Continuing Education Activity

Crohn disease (CD) and ulcerative colitis (UC) are two conditions commonly referred to as inflammatory bowel disease (IBD). They are immunologically mediated inflammatory diseases of the gastrointestinal tract. In Crohn disease, the inflammation extends through the entire thickness of the bowel wall from the mucosa to the serosa. The disease runs a relapsing and remitting course. With multiple relapses, Crohn disease can progress from initially mild to moderate inflammatory conditions to severe penetrating (fistulization) or stricturing disease. This activity reviews the etiology, presentation, evaluation, and management of Crohn disease and highlights the role of the interprofessional team in evaluating, diagnosing, and managing the condition.

Objectives:

• Review the pathophysiology of Crohn disease.
• Describe the extraintestinal manifestations of Crohn disease.
• Summarize the management of Crohn disease.
• Explain the importance of interprofessional team strategies for improving care coordination and communication to aid in prompt diagnosis of Crohn disease and improving outcomes in patients diagnosed with the condition.

Introduction

Crohn disease (CD) and ulcerative colitis (UC) are two conditions commonly referred to as inflammatory bowel disease (IBD). They are immunologically mediated inflammatory diseases of the gastrointestinal tract. In CD, the inflammation extends through the entire thickness of the bowel wall from the mucosa to the serosa. The disease runs a relapsing and remitting course. With multiple relapses, the CD can progress from initially mild to moderate inflammatory conditions to severe penetrating (fistulization) or stricturing disease.[1][2][3][4][5]

Crohn disease can affect any part of the gastrointestinal tract. About one-third of patients have small bowel involvement, especially the terminal ileum, another 20% have only colon involvement and about 50% have involvement of both the colon and small bowel. There is no cure and most patients experience bouts of remissions and relapse at unpredictable times. This disease leads to very poor quality of life.

Etiology

Although the exact etiology of inflammatory bowel disease (IBD) is not known, there is substantial evidence to suggest that the disease is resulting from an inappropriate immune response in the bowel to situations from environmental factors such as drugs, toxins, infections, or intestinal microbes in a genetically susceptible host. More than a hundred genes associated with IBD have been identified. In Crohn disease particularly, there appears to be a genetic association with phenotypes. Specifically, NOD2/CARD15 mutations were found to be associated with a phenotype of Crohn disease which was associated in those diagnosed at a younger age, with ileal involvement, increased severity of ileal disease requiring surgical intervention/reoperation. In the future, this genotyping could potentially provide prognostic information on the severity of the disease. Furthermore, it could predict which patient should be considered for surgical management vs. medical management based on a more detailed understanding of genetic analysis.[6]

Epidemiology

Crohn disease (CD) is most commonly seen in the western developed world in North America, northern Europe, and New Zealand. Its incidence has a bimodal distribution with the onset occurring most frequently between ages 15 to 30 years and 40 to 60 years old. It is more prominent in urban than rural areas. There is a high incidence in Northern Europeans and Jewish descent (incidence 3.2/1000) contrasting to a significant infrequent prevalence in Asians, Africans, and South Americans.[7] However, recent studies have shown a significant increase in incidence in rapidly industrializing areas of Asia, Africa, and Australasia.[8]

Pathophysiology

The pathophysiology is multifactorial and involves genetic predisposition, infectious, immunological, environmental, and dietary. The characteristic transmural inflammation can include the entire GI tract from mouth to the perianal area; although most frequently involve terminal ileum and right colon. The initial lesion starts out as an infiltrate around an intestinal crypt. This goes on to develop ulceration first in the superficial mucosa and involves deeper layers. As the inflammation progresses, non-caseating granulomas form involving all layers of the intestinal wall. It can develop into the classic cobblestone mucosal appearances and skip lesions along the length of the intestine sparing areas with normal mucosa. As the flare of Crohn settles, scarring replaces the inflamed areas of the intestines.[9]

Granuloma formation is very common in Crohn disease but their absence does not exclude the diagnosis. The ongoing inflammation and scarring lead to bowel obstruction and stricture formation. Crohn disease is also associated with enterovesical, enteroenteral, enterocutaneous, and enterovaginal fistulas.

Toxicokinetics

The immune-mediated response in Crohn disease involves both innate and acquired mechanisms by macrophages, neutrophils, and T-cells in the intestine which promote pro-inflammatory mediators like tumor necrosis factor-alpha. Colonic Crohn lesions were found to have high levels of cytokines like interferon-gamma, IL-2, IL-12, and IL-18. Crohn disease is primarily regulated by helper T 1 and 17 mediated processes.[10]

History and Physical

Patients with flare-ups of Crohn disease typically present with abdominal pain (right lower quadrant), flatulence/bloating, diarrhea (can include mucus and blood), fever, weight loss, anemia. In severe cases, perianal abscess, perianal Crohn disease, and cutaneous fistulas can be seen.

When the small bowel is involved, it may present with diarrhea, malabsorption, weight loss, abdominal pain, and anorexia. Enterovesical fistulae may present with pneumaturia, recurrent urinary tract infections, and feculent vaginal discharge.

Crohn disease is associated with extraintestinal manifestations including episcleritis, uveitis, stomatitis, aphthous ulcers, liver steatosis, gallstones, cholangitis, primary sclerosing cholangitis, nephrolithiasis, hydronephrosis, urinary tract infections, arthritis (spine - sacral, knee, ankles, hips, wrist, elbows), ankylosing spondylitis, erythema nodosum, and pyoderma gangrenosum.[11]

Thromboembolic disease is now recognized to be a common complication of Crohn disease. It may present with deep vein thrombosis, stroke, or pulmonary embolism.

The perineum must be examined in all patients. The inspection may reveal skin tags, ulcers, fistulas, scarring, and abscess. Frank perforation is rare but can be a presentation of Crohn disease. Finally, colon cancer is another complication of Crohn disease.

Evaluation

Stool tests to rule out infections include culture and sensitivities, ovum and parasites, Clostridium difficile toxins, leukocyte count. Stools for calprotectin can detect active Crohn disease and are also used for monitoring disease.[12][13][14][15]

Blood tests including complete blood count and a metabolic panel can highlight the presence of anemia (B12  or iron deficiency) or liver disease. Special serology such as normal anti-neutrophil cytoplasmic antibodies (ANCA) and raised anti-saccharomyces cerevisiae antibodies (ASCA) can distinguish Crohn disease from ulcerative colitis. C-reactive protein (CRP) or erythrocyte sedimentary rate (ESR) can reflect the severity of the inflammation.

A computed tomography scan/magnetic resonance enterography (MRE) of the abdomen and pelvis can detect abscesses and fistulization. The choice between CT or MRE is largely directed at minimizing radiation exposure in younger populations. Both give a higher definition of the diseased intestine. However, MRI can provide more detail when investigating the fistulizing disease. The use of video capsule endoscopy (VCE) can visualize the small bowel for CD when regular endoscopy or colonoscopy cannot reach to visualize these areas. Capsule endoscopy can only detect mucosal changes, whereas MRI can detect transmural inflammation and also identify other complications.

Plain x-rays are ordered when bowel obstruction is suspected.

Small bowel follow-through is often used to assess the involvement of the terminal ileum and can also detect fistulas. The classic string sign due to stricture formation or spasm is often seen.

For those patients too ill to undergo colonoscopy or CT scan, nuclear imaging may reveal sites of inflammation.

Before initiation of any treatment, vaccination history (tetanus, diphtheria, pertussis, human papillomavirus, influenza, pneumococcal, hepatitis A, hepatitis B, measles, mumps, rubella, varicella-zoster virus) should be known, if no prior history titers of hepatitis A, hepatitis B, measles, mumps, rubella, and the varicella-zoster virus should be checked. Baseline Mantoux test with chest radiograph should also be checked before any treatment. Baseline thiopurine methyltransferase (TPMT) levels should be checked before deciding on treatment options. Low levels of TMPT may result in an increased risk of side effects, whereas very high levels may decrease the effectiveness of prescribed treatment.

Treatment / Management

The medical treatment is broadly grouped into two classes:

• Mild to moderate disease can be treated by oral mesalamine, immunomodulators such as thiopurines (mercaptopurines, azathioprine), methotrexate, and steroids.
• Moderate to severe disease (including fistulizing disease) will be best treated using a combination of immunomodulators and biologics (infliximab, adalimumab, golimumab, vedolizumab) or biologics alone.[10]

Biologics are immunoglobulins engineered to direct against specific cytokines or receptors involved in the inflammation process. Each biologic agent works against one specific site at a molecular level. Anti-tumor necrosis factor (TNF) alpha is a monoclonal antibody that can block the TNF in circulation from their inflammatory actions. Anti-integrin agents are adhesion molecule inhibitors that bind the subunits of the MAdCAM receptors of the endothelial cells at the inflammatory sites. They halt the trafficking of lymphocytes from the circulation into the wall of the intestine, thereby stopping the inflammatory response targeted at the bowel. Examples of anti-TNF agents are infliximab, adalimumab, golimumab. Examples of adhesion molecule inhibitors are natalizumab, vedolizumab. Vedolizumab is gut-specific and has fewer systemic side effects. Many newer therapeutic agents for inflammatory bowel disease are in the pipeline.

Surgical treatments are used for complications such as bowel obstructions, abscess, fistulas, or perforated bowel.

Dietician input and nutritional supplementation are highly recommended before and during the treatment of Crohn disease.[16][17][18][19]

Guidelines published by the American College of Gastroenterology for the management of Crohn disease in 2018:

1. Fecal calprotectin may help differentiate between IBD and IBS
2. Chromoendoscopy should be utilized during colonoscopy as it may increase diagnostic yield for colorectal dysplasia
3. Avoid NSAIDs as they may exacerbate disease
4. Avoid smoking
5. Get mental health counseling as many patients develop depression
6. Sulfasalazine is effective for mild disease
7. Controlled ileal release budesonide can be used for induction of remission in patients with moderate ileocecal disease
8. Avoid the use of metronidazole as it is ineffective in Crohn disease
9. Mild diarrhea can be managed with antidiarrheals
10. Thiopurines can be used for steroid-sparing
11. Anti TNFs can be used in patients resistant to steroids
12. Drain abscess radiologically if possible

Differential Diagnosis

While assessing a patient with Crohn disease following differentials should be kept in mind:

• Amebiasis
• Behcet disease
• Celiac disease
• Intestinal carcinoid
• Intestinal tuberculosis
• Mesenteric ischemia
• Ulcerative colitis

Prognosis

Crohn disease is a chronic inflammatory disorder with no cure. Despite optimal therapy, most patients have a poor quality of life. The life expectancy is slightly reduced to the development of malignancies, genitourinary disease, liver, and biliary tract complications. The majority of Crohn patients who develop complications need surgery and as the disease progresses, some need multiple procedures. Overall, patients with the proximal disease have higher mortality than those with the distal disease.

Once a patient has had surgery, surveillance endoscopy is recommended in six to 12 months. If there is no endoscopic recurrence, ileocolonoscopy should be repeated in 1 to 3 years.

Complications

Crohn disease is a systemic disease with many intestinal and extra-intestinal complications. Following are a few complications caused by Crohn disease:

• Stricture formation
• Fistulae and abscesses
• Colorectal carcinoma
• Ankylosing spondylitis
• Episcleritis, iritis
• Erythema nodosum, pyoderma gangrenosum
• Renal calculi
• Cholelithiasis
• Anemia
• Hypercoagulable state
• Osteoporosis

Deterrence and Patient Education

Education of patients regarding the nature of the disease is very crucial. Patients should undergo screening for skin cancers, irrespective of biological therapy. Bone density should be assessed regularly so that osteoporosis if occurs, is diagnosed early and treated timely. Vaccination against pneumococcus, Haemophilus influenzae, and flu shot should be done. Screening annual colonoscopy should be advised to early detect colon cancer.

Enhancing Healthcare Team Outcomes

Crohn disease is a serious chronic inflammatory disorder that is difficult to diagnose and manage. Besides the GI tract, the disease affects many other organs leading to high morbidity and even premature death. The current consensus is that this disorder should be managed by an interprofessional team dedicated to the management of inflammatory bowel disease.

The diagnosis and management of Crohn disease require an interprofessional team that includes a nurse practitioner or provider assistant, internists, hematologists, gastroenterologists, general surgeons, dietitians, stoma nurses, and a pharmacist. The disorder affects many organs in the body and hence the appropriate specialist should be consulted early on in the disease course.

A nurse practitioner or provider assistant should follow the patient throughout the course and monitor the course of the disease. Any change in the symptoms should be immediately reported to the team. A dietitian should educate the patient on foods to eat and what to avoid. A stoma nurse should educate the patient on the cleaning of the skin and managing everyday problems with this method of stool evacuation.

The pharmacist should educate the patient on the different medications, their benefits, their adverse effects, and the importance of compliance.

Many different providers see these patients as they may develop extraintestinal problems. The patient should be urged to undergo tests to screen for skin and colon malignancies. Finally, most patients develop depression and severe anxiety and hence a mental health nurse should provide continuous counseling.

The disorder is usually managed with medications but complications require surgery. Most patients have relapses and remissions and need lifelong follow-up. The prognosis for most patients with Crohn disease is guarded and the quality of life is poor.[20] An interprofessional team approach can optimize outcomes within the limitations of the condition. (Level 5)