Introduction

Inflammatory bowel disease (IBD) is characterized by repetitive episodes of inflammation of the gastrointestinal tract caused by an abnormal immune response to gut microflora. Inflammatory bowel disease encompasses two types of idiopathic intestinal disease that are differentiated by their location and depth of involvement in the bowel wall. Ulcerative colitis (UC) involves diffuse inflammation of the colonic mucosa. Most often, UC affects the rectum (proctitis), but it may extend into the sigmoid (proctosigmoiditis), beyond the sigmoid (distal ulcerative colitis), or include the entire colon up to the cecum (pancolitis). Crohn disease (CD) results in transmural ulceration of any portion of the gastrointestinal tract (GI), most often affecting the terminal ileum and colon. Both diseases are classified by extent (mild, moderate, or severe) and location. CD is also classified by phenotype- inflammatory, stricturing, or penetrating.[1][2][3]

In addition to the GI tract, both Crohn disease and ulcerative colitis have many extraintestinal manifestations. While in most patients, the disorders can be distinguished, in at least 10% of patients, the features are so similar that it is not possible to initially differentiate between the 2 disorders. Both disorders have a genetic predisposition; neither is curable, and they both carry enormous morbidity. Finally, both increase the risk of colorectal cancer.

Etiology

Inflammatory bowel disease (IBD) occurs in genetically susceptible individuals after an inappropriate immune response to the intestinal flora. To date, the cause of IBD remains a mystery. Many causes have been implicated, but none is universally present in all patients. The one consistent feature of Crohn disease is that it has a strong link with tobacco. On the other hand, it appears that smoking protects against ulcerative colitis. The role of diet remains debatable. The CARD15 gene has been associated with IBD, but because of its polymorphic features, it is not possible to determine which part of the GI tract will be affected. The role of genes in ulcerative colitis is not as strong as in Crohn disease.

Epidemiology

The North American incidence of inflammatory bowel disease (IBD) ranges from 2.2 to 19.2 cases per 100,000 person-years for ulcerative colitis and 3.1 to 20.2 cases per 200,000 person-years for CD. The prevalence of adult ulcerative colitis in the United States was 238 and 201 per 100,000 population, based on data from a large study of insurance claims. IBD is much more prevalent in North America and Europe than in Asia or Africa. Although most IBD occurs in people aged 15 to 30 years, up to 25% of patients will develop IBD by adolescence. There appears to be a bimodal distribution with a second peak of 10% to 15% developing IBD after age 60.[4]

Crohn disease is slightly more common in females than in males, whereas ulcerative colitis appears to be equally common in both genders. IBD is generally a disorder in developed countries and colder climates.

Pathophysiology

The intestinal immune system is key to the pathogenesis of inflammatory bowel disease (IBD). The intestinal epithelium prevents bacteria or antigens from entering the circulation through sealed intercellular junctions. In IBD, these junctions are defective either due to primary failure of barrier function or as a result of severe inflammation. Additional protective mechanisms include mucus production by goblet cells and Paneth cells' secretion of a-defensins with intrinsic antimicrobial activity. Excessive inflammatory reactions lead to continued deterioration of the epithelium and further exposure to intestinal microbes, thereby further worsening the inflammation.

In ulcerative colitis, there is always mucosal inflammation that leads to edema, ulcers, bleeding, and electrolyte losses. The inflammation in ulcerative colitis usually starts in the rectum and progresses uninterrupted to the proximal colon. In Crohn disease, there are skip lesions. In close to 20% of patients with UC, the disease remains confined to the rectum. Pancolitis is seen in about 15% of patients. As the disorder becomes chronic, the colon becomes more rigid and short, with a loss of the haustral markings leading to a 'lead-pipe appearance on a barium enema.

Crohn disease can affect any segment of the GI tract; it may induce strictures and inflammation or lead to the development of fistulas. The key feature of Crohn disease is that it involves all layers of the bowel (transmural). During the later phase of the disease, the mucosa will show a cobblestone appearance due to linear ulcers within the normal mucosa. Crohn disease most affects the colon and ileum, and only 5% of cases affect the gastroduodenal segments. Sparing of the rectum is typical of Crohn disease, but anorectal complications like fistulas and abscesses are very common.

UC predisposes patients to the extraintestinal involvement of the skin, eyes, and bones. Most commonly, these include inflammatory arthropathies and primary sclerosing cholangitis. CD preferentially attacks the ileum and colon but can involve the esophagus, duodenum, or stomach. Pediatric-onset cases have greater upper GI tract involvement. As in the case of UC, CD predisposes patients to extraintestinal manifestations, including arthritis, aphthous stomatitis, uveitis, erythema nodosum, and ankylosing spondyloarthropathy.[5][6]

In Crohn disease, the incidence of kidney disease and gallstones is high due to malabsorption of bile salts and fatty acids. Patients with Crohn disease who undergo resection of the ileum but intact colon are also more likely to develop calcium oxalate renal stones.

Histopathology

Microscopic evaluation in patients with active inflammatory bowel disease (IBD) reveals pronounced infiltration of the lamina propria by neutrophils, macrophages, dendritic cells, and natural killer T cells. Increased numbers and activation of these cells increase the level of tumor necrosis factor-a (TNF-a), interleukin-1b, interferon-gamma, and cytokines of the interleukins-23-TH17 pathway.

The histopathology of ulcerative colitis will show involvement only of the mucosa and submucosa, with the formation of cryptic abscesses and mucosal ulcers. Biopsy specimens show a neutrophilic infiltrate along with crypt distortion and crypt abscesses. Granulomas are not seen in ulcerative colitis. The disease is contagious and usually involves the rectum. Another feature of ulcerative colitis is the presence of pseudopolyps. In Crohn disease, the entire intestinal wall is involved, and granulomas may be seen. Inflammation in Crohn disease is transmural and characterized by lymphocytic infiltrate.

History and Physical

Ulcerative colitis most commonly presents as bloody diarrhea with or without mucus. Patients commonly describe tenesmus, a sensation of incomplete evacuation, and abdominal pain. The physical exam may reveal predominantly left lower- or left upper-quadrant abdominal pain. Signs of an acute abdomen, including guarding, rebound tenderness, or percussion tenderness, warrant investigation for toxic megacolon.

Presentations of Crohn disease vary considerably depending on the region of the gastrointestinal tract involved. Manifestations vary depending on the underlying etiology, including inflammation, fistula formation, or stricture formation. The symptom complex of right lower quadrant pain, weight loss, and non-bloody diarrhea are suggestive of Crohn disease flare-up. Fistula formation may result in fecaluria, pneumaturia, and rectovaginal fistulas. Masses in the right lower quadrant suggest an abscess.

Affected children may present with growth retardation and delay in sexual maturation.

The World Gastroenterology Organization-Based Symptoms for IBD

• Diarrhea may be associated with blood or mucus; diarrhea may also occur at night, and fecal incontinence is not uncommon
• Some patients with ulcerative colitis may present with constipation when the disease is localized to the rectum
• Abdominal pain, tenesmus, and severe urgency are also common presentations
• Crohn disease can present with right lower quadrant pain, and ulcerative colitis may present with left lower quadrant pain
• Nausea and vomiting are more common in Crohn disease

Physical Exam

• Tachycardia, anxiety, fever, and dehydration are common.
• Depending on the anemia, pallor may be noted.
• Toxic megacolon may present with severe pain, fever, abdominal distension, chills, and lethargy. This surgical emergency should always be considered as it is fatal if missed.
• In Crohn disease, one may note anal fistulas, abscesses, or even rectal prolapse.
• Occult blood on a digital rectal exam is common.
• In children, one may only note growth retardation.

Evaluation

Diagnosing inflammatory bowel disease (IBD) requires a combination of clinical findings, inflammatory laboratory markers, imaging findings, and endoscopic biopsies. Hematologic findings include microcytic anemia, leukocytosis, and thrombocytosis. Inflammatory markers such as the erythrocyte sedimentation rate (ESR) and high-sensitivity C-reactive protein (hs-CRP) are commonly elevated.[7][8]

In some patients, the diagnosis may require ruling out parasitic diseases like Giardia, amebiasis, Strongyloides, and tuberculosis. A complete blood count will identify anemia, leukocytosis, and albumin levels.

Fecal calprotectin levels can be used as a marker for intestinal inflammation. Levels of perinuclear antineutrophilic cytoplasmic antibody and anti-Saccharomyces cerevisiae antibody may be elevated in Crohn disease. Finally, stool studies must be done to rule out ova and parasitic organisms.

The abdominal X-ray can assess for free air, bowel obstruction, or toxic megacolon. Barium studies are performed to characterize bowel disease; a lead-pipe appearance indicates ulcerative colitis; sparing of the rectum indicates Crohn disease, and thumbprinting indicates mucosal inflammation. Further, the barium studies may reveal skip lesions and stricture formation in the ileum, which are indicative of Crohn disease.

Ultrasound (US), computed tomography (CT), and magnetic resonance imaging (MRI) have all been used in the diagnosis of IBD or to assess for complications. Trained individuals can evaluate the right lower quadrant for ileal disease. MRI can evaluate for rectal fistulas. Most commonly, CT is employed to evaluate for perforation or bowel obstruction. CT enterography can be helpful in assessing for strictures or in operative planning. Endoscopic evaluation with esophagogastroduodenoscopy, colonoscopy, or both is essential for obtaining biopsies to confirm a diagnosis of IBD.

Treatment / Management

The goal of treatment is to induce remission for either UC or CD. Treatment of IBD is divided into the management of mild, moderate, and severe disease. Agents formerly reserved for more severe disease are now initiated earlier. UC treatment depends largely on the extent of the disease and the presence of extraintestinal manifestations. For those with mild to moderate disease limited to the rectum, aminosalicylate agents like mesalamine are the mainstays. Mesalamine is administered rectally but may be combined with oral therapy to induce or maintain remission. For patients with moderate disease who are refractory to mesalamine, oral glucocorticoids, or immunomodulators such as TNF-alpha monoclonal antibodies (eg, infliximab) may be an option. Up to 25% of all UC patients will require total colectomy for the uncontrolled disease. Proctocolectomy with ileal pouch-anal anastomosis (IPAA) is the procedure of choice for elective cases.[9][10][11]

Flare-ups are usually managed with corticosteroid therapy. For those who have more than 1-2 flare-ups a year, the use of anti-TNF agents or other immunosuppressants is recommended.

CD treatment depends on the portion of the GI tract involved, the degree of fistulizing or stricturing, and any extraintestinal complications. Treatment of mild ileocecal disease is usually initiated with mesalamine, which can be further augmented with oral budesonide, a steroid with significant first-pass metabolism to limit systemic side effects. For more extensive disease, systemic steroid therapy with prednisone is necessary. The goal is to wean these steroids within six weeks. In patients who cannot be weaned, an immunomodulating agent such as 6-mercaptopurine, azathioprine, or low-dose methotrexate is added. In patients with moderate-to-severe disease, anti-tumor necrosis factor (anti-TNF) therapy should be initiated. Before initiating biologic therapy, patients must complete a purified protein derivative (PPD) test to assess for latent tuberculosis. Surgical treatment may be necessary for those with severe fistulizing disease, including a diverting ostomy.[1][12][13]

It is vital to assess the bone density in patients who are administered steroids; osteoporosis has significant morbidity in these patients. If steroid use for more than three months is expected, then calcium supplements and bisphosphonates should be introduced.

Stepwise Therapy

A stepwise approach to IBD management is outlined below.

The first step in pharmacologic therapy for IBD is aminosalicylates. If the patient does not respond to an appropriate dose of aminosalicylates, the second step is to add corticosteroids, which tend to result in a significant decrease in inflammation. Once the response is seen, the dose can be tapered.

Immune-modifying agents (eg, anti-TNF agents) are step-three drugs. These are used when the patient does not respond to corticosteroids, steroids are required for prolonged periods, or the steroids cannot be tapered down without recurrence of symptoms.

Lately, a step-down approach is being favored more for patients with high-risk or severe disease. This includes the early introduction of higher-step medications, such as anti-TNF agents, with rapid de-escalation upon response. Step-down approach improves patient outcomes and prevents complications in patients with high-risk or severe disease.Step four includes clinical trial agents that tend to be disease-specific ie, some work only for ulcerative colitis and others for Crohn disease. Examples of these experimental agents include thalidomide and interleukin (IL)-11 for Crohn disease, butyrate enema, nicotine patch, and heparin for ulcerative colitis. Multiple contraindications and serious side effects are associated with these experimental agents.

Differential Diagnosis

In patients presenting with new diarrhea, infectious etiologies, including parasites, Escherichia coli 0157:H7, and Clostridioides difficile, must be ruled out first. Other colitis etiologies should be considered, including but not limited to microscopic, lymphocytic, and collagenous colitis. Those presenting with abdominal pain must have other causes considered as well, including, but not limited to, appendicitis, irritable bowel disease, celiac disease, and functional abdominal pain.

Staging

The most commonly used objective measure for Crohn disease is the Crohn disease activity index (CDAI). This index, which includes patients' demographic characteristics, subjective complaints and symptoms, laboratory values, and extraintestinal findings, classifies the disease activity. Different online tools are available to calculate this score and help predict the disease stage. Another tool for Crohn disease is Harvey-Bradshaw Index (HBI). Similarly, such tools are available for ulcerative colitis, including the simple clinical colitis activity index (SCCAI), Mayo score/disease activity index (DAI), and the Seo index for disease quantification.

Prognosis

The prognosis for both UC and CD depends on the extent of the disease and treatment response. The stool markers lactoferrin and calprotectin are useful in determining the postoperative recurrence of CD. Some evidence exists that these can also be used to predict future flares. However, patients with IBD tend to have much higher mortality compared to the general population. Causes of death include primary disease, infections, and respiratory illness. Heart disease is not a risk factor for death in IBD. Finally, psychological morbidity is very high in IBD patients, and the quality of life is poor.

Continued surveillance for dysplasia is critical for long-standing patients with UC. The cumulative risk of colorectal cancer is estimated to be as high as 30% for those with the disease for 30 years or more. The extraintestinal manifestation of primary sclerosing cholangitis leads to liver failure.[14][15]

Complications

 The complications of inflammatory bowel disease (IBD) are divided into two categories, intestinal and extraintestinal.

Intestinal

• Hemorrhage
• Strictures
• Colon perforation
• Anal fistulas
• Pelvic or perirectal abscesses
• Toxic megacolon
• Cholangiocarcinoma, colon cancer

Extra Intestinal

• Osteoporosis
• Deep vein thrombosis
• Anemia
• Gallstones
• Primary sclerosing cholangitis
• Aphthous ulcers
• Arthritis
• Iritis
• Pyoderma gangrenosum

Deterrence and Patient Education

Patients with inflammatory bowel disease (IBD) are usually young, and the disease is chronic and lifelong hence increasing patient knowledge improves compliance and helps in management. Patients with IBD need lifelong follow-up for their disease. There is no particular diet or supplement that has been shown to delay or prevent the symptoms of the disease.

Pearls and Other Issues

The pitfalls of Inflammatory Bowel Disease include:

• UC and CD are differentiated histologically by the depth of involvement in the bowel wall.
• Both forms of IBD can develop with extraintestinal manifestations.

Enhancing Healthcare Team Outcomes

There are several gaps in our knowledge regarding the care of patients with IBD. Even though many advances have been made in treatment, many patients continue to miss out on these treatments. The best care for patients with IBD is provided by an interprofessional team dedicated to this pathology and fully aware of the latest guidelines. Patients with IBD lead an unpredictable life with constant flare-ups, and hence, the interprofessional team should establish dedicated phone and support lines staffed by nurses and pharmacists. A network of healthcare providers should be easily accessible to deal with emergencies. Provider and allied healthcare collaboration is vital to avoid delays in treatment. The goal is to halt the disease before widespread bowel damage and disability occur. Furthermore, patient-healthcare communication should be improved, and patients should be supported during times of crisis. Finally, evidence suggests a strong need to establish centers of excellence to ensure patients receive a consistent level of quality care across different healthcare settings.[16][17]

Outcomes

The mortality of patients with IBD is about 1.5-5 times higher compared to the general population. Patients with Crohn disease suffer the highest morbidity and mortality. The major causes of death include infections, the progression of the disease, surgical complications, and multiorgan involvement. More importantly, patients with IBD also have a high rate of colorectal cancer. Patients who develop pancolitis have the highest risk of colon cancer within two decades. Hence, screening colonoscopy is recommended at 1 to 2-year intervals.[18]

In addition to the disease, these patients are also managed with potent medications like steroids and biological agents, which have a host of adverse effects. Thus, the pharmacist should be alert for any adverse reaction. Patients with IBD are also at risk for asthma or COPD.

Finally, IBD has enormous mental morbidity. Many patients develop depression, suicidal tendencies, and anxiety. Thus, at every visit, the nurse should monitor the patient's mental status and make appropriate referrals.[19][20] The quality of life for most patients is poor to okay.

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Disclosure: Christopher McDowell declares no relevant financial relationships with ineligible companies.

Disclosure: Umer Farooq declares no relevant financial relationships with ineligible companies.

Disclosure: Muhammad Haseeb declares no relevant financial relationships with ineligible companies.