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Ileitis

Ileitis is an inflammatory condition of the , the terminal portion of the , which can involve ulceration, , or of the mucosal lining. It most commonly presents as terminal ileitis, affecting the distal and , though it may extend proximally depending on the underlying cause. While ileitis is strongly associated with —a chronic that can affect any part of the —it is not exclusive to this condition and often requires differentiation from other pathologies. The etiology of ileitis is multifaceted, encompassing infectious agents such as , , Clostridium difficile, and ; non-infectious inflammatory disorders like spondyloarthropathies, eosinophilic enteritis, and backwash ileitis in ; vascular issues including ischemia; neoplastic processes; and iatrogenic factors such as (NSAID) use. Crohn's disease accounts for the majority of cases, particularly in chronic or recurrent presentations, where transmural inflammation leads to complications like strictures or fistulas. Less common causes, such as or , may mimic these features and necessitate targeted evaluation. Clinically, ileitis typically manifests with right lower quadrant , diarrhea (which may be bloody or non-bloody), fever, , vomiting, and unintended , though symptoms vary by cause and severity. Acute infectious ileitis may resolve spontaneously or with antibiotics, while chronic forms like those in often present with relapsing obstructive symptoms or systemic fatigue. relies on a combination of clinical history, laboratory tests (e.g., inflammatory markers like ), ileocolonoscopy with for histopathological confirmation, and imaging modalities such as computed tomography () or magnetic resonance enterography to assess extent and complications. Management of ileitis is etiology-specific and aims to control , alleviate symptoms, and prevent complications. For Crohn's-related ileitis, first-line therapies include corticosteroids like or immunomodulators, alongside dietary modifications to reduce fiber intake during flares. Infectious causes are treated with targeted antibiotics, while drug-induced cases often resolve upon discontinuation of the offending agent. In refractory or complicated scenarios, such as stricturing disease or neoplasms, surgical intervention like resection may be required. Early identification of the underlying cause is crucial for optimizing outcomes and avoiding unnecessary escalation of therapy.

Definition and Background

Definition

Ileitis is defined as of the , the terminal portion of the located between the and the . This condition specifically targets the distal segment of the small bowel, where the facilitates the absorption of bile salts, , and remaining nutrients from digested food. Ileitis can manifest in various forms, broadly classified as acute or based on duration and persistence; acute ileitis involves short-term inflammatory episodes, while ileitis features ongoing or recurrent . Subtypes include terminal ileitis, which affects the most distal end of the near the , and backwash ileitis, characterized by mild extending into the distal contiguous with colonic involvement. The term ileitis gained prominence in the early through its association with a newly recognized inflammatory bowel condition. In 1932, Burrill B. Crohn, Leon Ginzburg, and Gordon D. Oppenheimer published a seminal paper titled "Regional Ileitis: A and Clinical Entity," describing cases of chronic inflammation confined to the terminal , which laid the foundation for understanding what is now known as . This historical description distinguished ileitis as a discrete entity from other gastrointestinal inflammations, emphasizing its pathologic features such as transmural involvement and regional skip lesions. Ileitis must be differentiated from broader inflammatory conditions of the intestines to ensure precise diagnosis and management. Unlike , which encompasses inflammation of the entire including the duodenum, jejunum, and , ileitis is restricted to the alone. Similarly, it differs from , defined as inflammation of the or colon, which does not typically involve the small bowel unless in specific extensions. These distinctions highlight ileitis's specificity to the ileal segment, aiding in targeted clinical approaches.

Anatomy of the Ileum

The is the terminal segment of the , extending from the jejunoileal junction to the , where it connects to the of the . It is located primarily in the lower right quadrant of the and measures approximately 3 to 4 meters in length, comprising about 60% of the total . This portion is intraperitoneal, suspended by the , and features a thinner wall compared to the , with narrower and more pronounced arterial arcades. Histologically, the ileum's mucosa consists of lined with enterocytes and goblet cells, forming finger-like villi that are shorter and fewer than in the proximal , along with circular folds (plicae circulares) to maximize surface area. Microvilli on the apical surface of enterocytes further amplify , while the contains prominent Peyer's patches—aggregates of lymphoid follicles, each spanning 2 to 5 cm and consisting of around 300 follicles—that facilitate immune surveillance. The underlying layers include the muscularis externa with inner circular and outer longitudinal , and an outer serosa of , all contributing to and barrier function. Physiologically, the ileum primarily absorbs bile salts, (via binding), and any remaining nutrients such as fats and electrolytes not taken up proximally, ensuring efficient reclamation before colonic transit. It also plays a key role in function, where Peyer's patches enable sampling through M cells in the follicle-associated epithelium, supporting adaptive immunity against luminal pathogens. The blood supply to the ileum arises from the via ileal branches that form vasa recta, providing oxygenated blood through extensive arcades in the , with venous drainage converging into the to the . Innervation involves sympathetic fibers from the superior mesenteric for and motility inhibition, and parasympathetic input from the via the celiac and superior mesenteric plexuses to enhance secretion and , both of which can modulate inflammatory responses in the region.

Causes

Infectious Causes

Infectious causes of ileitis primarily involve microbial that invade the ileal mucosa, triggering acute inflammation through mechanisms such as direct tissue destruction, cytokine release, and neutrophil infiltration. These infections often target the terminal ileum due to its rich lymphoid tissue and slower transit time, which facilitate pathogen and . Common transmission routes include of contaminated food or water, with risk factors encompassing international travel to endemic areas, (e.g., in or post-transplant patients), and exposure to undercooked meats or unpasteurized dairy. Bacterial infections represent the most frequent microbial etiology of acute ileitis. Yersinia enterocolitica is a leading cause, particularly in temperate climates, where it invades the ileal epithelium via its invasin protein binding to β1 integrins on host cells, leading to pseudoappendicitis-like symptoms from terminal ileitis and mesenteric adenitis; outbreaks are often linked to contaminated pork products. Salmonella species, such as nontyphoidal strains, can produce circumferential terminal ileitis by penetrating the mucosa and eliciting a self-limited inflammatory response, mimicking Crohn's disease on imaging. Campylobacter jejuni similarly causes ileocolitis through toxin-mediated and invasive mechanisms, resulting in mucosal ulcers and lymphoid hyperplasia in the ileocecal region. Clostridium difficile, particularly hypervirulent strains like BI/NAP1/027, can cause ileitis or enteritis, often in postoperative or antibiotic-exposed patients, leading to toxin-mediated mucosal damage and inflammation. Mycobacterium tuberculosis induces chronic granulomatous ileitis in intestinal tuberculosis, predominantly affecting the ileocecal junction via hematogenous spread or ingestion, with caseation necrosis and stricture formation as hallmarks. Viral pathogens contribute to ileitis, especially in vulnerable populations. (CMV) is a key opportunistic agent in immunocompromised individuals, where it infects endothelial and epithelial cells of the , causing ischemic mucosal injury and ulceration; this is prevalent in transplant recipients or those with advanced . , a common cause of outbreaks, can lead to acute ileitis through direct enterocyte damage and inflammatory cascades, though it more typically presents as self-resolving . Parasitic infections, while less common, are significant in endemic regions or among travelers. invades the ileal mucosa via adherence and lysis, resulting in flask-shaped ulcers and potential strictures that mimic . primarily affects the proximal but can extend to the , inducing and through attachment to epithelial cells and disruption of the mucosal barrier. These infections occasionally present with features overlapping those of , necessitating microbiological confirmation to differentiate.

Non-Infectious Causes

Non-infectious causes of ileitis encompass a range of immune-mediated, vascular, iatrogenic, and other etiologies that lead to inflammation of the without microbial involvement. Among these, , particularly , represents the most common chronic form, characterized by transmural inflammation and discontinuous skip lesions predominantly affecting the terminal . Backwash ileitis, a milder form seen in up to 35% of extensive cases, involves continuous inflammation extending from the into the distal due to reflux of colonic contents. arises from a complex interplay of genetic susceptibility and environmental triggers, with mutations in the gene being a key genetic factor that impairs innate immune responses to gut bacteria, increasing the risk of ileal involvement by approximately twofold. Environmental factors such as cigarette smoking double the risk of developing and exacerbate its ileal manifestations, while diets high in processed foods and low in contribute to and inflammation. Drug-induced ileitis often results from nonsteroidal anti-inflammatory drugs (NSAIDs), which inhibit cyclooxygenase-1, reducing mucosal blood flow and synthesis in the , leading to erosions, ulcers, and strictures in the . Chronic NSAID use is implicated in approximately 66% of cases of small bowel detected endoscopically, with the ileocecal region particularly vulnerable due to its vascular supply. agents, such as fluoropyrimidines (e.g., ) and , can induce ileitis through mucosal toxicity and , causing villous atrophy and inflammatory infiltrates, often presenting as and during treatment. Ischemic ileitis occurs due to reduced blood flow to the , typically from by or in older patients, or nonocclusive mesenteric ischemia from low-flow states like . This condition affects the 's end-arterial blood supply, leading to mucosal ischemia, ulceration, and potential , with accounting for over 50% of small bowel ischemia cases in the elderly. Other non-infectious causes include radiation enteritis, which develops following pelvic or abdominal radiotherapy for malignancies, damaging ileal mucosa through vascular sclerosis and , often manifesting months to years post-treatment with symptoms like and . Autoimmune disorders such as can involve the with deep, punched-out ulcers in the ileocecal region, driven by and hyperactivity. Spondyloarthropathies, including , are associated with subclinical or overt ileal in up to 60% of cases, linked to gut and immune dysregulation. Eosinophilic enteritis involves eosinophil-rich infiltration of the ileal wall, causing , ulceration, or strictures, often with peripheral . Neoplastic processes, such as or , can present with ileitis-like due to tumor invasion or secondary effects. Rare systemic conditions like may cause granulomatous ileitis mimicking Crohn's, while leads to protein deposition causing motility issues and . Additionally, ileal , though rare (incidence 0.3-2.3%), causes localized and perforation in the terminal due to diverticular outpouchings, mimicking . is essential to differentiate these from infectious mimics, revealing features like transmural in Crohn's or ischemic without pathogens.

Clinical Presentation

Signs and Symptoms

Ileitis commonly presents with right lower quadrant , which arises from in the terminal and may mimic in acute cases. Chronic , often watery due to from impaired ileal reabsorption, is a hallmark symptom, leading to frequent bowel movements and urgency. Patients frequently experience and , resulting from reduced and the systemic effects of ongoing . Additional gastrointestinal symptoms include , , and anorexia, which contribute to diminished oral intake and further nutritional compromise. In cases associated with , extraintestinal manifestations such as arthralgias and skin lesions like may occur, affecting up to one-third of patients and paralleling intestinal disease activity. Presentations vary by etiology: infectious ileitis often manifests acutely with fever and bloody stools, reflecting mucosal invasion and systemic response, whereas inflammatory bowel disease-related ileitis typically has an insidious onset with progressive symptoms. These symptoms significantly impact quality of life, potentially leading to nutritional deficiencies such as anemia from ileal dysfunction, which can cause neurological symptoms and exacerbate .

Complications

Ileitis, particularly in its chronic form associated with , can lead to structural complications such as strictures, fistulas, and abscesses due to ongoing inflammation and in the . Strictures narrow the intestinal , potentially causing partial or complete , while fistulas create abnormal connections between the and other organs or , often leading to recurrent infections. Abscesses form as localized collections of , commonly in the mesenteric area, and may require to prevent spread. These complications affect approximately half of Crohn's patients within 20 years of . Nutritional deficiencies arise from severe malabsorption in the inflamed ileum, impairing uptake of bile salts, vitamin B12, and fats, which can result in diarrhea, weight loss, and anemia. In children with ileitis-related Crohn's disease, chronic inflammation contributes to growth failure, observed in 15-40% of pediatric cases at diagnosis, and delayed puberty in 20-30%. Long-term malabsorption also increases the risk of osteoporosis and osteopenia due to deficiencies in vitamin D, calcium, and other nutrients essential for bone health. Systemic complications include an elevated risk of small bowel in long-standing ileal , with relative risks estimated from 6 to 320 times higher than the general , stemming from mucosal and . Perforations of the ileal wall can lead to or , a life-threatening condition requiring immediate intervention. In cases of extensive involvement, may rarely develop, characterized by colonic dilation and systemic toxicity, though it is less common in isolated ileitis than in . Psychological impacts, such as and anxiety, frequently accompany chronic ileitis, with depressive symptoms reported in over 20% of patients and anxiety in up to 35%, exacerbated by persistent symptoms and disease burden. These issues can further impair and adherence to management.

Diagnosis

Clinical Evaluation

The clinical evaluation of suspected ileitis begins with a thorough history to identify potential etiologies and guide further assessment. Patients are questioned about the duration of symptoms, with acute onset (typically days to weeks) suggesting infectious causes such as bacterial , while chronic or relapsing patterns over months to years raise concern for (IBD) like . Travel or exposure history is elicited to assess risks for infectious agents, including recent of undercooked or unpasteurized dairy potentially linked to or . Family history of IBD is explored, as it increases susceptibility to Crohn's ileitis, and medication use, particularly nonsteroidal anti-inflammatory drugs (NSAIDs), is reviewed due to their association with drug-induced ileitis. Physical examination focuses on abdominal and systemic findings to detect and complications. Tenderness in the right lower quadrant is common in ileal involvement, often accompanied by guarding or if is present. Palpable masses may indicate thickened bowel loops or abscesses in chronic cases, while signs of such as dry mucous membranes or reduced skin turgor, and evidenced by or , suggest ongoing disease activity. Extraintestinal manifestations, including oral aphthous ulcers or peripheral , provide clues to underlying IBD. Initial laboratory tests support the history and exam by identifying or . Blood work typically includes a to evaluate for , often due to chronic blood loss or in ileitis, and inflammatory markers such as (CRP) or (ESR), which are elevated in active disease. studies are essential, encompassing cultures and pathogen-specific assays to detect infectious causes like difficile toxin or bacterial pathogens, alongside fecal calprotectin to quantify intestinal . Risk stratification differentiates acute infectious ileitis from chronic IBD based on clinical features and demographics to prioritize . Acute, self-limited presentations in younger patients with exposure risks favor , whereas chronic symptoms in individuals with a positive family or exposure (a known for Crohn's) suggest IBD, particularly in those aged 15-35 or over 50. This initial assessment helps avoid unnecessary interventions while identifying high-risk patients for prompt referral.

Diagnostic Tests

Diagnostic tests for ileitis primarily involve a combination of endoscopic procedures, modalities, and laboratory assessments to visualize , obtain tissue samples, and differentiate underlying causes such as or infections. These tests are essential for confirming ileal involvement and excluding mimics, following initial clinical suspicion. , particularly ileocolonoscopy, is a cornerstone for direct visualization of the terminal and allows for acquisition to identify specific histological features. In -associated ileitis, biopsies often reveal noncaseating granulomas, transmural , and architectural distortions like villous irregularity and fibrosis. For infectious causes, such as or , biopsies may show crypt abscesses, acute with neutrophilic infiltrates, or caseating granulomas depending on the pathogen. Imaging techniques provide non-invasive evaluation of ileal wall changes and extent of disease. Computed tomography () enterography and magnetic resonance () enterography detect bowel wall thickening (typically >3 mm indicating ), hyperenhancement, and complications like strictures, with preferred to avoid . enteroclysis, involving luminal distension, enhances detection of strictures through prestenotic dilatation and narrowed lumen visualization. is particularly useful for the accessible terminal , identifying mural thickening (often 4-7 mm), increased vascularity, and mesenteric enlargement in active ileitis. Additional tools include for comprehensive small bowel assessment beyond the terminal , revealing ulcers, erosions, or villous in proximal ileitis not reachable by standard . Fecal calprotectin serves as a non-invasive , with elevated levels (>50 μg/g) indicating intestinal in ileitis due to IBD or , aiding in triage before invasive testing. Histological patterns from biopsies play a critical role in , distinguishing ileitis from mimics like (showing suppurative without granulomas) or (with atypical lymphoid infiltrates and lack of crypt abscesses). Transmural and granulomas favor Crohn's, while superficial changes and specific organisms on special stains rule out infections or neoplasms.01074-9/fulltext)

Management

Medical Treatment

The medical treatment of ileitis is tailored to the underlying , with the goal of reducing , controlling symptoms, and addressing complications while minimizing side effects. For infectious causes, antimicrobial therapy is the cornerstone, selected based on the identified pathogen. Supportive measures and disease-modifying agents are employed for non-infectious forms, particularly (IBD)-associated ileitis, following evidence-based guidelines. For non-infectious, non-IBD causes, management includes discontinuing offending agents like NSAIDs for drug-induced ileitis, which often resolves with supportive care; backwash ileitis in is treated with standard therapies such as aminosalicylates or biologics; vascular ileitis may require anticoagulation or depending on ischemia severity. In cases of bacterial infectious ileitis, such as that caused by , antibiotics such as trimethoprim-sulfamethoxazole or fluoroquinolones like (typically 500 mg orally twice daily for 5-7 days in uncomplicated cases) are used based on susceptibility and guidelines due to their efficacy against this pathogen. or other broad-spectrum agents may be used for anaerobic or mixed infections, with treatment duration guided by clinical response and culture results. For viral causes like (CMV) ileitis, particularly in immunocompromised patients, antiviral agents such as (5 mg/kg intravenously every 12 hours for 2-3 weeks, followed by oral ) are indicated to inhibit and promote mucosal healing. Antiparasitic medications, such as (500 mg orally three times daily for 5-10 days) or for rare parasitic etiologies like affecting the , are prescribed when stool studies confirm protozoal or helminthic involvement. For ileitis associated with Crohn's disease, a step-up approach begins with aminosalicylates like mesalamine (2.4-4.8 g daily orally) for mild ileal involvement to maintain remission, though evidence for their efficacy in isolated ileitis is modest. Corticosteroids, such as budesonide (9 mg daily for 8 weeks, with controlled ileal release to target the ileum), are used for moderate flares to induce remission by suppressing inflammation, with systemic options like prednisone reserved for more severe cases. Immunomodulators including azathioprine (2-2.5 mg/kg daily) or methotrexate (25 mg subcutaneously weekly) serve as steroid-sparing maintenance therapy. Biologic agents, particularly anti-TNF therapies like infliximab (5 mg/kg intravenously at weeks 0, 2, and 6, then every 8 weeks), are recommended for moderate-to-severe or refractory ileitis, offering deep remission rates of 30-50% in clinical trials. Small-molecule JAK inhibitors, such as upadacitinib (45 mg daily induction, then 15-30 mg maintenance), and IL-23 antagonists like risankizumab (600 mg intravenously at weeks 0, 4, and 8 for induction, then 180 mg subcutaneously every 8 weeks) are newer options for patients failing conventional therapies, as per the 2025 AGA living guidelines. Supportive therapies complement across etiologies. Nutritional interventions, including exclusive enteral nutrition with polymeric formulas (e.g., 2000-2500 kcal/day for 6-8 weeks), can induce remission in up to 80% of pediatric Crohn's ileitis cases and support adults by promoting mucosal repair and correcting . Antidiarrheal agents like (2-4 mg as needed, up to 16 mg/day) help manage symptoms without altering disease course, while supplementation (1000 mcg intramuscularly monthly) addresses ileal resection-related deficiencies. Treatment response is monitored using clinical symptom scores like the Crohn's Disease Activity Index (CDAI <150 indicating remission) and biomarkers such as fecal calprotectin (<250 μg/g) or levels, with endoscopic reassessment every 6-12 months per AGA recommendations. Adjustments are made based on these metrics to optimize therapy while minimizing risks like infections or from prolonged steroids.

Surgical Options

Surgical intervention is considered for ileitis, particularly in , when medical therapies fail to control symptoms or when complications necessitate urgent . Indications for surgery primarily include strictures that cause obstructive symptoms, enterocutaneous or enteroenteric fistulas leading to persistent or , and intra-abdominal abscesses unresponsive to percutaneous and antibiotics. In such cases, aims to alleviate symptoms, resolve complications, and improve , though it does not the underlying disease. Common procedures for ileal involvement include of the affected followed by primary , which is the standard approach for localized terminal ileitis or ileocolitis to remove diseased tissue while restoring bowel continuity. For patients with multiple fibrotic strictures, particularly in the small bowel, strictureplasty is preferred to widen the narrowed segments without resection, thereby preserving bowel length and reducing the risk of nutritional deficiencies. If ileitis extends to involve the colon significantly, as in ileocolitis, a —either segmental or total—may be performed, often with ileorectal or creation depending on disease extent. Surgical risks are notable, including the development of in patients undergoing multiple resections, which can lead to and dependence on if remaining small bowel length falls below 200 cm. Clinical recurrence of after ileal surgery occurs in up to 50% of cases within 5-10 years, with surgical reoperation rates of 20-30%; additional medical therapy is often required to manage recurrence. Postoperative , characterized by temporary bowel , affects up to 20-30% of patients, with higher incidence in open procedures compared to minimally invasive approaches. Advances in surgical techniques as of 2025 emphasize minimally invasive methods to optimize outcomes. for ileocecal has become the first-line approach, offering reduced hospital stays (typically 5 days versus 7-9 for open ), lower complication rates, and faster recovery of bowel function. Robotic-assisted is gaining traction for complex cases involving fistulas or recurrent disease, providing enhanced precision and intracorporeal , though with longer operative times; meta-analyses indicate reduced morbidity compared to conventional . Additionally, the Kono-S technique, which creates a wide, antiperistaltic neoterminal , has shown promise in lowering endoscopic recurrence rates at 1 year compared to conventional side-to-side .

Epidemiology and Prognosis

Epidemiology

Ileitis, particularly when associated with (IBD) such as , exhibits higher incidence rates in developed countries, with annual estimates for Crohn's-related ileitis ranging from 3 to 20 cases per 100,000 population in regions like and . In contrast, infectious causes of ileitis, including those due to pathogens like or , are more prevalent in developing regions, where environmental and factors contribute to higher transmission rates, though specific global incidence data for these etiologies remain limited and vary by locale. Nonspecific terminal ileitis, often incidental, has a prevalence of 0.3% to 6.8% among asymptomatic individuals undergoing screening . Demographically, Crohn's ileitis predominantly affects young adults, with peak incidence occurring between ages 15 and 35 years, and a slight predominance among females in studies. Ethnic variations are notable, with higher rates observed among individuals of Ashkenazi Jewish descent and non- White populations compared to other groups, such as Asian or individuals, where is lower but rising. Recent trends indicate an increasing incidence of IBD-related ileitis in , attributed to and adoption of Western dietary patterns, with rates climbing from approximately 0.5 per 100,000 in earlier decades to 3.4 per 100,000 in recent years across East and South Asian countries. The has been linked to elevated cases of infectious or post-infectious ileitis, with reports of acute terminal ileitis incidence accelerating during and after 2020 (as of 2023), potentially due to disruptions in healthcare access and secondary infections. Key risk factors for ileitis, especially Crohn's-associated forms, include , with family history conferring a significantly elevated , alongside environmental influences such as living and early-life exposure, which disrupt and increase susceptibility.

Prognosis

The of infectious ileitis is generally excellent with appropriate , leading to of symptoms within weeks and rare progression to . For instance, in infections, acute symptoms such as and typically resolve spontaneously within 7 to 22 days, with mucosal lesions healing in about one month, and bacterial shedding in stool persisting for a median of 40 days but seldom causing long-term complications. Similarly, Salmonella-induced ileitis often improves as the infection clears, with acute symptoms subsiding by the second week in most cases. Chronicity is uncommon, occurring in fewer than 5% of cases, and isolated acute terminal ileitis rarely progresses to (approximately 1-4.6%). In contrast, ileitis associated with (IBD), particularly , follows a relapsing-remitting course, with long-term outcomes influenced by disease extent and response to therapy. Approximately 47% of patients with require surgical intervention within 10 years of diagnosis due to complications like strictures or fistulas, though early biologic therapy can reduce this risk. Remission rates with biologics exceed 70% in initial responders, with 74.7% achieving clinical remission on first-line biologic treatment, though maintenance rates vary from 30-50% over 2-5 years without de-escalation. Postoperative recurrence is common, with endoscopic relapse in up to 70-90% within one year after ileocecal resection, necessitating ongoing medical management. Several factors modulate recovery trajectories in IBD-related ileitis. Early and significantly improve outcomes by preventing irreversible damage, such as . Poor prognostic indicators include , which increases the risk of disease escalation and surgical needs; perianal disease at onset, associated with a disabling course; and young age at (under 40 years), linked to more aggressive progression and higher requirements. Quality of life in ileitis patients is assessed using tools like the Questionnaire (IBDQ), which scores from 32 to 224, with higher values indicating better health-related quality of life; scores below 190 often reflect moderate impairment due to recurrent symptoms and complications. Mortality in cohorts is low and slightly above the general population (standardized mortality ratio of 1.39, 95% CI 1.30–1.49), but morbidity is high from repeated flares, surgeries, and extraintestinal manifestations, leading to substantial long-term in up to 50% of cases.

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