis associated with diverticulosis
  • Small vessel vasculitis
  • Solitary rectal ulcer syndrome

Prognosis

High-risk patients with moderate-to-severe Crohn disease often have the following characteristics:

• Relatively younger age, ie, younger than 30 years
• History of active or recent tobacco consumption
• Elevated CRP or fecal calprotectin levels
• Deep ulcers on colonoscopy
• Involvement of long bowel segments
• Perianal disease
• Extraintestinal manifestations
• History of bowel resections [56][57]

Without immunomodulator or biologic therapy, up to 50% of patients may become steroid-dependent or treatment-resistant, with a cumulative incidence of abdominal surgery of 46.6% 10 years after diagnosis.[58] The postsurgical endoscopic recurrence risk at or above the surgical anastomosis is around 90%. Risk factors for early recurrence include cigarette smoking, short duration between Crohn disease diagnosis to the first surgery, need for multiple resections, and penetrating disease.[59] Surveillance endoscopy is recommended in 6 to 12 months once a patient has had surgery. Ileocolonoscopy should be repeated in 1 to 3 years without endoscopic recurrence.

Prior meta-analyses show a slight mortality risk in patients with Crohn disease, with a standardized pooled mortality ratio of 1.4 to 1.5 compared to the general population. This outcome is attributable to gastrointestinal disease, gastrointestinal cancer, and pulmonary disease.[60][61] Current corticosteroid use is further associated with increased mortality.[62]

Complications

Crohn disease is a systemic illness with many intestinal and extraintestinal manifestations. Some of the complications associated with this condition are listed below. Early detection and treatment adherence can reduce the risk of these complications.

• Stricture formation
• Fistulae and abscesses
• Colorectal carcinoma
• Ankylosing spondylitis
• Episcleritis, iritis
• Erythema nodosum, pyoderma gangrenosum
• Nephrolithiasis
• Cholelithiasis
• Anemia
• Hypercoagulable state
• Osteoporosis
• Osteonecrosis
• Macro and micronutrient deficiencies
• Infections

Deterrence and Patient Education

Preventing Crohn disease is challenging because the exact cause of this condition remains unknown. However, the strategies below may help reduce the risk of developing Crohn disease or mitigate its severity:

• Genetic counseling: Individuals with a family history of Crohn disease may benefit from genetic counseling to understand their risk of developing the condition and discuss potential preventive measures or screening options.
• Early detection and treatment of symptoms: Being vigilant about recognizing and promptly addressing symptoms suggestive of Crohn disease, such as persistent abdominal pain, diarrhea, rectal bleeding, unexplained weight loss, and fatigue, may help prevent complications and improve long-term outcomes. Seeking medical attention promptly for early signs of Crohn disease is crucial for initiating appropriate treatment and disease management strategies.
• Dietary modifications: No specific diet has been proven to prevent Crohn disease, but some dietary factors may influence disease risk or exacerbate symptoms in susceptible individuals. Controlling sugar intake and avoiding foods that trigger the symptoms may help prevent flare-ups.
• Avoiding environmental triggers: Environmental factors that may contribute to Crohn disease development or exacerbation and thus must be avoided include cigarette smoke, air pollution, medications like nonsteroidal anti-inflammatory drugs, and infections.

Secondary prevention consists of measures that help avoid complications after a Crohn disease diagnosis. The following steps may help:

• Medication adherence: Compliance with prescribed treatment regimens is essential for managing symptoms, reducing inflammation, preventing disease flares, and minimizing the risk of complications. When counseling patients, taking medications as directed, attending regular follow-up appointments, and promptly communicating symptom changes must be emphasized.
• Cancer screening: Patients with Crohn disease are prone to malignancies, which may include skin and gastrointestinal tumors. Patients should undergo skin cancer screening irrespective of the regimen they received. More frequent screening colonoscopy, ie, every 1 to 3 years, is recommended to detect colon cancer early in patients with inflammation involving at least a third of the colon.
• Osteoporosis prevention: Steroid treatment and Crohn disease–related vitamin deficiencies make patients susceptible to osteoporosis. Bone density should be regularly assessed to allow timely osteoporosis recognition and management.
• Infection prevention: Immunosuppressive therapy makes patients with Crohn disease vulnerable to infections. Vaccination against lung pathogens, such as pneumococcus, H influenzae, and influenza virus, is recommended. The decision to vaccinate against other microbial agents must be based on patient and geographic factors.

Individual responses to these measures may vary, so not all may be applicable or effective for everyone. Further research is needed to better understand the underlying causes of Crohn disease and identify more targeted preventive and treatment approaches.

Enhancing Healthcare Team Outcomes

Crohn disease is a serious chronic inflammatory disorder that poses various diagnostic and management challenges. This condition's potential to cause multiorgan damage makes an interprofessional care approach imperative. The interprofessional team caring for patients with Crohn disease should include the following:

• Primary care physicians are usually the first to evaluate patients with mild abdominal complaints, prescribe initial treatment, and refer the patient to specialists for further evaluation and management.
• Internists may lend expertise in diagnosing recurrent abdominal symptoms associated with systemic manifestations like fever and weight loss. Internists may prescribe additional treatments and refer the patient for further specialized care.
• Gastroenterologists are specialists who can perform diagnostic and therapeutic endoscopies, prescribe more targeted therapies, and monitor the disease course.
• Colorectal surgeons may be involved if patients present with complications like fistulae and intestinal obstruction.
• Dietitians educate the patient on the appropriate diet to avoid malnutrition and micronutrient deficiencies. 
• Nurses: administer treatments, educate the postsurgical patient on treating stomas and surgical wounds, monitor patient progress, and coordinate care.
• Pharmacists educate the patient regarding their prescribed medical regimens, particularly the benefits, adverse effects, and cruciality of compliance.
• Rheumatologists, neurologists, ophthalmologists, hepatologists, nephrologists, dermatologists, and otorhinolaryngologists are specialists who may be consulted to manage Crohn associated extraintestinal problems. 
• Mental health providers may lend their expertise to patients who develop depression and severe anxiety due to their symptoms and possible complications.

The prognosis for most patients with Crohn disease is guarded, and the quality of life is often poor.[63] An interprofessional team approach can optimize outcomes within the condition's limitations.