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Crohn disease and ulcerative colitis are distinct disorders collectively referred to as inflammatory bowel disease. Crohn disease is multifactorial, involving genetic susceptibility, dysregulated immune responses, and environmental triggers such as smoking. Transmural inflammation driven by aberrant helper T-cell activity and cytokine signaling leads to noncaseating granuloma formation and progressive tissue injury. The condition can affect any segment of the gastrointestinal tract but most commonly involves the terminal ileum and proximal colon. Patients who develop Crohn disease often present with abdominal pain, chronic diarrhea, weight loss, and fatigue. Extraintestinal manifestations, including arthropathy and skin lesions, may also occur. Diagnosis is established using endoscopy, histopathology, and cross-sectional imaging. Management includes anti-inflammatory agents, immunomodulators, biologic therapy, and surgery for refractory disease or complications such as strictures, fistulas, and abscesses. The disease follows a chronic, relapsing course, and early recognition with appropriate treatment is essential to reduce morbidity and preserve quality of life. This activity for healthcare workers is designed to enhance learners' competence in evaluating and managing Crohn disease. Participants will gain deeper insights into the condition's etiology, risk factors, pathophysiology, clinical presentation, and evidence-based diagnostic and therapeutic approaches. Improved proficiency will equip learners to collaborate effectively with interprofessional teams caring for individuals with Crohn disease. 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. Develop a personalized, evidence-based plan for managing Crohn disease and mitigating its potential sequelae. Collaborate with the interprofessional team to educate, treat, and monitor patients with Crohn disease to improve long-term outcomes. Access free multiple choice questions on this topic.

Crohn disease is a chronic inflammatory bowel disease (IBD) distinct from ulcerative colitis, often presenting with subtle or nonspecific symptoms. Crohn disease is an immunologically mediated gastrointestinal disorder characterized by transmural inflammation that can involve any segment of the gastrointestinal tract. Population-based studies from Northern Europe and Minnesota report ileal, ileocolonic, and colonic involvement in roughly equal proportions, with disease migration occurring in only 6% to 14% of patients.[1] Pathology limited to the upper gastrointestinal tract, ileum, or ileocolonic region is associated with a higher risk of stricturing and fistulizing complications than isolated colonic involvement.[2] Minnesota data indicate that 19% of patients present with stricturing or fistulizing disease within 90 days of diagnosis, and approximately 50% develop complications such as fistulae, phlegmons, strictures, or abscesses within 20 years. Extraintestinal manifestations may involve the eyes, skin, liver, and joints. The disease follows a chronic, progressive course. Diarrhea, abdominal pain, nausea, and vomiting are common, while weight loss, fever, and fatigue reflect systemic inflammation. Without timely intervention, persistent inflammation can result in disabling complications. Early diagnosis and evidence-based management are essential to optimize long-term outcomes and preserve quality of life.[3][4][5][6][7]

The precise etiology of IBD is undefined. Evidence indicates that the condition arises from an inappropriate immune response to environmental antigens, including drugs, toxins, infections, and intestinal microbes, in genetically susceptible individuals. Large-scale genome-wide association studies have identified more than 200 IBD-associated genes and over 71 Crohn disease-susceptibility loci.[8][9][10] Specific genetic variants correlate with distinct Crohn disease phenotypes. Mutations in NOD2/CARD15, for example, are associated with ileal involvement, earlier onset, and increased disease severity, often necessitating surgical intervention. Although genotyping holds promise for prognostication and individualized treatment planning, genetic testing is not yet widely used in routine clinical practice and remains primarily a research tool.[11]

Crohn disease is most prevalent in North America, Northern Europe, and New Zealand. The condition exhibits a bimodal age distribution, with peak onset between 15 and 30 years and 40 and 60 years. Incidence is higher in urban compared with rural populations and is particularly elevated among individuals of Northern European or Jewish descent, with incidence rates typically ranging from approximately 5 to over 12 per 100,000 person-years in these groups.[12][13] Prevalence is low in Asian, African, and South American populations.[14] However, recent evidence indicates a marked rise in incidence in rapidly industrializing regions of Asia, Africa, and Australasia.[15]

Crohn disease is a multifactorial condition influenced by genetic, infectious, immunological, environmental, and dietary factors. Dysregulated immune responses arise from innate and adaptive mechanisms involving intestinal macrophages, neutrophils, and T-helper cells, promoting proinflammatory mediators such as tumor necrosis factor α (TNF-α). T-helper 1 (Th1) and T-helper 17 (Th17) cells are central to the Crohn disease inflammatory cascade. Colonic lesions exhibit elevated levels of cytokines, including interferon γ and interleukins 2, 12, and 18.[16][17][18] Inflammatory processes during the early stages of the illness generate systemic symptoms that are often nonspecific, such as fever and malaise. Intestinal injury leads to diarrhea and abdominal pain, with right lower quadrant (RLQ) discomfort commonly reflecting ileocecal involvement. Terminal ileal damage may result in malabsorption and vitamin deficiencies, while anemia can arise from vitamin B12 deficiency or chronic fecal blood loss, depending on the site of intestinal involvement. Transmural inflammation can extend to adjacent structures, forming fistulae and causing secondary organ dysfunction. Extraintestinal manifestations, primarily driven by systemic inflammation, include arthritis, uveitis, pericholangitis, and renal disorders, which may precede gastrointestinal symptoms. Rare late complications include systemic amyloidosis. Anatomy of the Small and Large Intestines The gastrointestinal tract consists primarily of the small and large intestines. Mucosal specialization allows for efficient absorption of nutrients in the small intestine and water in the large intestine. Consequently, the gastrointestinal tract permits greater exposure to environmental antigens than the skin or respiratory tract. The small intestine measures approximately 6 meters in length and is divided into the duodenum, jejunum, and ileum. The duodenum is retroperitoneal, whereas the jejunum and ileum are intraperitoneal. The ileum terminates at the ileocecal valve.

The gastrointestinal tract consists primarily of the small and large intestines. Mucosal specialization allows for efficient absorption of nutrients in the small intestine and water in the large intestine. Consequently, the gastrointestinal tract permits greater exposure to environmental antigens than the skin or respiratory tract. The small intestine measures approximately 6 meters in length and is divided into the duodenum, jejunum, and ileum. The duodenum is retroperitoneal, whereas the jejunum and ileum are intraperitoneal. The ileum terminates at the ileocecal valve. The small intestinal mucosa is composed of columnar absorptive epithelium interspersed with goblet, endocrine, and Paneth cells. Columnar cells, which occupy the majority of the mucosal surface, form villi that maximize nutrient absorption. Microscopically, these villi resemble a brush, hence the term “brush border.” Each villus contains a core of lamina propria housing blood and lymphatic vessels, leukocytes, fibroblasts, and smooth muscle cells. Crypts of Lieberkuhn are the invaginations between villus bases, extending to the muscularis mucosa. The normal villus-to-crypt height ratio ranges from 4:1 to 5.1:1. Goblet, endocrine, and Paneth cells are interspersed among the columnar cells and within the crypts. Goblet cells secrete mucin, providing mucosal protection and lubrication. Enteroendocrine cells release peptides that regulate digestive function, while Paneth cells produce antimicrobial proteins, including defensins. Crypts also house stem cells, which replenish damaged or sloughed epithelial cells. In the duodenum, the submucosa contains Brunner glands, which secrete mucus, bicarbonate, glycoproteins, and pepsinogen II. Histologically, Brunner glands resemble pyloric mucous glands. The muscularis mucosa consists of smooth muscle sheets that anchor villi and crypts. Contraction of these muscle fibers facilitates villous folding and unfolding, optimizing absorptive surface area. The large intestine measures approximately 1.5 meters in length and includes the cecum, ascending colon, transverse colon, and descending colon. The sigmoid colon extends from the pelvic brim within the peritoneum and transitions into the rectum at the S3 vertebral level. The distal rectum is extraperitoneal.

The muscularis mucosa consists of smooth muscle sheets that anchor villi and crypts. Contraction of these muscle fibers facilitates villous folding and unfolding, optimizing absorptive surface area. The large intestine measures approximately 1.5 meters in length and includes the cecum, ascending colon, transverse colon, and descending colon. The sigmoid colon extends from the pelvic brim within the peritoneum and transitions into the rectum at the S3 vertebral level. The distal rectum is extraperitoneal. The colon's mucosal surface is lined primarily by columnar absorptive cells, which have shorter villi than those of the small intestine. Colonic crypts also contain goblet, endocrine, Paneth, and stem cells. Both small and large intestinal mucosae exhibit high regenerative capacity, with complete epithelial turnover occurring within approximately 1 week. Thus, these segments possess remarkable reparative ability but remain susceptible to cytotoxic injury from cancer therapies. Bacterial colonization occurs throughout the small and large intestine, with the highest density in the ileum. Nonpathogenic gram-negative strains, such as Escherichia coli, typically comprise the intestinal flora. Mucosal and submucosal lymphoid nodules are distributed throughout the intestines. In the ileum, these nodules aggregate to form Peyer patches. M cells in the epithelium overlying lymphoid nodules transport intact antigens from the intestinal lumen to underlying antigen-presenting cells, which include macrophages and dendritic cells. T lymphocytes, activated B cells, and plasma cells are dispersed throughout the lamina propria. Immunoglobulins are also present, with immunoglobulin A being the most abundant. The outer muscular layers of the intestines generate peristaltic movements, which are coordinated by the myenteric plexus. The serosa consists primarily of collagen and elastic fibers and is covered by a layer of mesothelial cells that secrete serous fluid to lubricate the outer intestinal surfaces (see Image. Large Intestine Transverse Section).

Crohn disease is characterized by transmural inflammation that can affect the entire gastrointestinal tract, from the oral cavity to the perianal region. The terminal ileum and right colon are most commonly involved. The initial lesion begins as an inflammatory infiltrate surrounding an intestinal crypt. Ulceration develops, initially limited to the superficial mucosa, and subsequently extends into deeper layers. Persistent inflammation may lead to noncaseating granuloma formation, which occurs in up to 33% of patients. Absence of granulomas does not exclude the diagnosis. The classic mucosal cobblestone pattern with skip lesions develops along affected bowel segments, interspersed with areas of normal mucosa. Resolution of acute inflammation leaves fibrotic scarring in previously affected areas.[19] Recurrent cycles of inflammation and scarring may result in stricture formation and bowel obstruction. Extension of inflammation to adjacent organs can produce enterovesicular, enteroenteral, enterocutaneous, or enterovaginal fistulae.

History Crohn disease presents variably, depending on the affected gastrointestinal segment. Initial symptoms often include recurrent mild abdominal pain, diarrhea, flatulence, and low-grade fever, interspersed with asymptomatic periods lasting weeks to months. Physical or emotional stress may precipitate symptom flares. Repeated exacerbations eventually produce more localized and severe manifestations. A family history of IBD may or may not be reported. Ileocolic involvement Patients with ileocolitis commonly report recurrent RLQ pain and diarrhea. The pain is often colicky and may be relieved by defecation. Crohn disease can mimic acute appendicitis, which also presents with RLQ pain, fever, and diarrhea. An inflammatory RLQ mass may be palpable in some cases. Low-grade fever is typical. High-grade fever should prompt consideration of alternative pathology, such as an intra-abdominal abscess. Weight loss frequently occurs due to chronic diarrhea and reduced oral intake. Chronic, recurrent inflammation commonly results in fibrostenotic changes and stricture formation at the ileocecal region. Diarrhea may be replaced by chronic bowel obstruction. Progressive ileocecal wall thinning can lead to microperforation and fistula formation involving adjacent organs. Enterovesical fistulae may present with dysuria, pneumaturia, or recurrent urinary tract infections. Enterocutaneous fistulae may manifest as drainage from surgical scars, which are structurally weaker than intact skin. Enterovaginal fistulae may produce dyspareunia and feculent vaginal discharge. Jejunoileal disease Involvement of the jejunum and ileum frequently leads to malabsorption and steatorrhea. Nutritional deficiencies may develop, compounded by reduced oral intake. Chronic diarrhea can result in loss of iron, albumin, calcium, magnesium, fat-soluble vitamins (A, D, E, and K), niacin, folic acid, vitamin B12, and trace elements such as zinc, selenium, and copper. Patients may present with clinical manifestations related to specific nutrient deficiencies. Jejunoileal pathology can also contribute to fistula formation and electrolyte imbalances. Colitis with perianal involvement

Involvement of the jejunum and ileum frequently leads to malabsorption and steatorrhea. Nutritional deficiencies may develop, compounded by reduced oral intake. Chronic diarrhea can result in loss of iron, albumin, calcium, magnesium, fat-soluble vitamins (A, D, E, and K), niacin, folic acid, vitamin B12, and trace elements such as zinc, selenium, and copper. Patients may present with clinical manifestations related to specific nutrient deficiencies. Jejunoileal pathology can also contribute to fistula formation and electrolyte imbalances. Colitis with perianal involvement Characteristic manifestations include hematochezia, pain on defecation, reduced rectal wall elasticity, incontinence, anorectal pain, fistulae, perirectal abscesses, anal strictures, and hemorrhoidal tags. Colonic strictures may cause bowel obstruction, occasionally requiring surgical intervention. Fistulization into the stomach can result in feculent emesis, while small bowel fistulae may lead to bacterial overgrowth and malabsorption. Rectovaginal fistulae may also occur in affected women. Gastroduodenal pathology Upper gastrointestinal involvement is more common in these patients than in other forms of Crohn disease. Symptoms include nausea, emesis, and epigastric pain. Gastric ulcer evaluation often reveals the absence of Helicobacter pylori infection. Upper gastrointestinal obstruction is frequent, and children may develop esophageal involvement. Extraintestinal manifestations Crohn disease is frequently associated with extraintestinal manifestations affecting multiple organ systems. These manifestations include the following: 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, pyoderma gangrenosum [20] Crohn disease also promotes a hypercoagulable state, increasing the risk of thromboembolic events.[21] Reduced mobility, particularly in hospitalized patients, may predispose to deep vein thrombosis, stroke, or pulmonary embolism. Physical Examination

Joints: Axial (ankylosing spondylitis) or peripheral (knees, ankles, wrists, elbows) arthritis Skin: Erythema nodosum, pyoderma gangrenosum [20] Crohn disease also promotes a hypercoagulable state, increasing the risk of thromboembolic events.[21] Reduced mobility, particularly in hospitalized patients, may predispose to deep vein thrombosis, stroke, or pulmonary embolism. Physical Examination A thorough physical examination, including a detailed abdominal assessment, is essential in patients presenting with abdominal complaints. General examination may reveal signs of malnutrition, such as pallor and low body weight. Vital signs may demonstrate fever, tachycardia, or hypotension. Abdominal inspection can identify enterocutaneous fistulae in patients with advanced disease. Hyperactive bowel sounds may indicate inflammation or obstruction, whereas absent bowel sounds suggest ileus or severe inflammation. Palpation may elicit tenderness corresponding to the affected intestinal segment. Guarding is indicative of peritonitis in cases of intra-abdominal perforation or abscess. Advanced perianal disease may manifest as perianal fistulae or hemorrhoids, warranting a digital rectal examination. The skin, eyes, oral cavity, and joints should be examined for extraintestinal manifestations of Crohn disease. Liver involvement may present with right upper quadrant tenderness and jaundice. Renal pathology should be considered in patients with flank tenderness or genitourinary abnormalities, including genital fistulae and perineal skin tags. Female patients with gynecological complaints require a pelvic examination. Neurologic deficits may arise from vitamin deficiencies, manifesting as diminished sensation, muscle atrophy, or gait abnormalities. Comprehensive physical examination of patients with Crohn disease allows identification of active inflammation and evaluation of disease severity. The examination also aids in detecting complications and guiding subsequent diagnostic and management decisions.

Laboratory Tests Stool tests to exclude infections include culture and sensitivity, ova and parasites, and Clostridioides difficile toxins. Stool calprotectin can detect active Crohn disease and is useful for monitoring disease activity.[22][23][24][25] Blood tests, including complete blood count and metabolic panel, may reveal anemia secondary to vitamin B12 or iron deficiency and evidence of liver disease. Electrolyte disturbances may result from diarrhea. Elevated creatinine, blood urea nitrogen, or liver enzymes may indicate renal or hepatic involvement. Urinalysis can detect bacteriuria or leukocyturia. Specific nutrient deficiencies, such as iron and calcium, may be documented with serum measurements when results guide therapeutic correction. Special serologic tests, including antineutrophil cytoplasmic antibodies and anti-Saccharomyces cerevisiae antibodies, are not routinely indicated to distinguish Crohn disease from ulcerative colitis. Elevated C-reactive protein (CRP) or erythrocyte sedimentation rate may reflect the severity of inflammation.[26][27] Imaging Plain radiographs are indicated when bowel obstruction is suspected. Small bowel follow-through is frequently used to evaluate terminal ileal involvement and can also detect fistulae. The classic “string sign,” caused by stricture formation or spasm, is often observed. Gastroenterologists may perform abdominal ultrasonography to evaluate flare-ups or monitor treatment response (see Image. Periumbilical Fistula Ultrasonography). Ultrasound does not involve ionizing radiation and is widely accessible, although spatial resolution may be limited. Findings that can be assessed with this modality include fistulae, free intraperitoneal fluid, abscesses, and increased superior mesenteric artery flow. Doppler ultrasonography can document elevated flow volume in the superior mesenteric artery during active disease. Abdominal and pelvic computed tomography (CT), magnetic resonance imaging (MRI), or magnetic resonance enterography can detect abscesses, strictures, and fistulae (see Image. Crohn Disease on Computed Tomography). These modalities provide clearer visualization of diseased intestinal segments, though MRI offers superior detail for evaluating fistulizing disease. MRI is preferred over CT in pediatric populations due to minimal exposure to ionizing radiation.

Abdominal and pelvic computed tomography (CT), magnetic resonance imaging (MRI), or magnetic resonance enterography can detect abscesses, strictures, and fistulae (see Image. Crohn Disease on Computed Tomography). These modalities provide clearer visualization of diseased intestinal segments, though MRI offers superior detail for evaluating fistulizing disease. MRI is preferred over CT in pediatric populations due to minimal exposure to ionizing radiation. The bowel mucosa may be directly examined via upper endoscopy and colonoscopy. These procedures allow assessment of inflammation extent and permit tissue sampling for diagnostic confirmation. Endoscopy is also useful for monitoring treatment response. Video capsule endoscopy (VCE) enables visualization of small bowel segments inaccessible by conventional endoscopy or colonoscopy. Caution is warranted in patients with known strictures, given the risk of capsule retention. Video capsule endoscopy is limited to detecting mucosal changes, whereas MRI can assess transmural inflammation and related complications. Miscellaneous Tests Crohn disease treatments suppress the immune system, making knowledge of the patient’s vaccination history essential prior to therapy initiation. Vaccines to review 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. Baseline tuberculosis screening is recommended, particularly for patients initiating anti-TNF biologics. Screening for latent tuberculosis may involve history taking, tuberculin skin testing, interferon-γ release assays, and chest radiography.[28] Thiopurine methyltransferase (TPMT) activity should be assessed before selecting treatment options. Low TPMT activity increases the risk of adverse effects, whereas very high activity may reduce treatment efficacy.

Medical Management Medical management of Crohn disease is generally divided into induction and maintenance phases. The induction phase aims to achieve inflammation control, ideally within 3 months. The maintenance phase is designed to prolong remission. Selection of medical therapy is guided by the patient’s risk profile and disease severity. Mild-to-moderate disease Mild-to-moderate Crohn disease may be managed with oral mesalamine, immunomodulators such as thiopurines (6-mercaptopurine, azathioprine) or methotrexate (MTX), and corticosteroids. Mesalamines (5-ASAs) and sulfasalazine, a 5-ASA linked to a sulfapyridine moiety, exert anti-inflammatory effects. The efficacy of these agensts is less established in Crohn disease than in ulcerative colitis. Oral anti-inflammatory 5-ASAs may be considered in mild colonic Crohn disease but are generally ineffective for small bowel involvement.[29] Corticosteroids are primarily used to induce remission during disease flares and stabilize patients until immunomodulators or biologics achieve therapeutic effect, particularly in moderate-to-severe disease. Prolonged corticosteroid therapy is avoided for maintenance because of chronic adverse effects, including osteoporosis, osteonecrosis, and adrenal insufficiency. Immunomodulators are steroid-sparing drugs used effectively for maintenance therapy in moderate Crohn disease. These medications have a delayed onset of action, typically between 8 and 12 weeks, and are, therefore, not indicated for the induction of remission in active disease. Immunomodulators may be combined initially with corticosteroids to bridge this gap.[30][31][32][33] Standard dosing for Crohn disease includes azathioprine 1.5 to 2.5 mg/kg/day, 6-mercaptopurine 0.75 to 1.5 mg/kg/day, and MTX 15 to 25 mg once weekly. TPMT is the primary enzyme responsible for inactivating toxic thiopurine metabolites. As mentioned, low TPMT activity increases the risk of adverse effects, whereas high activity may reduce therapeutic efficacy.[34] MTX is teratogenic and may impair spermatogenesis. Therefore, women of childbearing potential and men should be counseled to use effective contraception for at least 3 months after MTX administration. Moderate-to-severe disease

Standard dosing for Crohn disease includes azathioprine 1.5 to 2.5 mg/kg/day, 6-mercaptopurine 0.75 to 1.5 mg/kg/day, and MTX 15 to 25 mg once weekly. TPMT is the primary enzyme responsible for inactivating toxic thiopurine metabolites. As mentioned, low TPMT activity increases the risk of adverse effects, whereas high activity may reduce therapeutic efficacy.[34] MTX is teratogenic and may impair spermatogenesis. Therefore, women of childbearing potential and men should be counseled to use effective contraception for at least 3 months after MTX administration. Moderate-to-severe disease Moderate-to-severe Crohn disease, including fistulizing forms, is optimally managed with biologics alone or in combination with immunomodulators. Corticosteroids are primarily employed to induce remission in moderate-to-severe disease and should be used sparingly to minimize adverse effects. Immunomodulators act as adjuncts by reducing immunogenicity against biologic therapies. Combination therapy with an immunomodulator and an anti-TNF agent has demonstrated greater efficacy than monotherapy with either drug alone.[35] Anti-TNF agents, including infliximab, adalimumab, and certolizumab pegol, inhibit downstream signaling in the TNF inflammatory cascade. These drugs are effective in steroid-resistant or immunomodulator-refractory Crohn disease, with clinical benefit often observed within 2 weeks of initiation. Anti-TNF therapy is particularly effective in treating fistulizing disease and reducing the risk of postsurgical endoscopic recurrence.[36] Caution is warranted in patients with a history of demyelinating disease, congestive heart failure, or malignancies such as lymphoma.[37] Current evidence indicates that anti-TNF therapy does not increase adverse maternal-fetal outcomes in pregnant patients.[38]

Anti-TNF agents, including infliximab, adalimumab, and certolizumab pegol, inhibit downstream signaling in the TNF inflammatory cascade. These drugs are effective in steroid-resistant or immunomodulator-refractory Crohn disease, with clinical benefit often observed within 2 weeks of initiation. Anti-TNF therapy is particularly effective in treating fistulizing disease and reducing the risk of postsurgical endoscopic recurrence.[36] Caution is warranted in patients with a history of demyelinating disease, congestive heart failure, or malignancies such as lymphoma.[37] Current evidence indicates that anti-TNF therapy does not increase adverse maternal-fetal outcomes in pregnant patients.[38] Leukocyte trafficking agents selectively inhibit the adhesion protein integrin α4β7 on a subset of memory T cells, preventing their binding to gut mucosal cells. This mechanism produces gut-specific anti-inflammatory effects. Vedolizumab, the agent in this class used for Crohn disease, has demonstrated superior efficacy compared with placebo in both inducing and maintaining remission, with or without concomitant immunomodulators.[39] The onset of clinical effect is slower than that of anti-TNF agents, typically around 10 weeks, particularly in patients previously treated with anti-TNF therapy.[40] Gut-specific action limits systemic toxicity, resulting in a relatively favorable side effect profile. Interleukin 12/23 (IL-12/23) inhibitors, including ustekinumab and risankizumab, are effective in patients with inadequate response to corticosteroids, immunomodulators, or anti-TNF therapy.[41][42][43] Ustekinumab acts as a nonselective IL-12/23 inhibitor, whereas risankizumab selectively targets IL-23. Safety surveillance data in patients with psoriasis indicate that these agents have a relatively favorable side effect profile.[44]

Interleukin 12/23 (IL-12/23) inhibitors, including ustekinumab and risankizumab, are effective in patients with inadequate response to corticosteroids, immunomodulators, or anti-TNF therapy.[41][42][43] Ustekinumab acts as a nonselective IL-12/23 inhibitor, whereas risankizumab selectively targets IL-23. Safety surveillance data in patients with psoriasis indicate that these agents have a relatively favorable side effect profile.[44] Janus kinase (JAK) inhibitors target signaling pathways involved in abnormal immune responses. Upadacitinib is the first oral selective Janus kinase inhibitor approved by the U.S. Food and Drug Administration for Crohn disease and is effective in patients who have failed conventional or biologic therapies.[45] Clinical benefit is often observed within 2 weeks. However, upadacitinib increases the risk of herpes zoster infection, so shingles vaccination is recommended prior to treatment initiation. Use of upadacitinib during pregnancy is not advised due to teratogenicity observed in animal studies.[46] In 2021, the American Gastroenterology Association (AGA) published guidelines for the management of perianal and fistulizing Crohn disease, strongly recommending infliximab over no treatment for induction and maintenance of remission. Infliximab is the only biologic with dedicated randomized controlled trial evidence demonstrating efficacy.[47] The AGA also strongly advocated combining biologic therapy with an antibiotic rather than using biologic monotherapy to induce fistula healing. This recommendation was based on 2 randomized controlled trials showing that anti-TNF agents combined with ciprofloxacin were more effective in achieving fistula remission than anti-TNF monotherapy. Surgical Management Surgical intervention is indicated for Crohn disease complications, including bowel obstruction due to fibrostenotic strictures, fistulization despite appropriate medical therapy, recurrent abscesses, bowel perforation, dysplasia, malignancy, and medically refractory disease. Surgical resection and stricturoplasty are options for managing fibrostenotic disease, the most common indication for surgery (see Image. Subtotal Colectomy in Severe Crohn Colitis). Short-segment strictures may be amenable to endoscopic dilation.

Surgical intervention is indicated for Crohn disease complications, including bowel obstruction due to fibrostenotic strictures, fistulization despite appropriate medical therapy, recurrent abscesses, bowel perforation, dysplasia, malignancy, and medically refractory disease. Surgical resection and stricturoplasty are options for managing fibrostenotic disease, the most common indication for surgery (see Image. Subtotal Colectomy in Severe Crohn Colitis). Short-segment strictures may be amenable to endoscopic dilation. Fistulotomy may be performed for simple fistulas, defined as superficial or low transsphincteric fistulas without associated proctitis. Complex fistulas may require chronic seton placement. Mesenchymal stem cell injection into the fistula tract to reduce inflammation shows therapeutic promise and is currently under investigation.[48] The American Society of Colon and Rectal Surgeons recommends total colectomy with ileorectal anastomosis or total proctocolectomy for patients with Crohn colitis exhibiting dysplasia not amenable to endoscopic resection. Additional indications include multifocal dysplasia and colorectal cancer. This recommendation is supported by the elevated risk of metachronous colorectal cancer (14%-40%) and the high prevalence of multifocal dysplasia in patients with Crohn colitis who underwent colectomy for low- or high-grade dysplasia.[49][50] A diverting ileostomy, rather than primary anastomosis, is generally considered during ileocolectomy in Crohn disease patients with multiple risk factors for anastomotic leak, including smoking, corticosteroid use, and weight loss. Residual postsurgical disease or a high risk of recurrence warrants initiation of postoperative biologic therapy, such as an anti-TNF agent, 2 to 4 weeks after surgery, once postoperative infections have been excluded.[51] Treatment Monitoring

A diverting ileostomy, rather than primary anastomosis, is generally considered during ileocolectomy in Crohn disease patients with multiple risk factors for anastomotic leak, including smoking, corticosteroid use, and weight loss. Residual postsurgical disease or a high risk of recurrence warrants initiation of postoperative biologic therapy, such as an anti-TNF agent, 2 to 4 weeks after surgery, once postoperative infections have been excluded.[51] Treatment Monitoring The AGA recommended in 2023 that monitoring of Crohn disease treatment response be guided by clinical symptoms and biomarker levels.[52] Biomarkers may be assessed every 6 to 12 months in patients in remission and more frequently in those requiring therapy adjustment. Recommended biomarkers include fecal calprotectin and serum CRP. A fecal calprotectin level below 150 μg/g and a CRP level below 5 mg/L indicate minimal or absent inflammation, potentially obviating the need for routine endoscopic assessment of disease activity. The AGA further recommended the following: Endoscopic or radiologic confirmation of disease remission within 3 years of symptomatic remission Assessment of therapeutic response during active disease using biomarkers every 2 to 4 months Follow-up endoscopy 6 to 12 months after symptom resolution to document mucosal healing A fecal calprotectin level below 50 μg/g is sufficient to exclude disease recurrence in patients who have remained asymptomatic for 12 months following surgical remission. Routine endoscopic evaluation is not required in these patients. The same biomarker threshold may be applied to asymptomatic individuals with low postoperative recurrence risk or those at higher risk who are already receiving prophylactic therapy. High-risk patients not on prophylactic therapy should undergo endoscopic assessment to evaluate disease activity. Dietary Management

A fecal calprotectin level below 50 μg/g is sufficient to exclude disease recurrence in patients who have remained asymptomatic for 12 months following surgical remission. Routine endoscopic evaluation is not required in these patients. The same biomarker threshold may be applied to asymptomatic individuals with low postoperative recurrence risk or those at higher risk who are already receiving prophylactic therapy. High-risk patients not on prophylactic therapy should undergo endoscopic assessment to evaluate disease activity. Dietary Management Diet serves as an adjunctive therapy in Crohn disease. Input from a dietitian and appropriate nutritional supplementation are strongly recommended, as symptomatic patients are at risk for malnutrition and micronutrient deficiencies. Patients with a history of terminal ileum inflammation or resection are particularly susceptible to vitamin B12 deficiency.[53][54][55][56] Evidence, primarily from pediatric populations, demonstrates that certain dietary interventions, including elemental and semielemental diets, can reduce mucosal inflammation.[57] However, these diets have been largely ineffective in adults due to poor adherence. Additionally, benefits are typically not durable, as inflammation often recurs after resumption of a nonrestrictive diet.

The differential diagnoses to consider in patients with suspected Crohn disease are listed below. Documentation of travel and exposure history, combined with judicious use of laboratory, imaging, and histologic investigations, facilitates differentiation among these conditions. Infectious enteritis and terminal ileitis Coccidioides Histoplasma Salmonella Mycobacterium tuberculosis Yersinia Infectious colitis Amebiasis Campylobacter Clostridium difficile Cytomegalovirus Escherichia 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 These conditions can present with similar patterns of inflammation, infection, or immune-mediated injury. Precise identification is critical for optimizing patient outcomes and avoiding inappropriate treatment.

High-risk patients with moderate-to-severe Crohn disease often exhibit the following characteristics: Relatively younger age, typically younger than 30 years History of active or recent tobacco use Elevated CRP or fecal calprotectin levels Deep ulcers identified on colonoscopy Involvement of long bowel segments Perianal disease Extraintestinal manifestations History of bowel resections [58][59] Without immunomodulator or biologic therapy, up to 50% of patients may develop steroid dependence or treatment resistance, with a cumulative incidence of abdominal surgery of 46.6% 10 years after diagnosis.[60] Postsurgical endoscopic recurrence at or above the surgical anastomosis occurs in approximately 90% of cases. Risk factors for early recurrence include cigarette smoking, a short interval from diagnosis to 1st surgery, multiple resections, and penetrating disease.[61] Surveillance ileocolonoscopy is recommended 6 to 12 months postoperatively and should be repeated every 1 to 3 years in the absence of endoscopic recurrence. Prior meta-analyses indicate a modestly increased 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 risk is primarily attributable to gastrointestinal disease, gastrointestinal cancer, and pulmonary pathology.[62][63] Current corticosteroid therapy further increases mortality risk.[64]

Crohn disease is a systemic disorder with both intestinal and extraintestinal manifestations. Complications associated with this condition include the following: Stricture formation Fistulae and abscesses Colorectal carcinoma Ankylosing spondylitis Episcleritis, iritis Erythema nodosum, pyoderma gangrenosum Nephrolithiasis Cholelithiasis Anemia Hypercoagulability Osteoporosis Osteonecrosis Macronutrient and micronutrient deficiencies Increased susceptibility to infections Early detection and adherence to therapeutic regimens can mitigate the risk of these complications and improve long-term patient outcomes. An interprofessional approach allows comprehensive assessment, including nutritional, immunologic, and psychosocial factors, critical for optimizing disease management.

Preventing Crohn disease remains challenging due to its incompletely understood etiology. Nonetheless, several strategies may help reduce the risk of disease onset or mitigate severity. Genetic counseling is advisable for individuals with a family history of Crohn disease, providing an understanding of their predisposition and guiding decisions on screening or preventive measures. Early recognition and prompt management of suggestive symptoms, such as persistent abdominal pain, diarrhea, rectal bleeding, unexplained weight loss, and fatigue, can help prevent complications and optimize long-term outcomes. Although no specific diet has been proven to prevent Crohn disease, controlling sugar intake and avoiding foods that exacerbate symptoms may reduce the frequency of flare-ups. Minimizing exposure to environmental triggers, including cigarette smoke, air pollution, certain medications (eg, nonsteroidal anti-inflammatory drugs), and infections, may further decrease disease risk or severity. Secondary prevention in Crohn disease focuses on measures that reduce the risk of complications following diagnosis. Adherence to prescribed medications is essential for controlling inflammation, managing symptoms, preventing disease flares, and minimizing complication risk. Patients should be counseled on the importance of taking medications as directed, attending scheduled follow-up appointments, and promptly reporting changes in symptoms. Cancer screening is recommended due to an increased risk of malignancies, including skin and gastrointestinal tumors. Skin examinations should be performed regularly, and a colonoscopy every 1 to 3 years is advised for patients with inflammation involving at least 1/3 of the colon to enable early detection of colorectal cancer. Osteoporosis prevention is critical, as corticosteroid therapy and nutrient deficiencies associated with Crohn disease increase fracture risk. Periodic bone density assessments facilitate early recognition and management. Immunosuppressive therapy also elevates susceptibility to infections, making vaccination against pathogens such as pneumococcus, Haemophilus influenzae, and influenza virus advisable, with additional immunizations guided by patient-specific and regional considerations.

Osteoporosis prevention is critical, as corticosteroid therapy and nutrient deficiencies associated with Crohn disease increase fracture risk. Periodic bone density assessments facilitate early recognition and management. Immunosuppressive therapy also elevates susceptibility to infections, making vaccination against pathogens such as pneumococcus, Haemophilus influenzae, and influenza virus advisable, with additional immunizations guided by patient-specific and regional considerations. Individual responses to secondary prevention strategies may vary, and not all interventions are universally applicable or equally effective. Continued research is necessary to elucidate the underlying pathophysiology of Crohn disease and develop more targeted preventive and therapeutic approaches.

Crohn disease is a chronic inflammatory disorder with significant diagnostic and management challenges. The potential of this condition to cause multiorgan involvement necessitates an interprofessional care approach. Primary care physicians often provide the initial evaluation for patients presenting with mild abdominal complaints, initiate treatment, and refer patients to specialists for further assessment. Internists may assist in diagnosing recurrent abdominal symptoms accompanied by systemic manifestations such as fever and weight loss, prescribing adjunctive therapies as needed. Gastroenterologists perform diagnostic and therapeutic endoscopies, prescribe targeted therapies, and monitor disease progression. Colorectal surgeons are involved when complications such as fistulae or intestinal obstruction arise. Dietitians guide nutritional management to prevent malnutrition and micronutrient deficiencies. Nurses administer treatments, educate patients who have undergone surgery on stoma and wound care, monitor progress, and coordinate care. Pharmacists provide education on medication regimens, emphasizing therapeutic benefits, potential adverse effects, and adherence. Additional specialists, including rheumatologists, neurologists, ophthalmologists, hepatologists, nephrologists, dermatologists, and otorhinolaryngologists, may be consulted to address extraintestinal manifestations. Mental health providers support patients experiencing depression or severe anxiety related to symptoms and complications. The prognosis for patients with Crohn disease is guarded, and quality of life may be diminished.[65] Interprofessional management allows timely recognition and intervention for complications while providing support for patients’ psychosocial needs.