Inflammatory Bowel Disease



Inflammatory Bowel Disease


David Dinh



Inflammatory bowel disease (IBD) is a generic term used to describe two main chronic inflammatory conditions of the gastrointestinal (GI) tract: Crohn disease (CD) and ulcerative colitis (UC). Although these conditions are similar in clinical presentation, CD is a chronic inflammatory disease characterized by transmural lesions located at any point on the GI tract, whereas UC is a chronic disease consisting of mucosal inflammation limited to the rectum and colon. IBD affects approximately 1 million Americans. In 1998, the prevalence of CD was estimated to be approximately 359,000, and for UC, it is estimated to be 619,000 (National Institute of Diabetes and Digestive and Kidney Diseases, 2013). The incidence of UC has been relatively stable over the past five decades, whereas the incidence of CD is rising (Kornbluth & Sachar, 2010; Lichtenstein, Diamond, et al., 2009; Lichtenstein, Hanauer, et al., 2009). Both conditions are more common in Whites than in any other race, and those of Jewish descent have a three- to sixfold greater incidence than does the non-Jewish population. IBD shows no gender predilection and is usually first diagnosed in men or women between ages 15 and 25 (Kappelman et al., 2007). Although the mortality rate is low for the disease, it significantly affects the patient’s overall mental status, physical health, and quality of life. The most common emotional issues surrounding uncontrolled IBD appear to be anger, frustration, depression, and low self-esteem. These issues usually stem from the patient’s inability to participate in routine activities, leading to a decreased quality of life. The disease has a negative impact on social interactions and daily functional status, leading to decreased productivity and attendance at work or school, decreased social engagements, and loss of independence. Health-related issues mirror those related to poor GI absorption, including nutritional deficiencies, electrolyte abnormalities, dehydration, cachexia, and iron deficiency anemia. Fatigue and lack of sleep are also common in patients with IBD. In addition, patients with long-standing CD may also be at risk for adenocarcinoma of the GI tract (Pederson et al., 2010). All of these may result in frequent hospitalizations, altered lifestyle, and poor general health. Overall, in 2004, IBD had an estimated financial burden of $328 million in indirect health care costs and over $1.8 billion dollars in direct costs (Everhart, 2008).


CAUSES

The etiology of CD and UC is related to the dysregulation of immunologic mechanisms. The inflammatory nature of the condition has led researchers to believe that an autoimmune mechanism may predispose patients to IBD. The development of IBD may be attributed to a defect in the GI mucosal barrier that results in enhanced permeability and increased uptake of proinflammatory molecules and infectious agents. Tissue biopsies of the GI mucosal lining from patients with IBD reveal a high proportion of immunologic cytokines, including tumor necrosis factor (TNF), leukotrienes, and interleukin-1 (IL-1). A few bacterial and viral organisms have been associated with disease progression, including Mycobacterium paratuberculosis, measles virus, and Listeria monocytogenes; however, none has been definitively correlated with IBD.

Much of the recent evidence suggests that IBD is a complex genetic disorder. The high incidence of IBD in the Jewish population supports a genetic component of the etiology of CD and UC. A study comparing relatives of patients with IBD with the general population found a 10-fold increase in risk of
development of IBD in those with familial occurrence. In addition, studies in twins support the notion that the disease course and occurrence of CD is genetically influenced (Halfverson et al., 2007). Recently, the NOD2/CARD 15 gene has been associated with CD. Those who carry two copies of the risk alleles have been noted to be at higher risk for developing CD than others. The relationship between IBD and other genetic mutations and polymorphisms is currently being investigated. Until there are sufficient data to link a specific genetic mutation to IBD, the identification of genetic polymorphisms remains a research tool and not a clinical diagnostic tool.

Other factors, including psychological well-being and environmental triggers, may contribute to the exacerbation of IBD, although these factors do not have a predictable effect over a large population. Various studies have associated isolated mental instability or stressful events with IBD exacerbations, but a positive correlation between psychiatric illness and IBD is unsupported.

Environmental factors, including geographic location, dietary habits, drug-induced factors, and smoking status, are theorized to affect CD and UC exacerbations. IBD is more prevalent in the northern parts of the United States as well as in England and Scandinavian countries rather than the Mediterranean countries, suggesting that temperature or weather patterns may have an impact on CD or UC. Various dietary habits such as high sucrose consumption have been identified as exacerbating CD or UC, but no one particular food or group of foods seems to have a reliable effect in a large population. Oral contraceptive use and cigarette smoking have variable effects on CD versus UC; oral contraceptives and nicotine have been found to exacerbate CD, but not UC (Khalili et al., 2013). In addition, recently, the use of the antiacne product isotretinoin (Accutane) has been associated with the development of IBD, especially UC. The exact mechanism by which isotretinoin may cause IBD is unknown. However, isotretinoin does affect many immunologic mechanisms that may trigger IBD (Crockett et al., 2010; Reddy et al., 2006).




PATHOPHYSIOLOGY

Differentiating CD from UC is difficult because of their similar clinical presentations. Hallmark symptoms of IBD are bloody diarrhea, weight loss, and fever. Generally, CD can be distinguished from UC based only on endoscopic findings. The GI mucosal lining in CD is usually characterized by discontinuous, narrowed, thick, edematous, leathery patches with the presence of lesions, ulcerations, fissures, strictures, granulomas, and fibrosis. Fistulas and abscess formation occur most commonly in patients with deep transmural lesions. Granulomas and fistulas usually occur exclusively in patients with CD. UC usually affects the rectum and areas proximal, possibly extending throughout the entire large intestine with continuous, superficial uniform inflammation and ulceration. Other pathologic findings are rare in UC but may occur in patients with chronic, long-standing inflammation (Table 31.1).








TABLE 31.1 Common Signs and Symptoms of Crohn Disease versus Ulcerative Colitis


Ulcerative Colitis

Crohn Disease


Signs


Abdominal mass

0

++


Fistulas

+/-

++


Strictures

+

++


Small bowel involvement

+/-

++


Rectal involvement

++

+/++


Extraintestinal disease

Arthritis/arthralgia

++

++

Erythema nodosum

+/-

+/-

Abnormal liver function test values

++

++

Iritis/uveitis

+/-

+/-

Ankylosing spondylitis

+

+

Growth retardation

+

+


Toxic megacolon

+

+/-


Recurrence after colectomy

0

+


Malignancy

+

+/-


Symptoms


Fever

+

++


Diarrhea

++

++


Weight loss

++

++


Rectal bleeding

++

+


Abdominal pain

+

++


Key: +, common; ++, very common; +/-, possible; 0, rare.


Extraintestinal complications, including skin malformations, liver disease, joint deformities, and ocular manifestations, may also occur, although they are more common in CD than UC because of the more aggressive nature of CD, resulting in a higher probability of malabsorption of nutrients (see Table 31.1). Because the complications affect a variety of organ systems and result in nonspecific complaints, it is difficult to associate the complaints with CD or UC; however, it is important to be aware of the complications because their presence indicates poorly controlled disease.


DIAGNOSTIC CRITERIA

Because the clinical presentation of patients with CD or UC is nonspecific, definitive diagnosis relies on endoscopic or radiologic studies. Initial diagnosis of IBD must rule out other causes of bloody diarrhea such as infectious causes and other colitis conditions. Visualization techniques must be used to differentiate CD from UC because of their similar clinical presentations. Usually, endoscopic techniques are preferred over radiographs and radioactive isotopes because endoscopy permits direct visualization of the mucosal lining with increased specificity as to the extent of lesions, ulcerations, and inflammation as well as provides the opportunity to obtain mucosal
specimens for biopsy and further evaluation. The risk of mucosal perforation, however, may limit the use of endoscopic technology in patients with severely active disease.

Sigmoidoscopy or colonoscopy is preferred as a first-line diagnostic procedure; however, for CD, an endogastroduodenoscopy may also be required to visualize the upper GI tract. Radiologic studies with contrast, including either an upper GI series or barium enema, may be preferred in patients with severely active symptoms to decrease the risk of mucosal perforation.

Antibody tests are sometimes helpful in determining the diagnosis of CD or UC. The perinuclear antineutrophil cytoplasmic antibody (pANCA) and/or the anti-Saccharomyces cerevisiae antibody (ASCA) tests may be positive in patients with IBD, but there is a significant rate of false-negative results, since only 60% to 70% of patients with CD or UC are actually antibody positive (Kornbluth & Sachar, 2010). The combination of a positive pANCA and a negative ASCA may indicate the presence of UC, whereas the opposite may indicate CD. However, the combined result still has a significant percentage of false negatives. Therefore, these tests are not used routinely to differentiate UC from CD.


INITIATING DRUG THERAPY

CD and UC share many clinical characteristics with pseudomembranous colitis, irritable bowel disease, peptic ulcer disease (PUD), traveler’s diarrhea, colon cancer, and hemorrhoids. Evaluation of patients with suspected IBD must include a complete history focusing on recent use of antibiotics, recent international travel, diet history, use of laxatives or antidiarrheals, frequency and quality of daily bowel movements, history of PUD, and family history of IBD to rule out similar presenting conditions.

Physical examination should include assessment of vital signs and weight loss, a thorough abdominal examination, and special attention to extraintestinal complications. Guaiac testing and stool cultures may be helpful in ruling out PUD or infectious causes. Although there are no reliable surrogate laboratory markers that may indicate the presence of CD or UC, baseline laboratory studies, including electrolytes, liver panel, complete blood count (CBC), and hematology panel, are important in assessing the severity of the condition and patient well-being.

Initiation of proper drug therapy is based on the severity and extent of disease. CD may present as luminal or fistulizing disease. CD confined to the GI lumen can initially present as mild, moderate, or severe disease and is not predictable in its course. Fistulizing disease also has a varied clinical course, whereby certain patients may never experience a fistula and others may develop one early in the course of the disease. Treatment of fistulizing disease is typically more aggressive than that of luminal disease and may vary depending on the location of the fistula (bowel to bladder, bowel to skin, etc.). UC may be confined to the distal colon and rectum or may extend throughout the colon. Due to the location of the disease, treatment options for distal UC are greater than for extensive disease. The Working Definitions of Crohn’s Disease Activity or the Criteria for Severity of Ulcerative Colitis may be used as a guide to determine severity (Tables 31.2 and 31.3). Both scales are frequently used in clinical trials; however, they are modified for use in clinical practice. There are many validated scales used to assess the severity of UC; however, there is not one gold standard. Each scale highlights specific subjective and objective parameters that should be evaluated when assessing the progression of disease. Both scales highlight certain key features when predicting the severity of the condition, such as the frequency of stools per day and the presence of abdominal pain, fever, and anemia.

Treatment for IBD consists of aminosalicylates, corticosteroids, immunosuppressive agents, antibiotics, and biological agents. The decision to use one or a combination of these agents is based on the presence of CD versus UC, the severity of the disease, and whether treatment is targeted at active disease or maintenance of remission. In general, aminosalicylates are used for treating mild to moderate exacerbations of UC and CD
as well as for maintaining remission in IBD. Corticosteroids are used to treat acute exacerbations and should not be used chronically to maintain remission. Immunosuppressive agents are used for the purposes of maintaining remission in IBD, whereas intravenous (IV) cyclosporine is used in a limited population to treat severely active, steroid-refractory UC. Antibiotics are reserved for treating and maintaining remission in patients with mild CD. Biologic agents are typically reserved for inducing and maintaining remission in patients with steroid-refractory CD; however, the current recommendation is to use biologics in combination with thiopurines to induce remission in moderately severe CD (Table 31.4).








TABLE 31.2 Working Definitions of Crohn’s Disease Activity











Mild to Moderate




  • Ambulatory patients



  • Able to tolerate oral alimentation



  • No evidence of:


    ○ Dehydration


    ○ High fevers


    ○ Rigors


    ○ Prostration


    ○ Abdominal tenderness


    ○ Painful mass


    ○ Abdominal obstruction



  • 10% weight loss


Moderate to Severe




  • Failed treatment for mild to moderate disease OR



  • Have


    ○ High fever


    ○ >10% weight loss


    ○ Abdominal pain/tenderness


    ○ Intermittent nausea or vomiting (without obstructive findings)


    ○ Significant anemia


Severe to Fulminant




  • Persistent symptoms despite outpatient steroid therapy OR



  • Have


    ○ High fever


    ○ Persistent vomiting


    ○ Intestinal obstruction


    ○ Rebound tenderness


    ○ Cachexia


    ○ Abscess


Remission




  • Asymptomatic without inflammatory sequelae



  • Not dependent on steroids









TABLE 31.3 Criteria for Severity of Ulcerative Colitis











Mild UC




  • <4 stools daily (with or without blood)



  • No presence of anemia, fever, or tachycardia



  • Normal erythrocyte sedimentation rate (ESR)


Moderate UC




  • >4 stools daily



  • Minimal anemia, fever, or tachycardia


Severe UC




  • >6 bloody stools daily



  • Positive fever, tachycardia, anemia, or elevated ESR


Fulminant UC




  • >10 stools daily



  • Continuous bleeding



  • Abdominal tenderness and distention



  • Anemia requiring blood transfusion



  • Colonic dilation



Goals of Drug Therapy

Because no pharmacologic cure is available for CD or UC, the goals of treatment focus on symptom management and quality-of-life issues. With proper treatment, the patient should be able to:



  • resume normal daily activities


  • restore general physical and mental well-being


  • attain appropriate nutritional status


  • maintain remission of disease


  • decrease the number and frequency of exacerbations


  • decrease side effects related to medications


  • increase life expectancy

Ideally, patients should expect to recover from an acute exacerbation within 2 to 4 weeks, have minimal exacerbations throughout the year, and participate in any desired activity.


Aminosalicylates

Aminosalicylates remain the gold standard for the treatment of mild to moderate CD and UC. Although the exact mechanism of action is unknown, these drugs decrease inflammation in the GI tract by inhibiting prostaglandin synthesis, which results in a decrease in various immune mediators,


including IL-1, cyclooxygenase, and thromboxane synthase. Therapy with these agents may improve symptoms within 1 week of initiating therapy or dosage adjustment. However, patients may need to take these agents long term to prevent exacerbations. Although they are safe for use in most patients, aminosalicylates are contraindicated in patients with aspirin allergy or glucose-6-phosphate dehydrogenase deficiency. Sulfasalazine is also contraindicated in patients who are hypersensitive to sulfa products (see Table 31.4). All of these agents must be used at maximum doses for maximum therapeutic benefit, although the incidence of side effects also increases with increased doses.








TABLE 31.4 Overview of Agents Used to Treat Inflammatory Bowel Disease

























































































































































































































Generic (Trade) Name and Dosage

Selected Adverse Events

Contraindications

Special Considerations


Aminosalicylates


sulfasalazine (Azulfidine, Azulfidine EN)

Stevens-Johnson syndrome, rash, photosensitivity, nausea, vomiting, skin discoloration, agranulocytosis, crystalluria, hepatitis

Sulfa allergy, aspirin allergy, G6PD deficiency

Most efficacious at high doses


Drug released in the proximal colon


Available in enteric-coated tablets


Dosage increases may occur as frequently as every other day.

Start: 500 mg twice daily


Range: 1-8 g/d


oral mesalamine (Apriso, Asacol HD, Delzicol, Lialda, Pentasa)

Nausea, headache, malaise, abdominal pain, diarrhea

Aspirin allergy, G6PD deficiency

Products released differently in the GI tract

Start: depends on product


Range: 1-4.8 g/d



May increase dose as frequently as every other day


rectal mesalamine (Rowasa Enema, Canasa suppository)

Malaise, abdominal pain

Aspirin allergy, G6PD deficiency

Only for distal ulcerative colitis, proctitis

Suppository


Start: 1 g at bedtime


Range: 1 g/d


Enema


Start: 4 g at bedtime


Range: 1-4 g/d



Suppository is most effective in sigmoid colon, and enema may treat distal and sigmoid colon.


olsalazine (Dipentum)

Nausea, headache, malaise, abdominal pain, diarrhea

Aspirin allergy, G6PD deficiency

Drug released in proximal colon


May increase dose as frequently as every other day


Higher incidence of diarrhea

Start: 500 mg twice daily


Range: 1-2 g


balsalazide (Colazide)

Headache, abdominal pain, diarrhea

Aspirin allergy, G6PD deficiency

Only approved for treatment of mild to moderate ulcerative colitis

Start: 1.5 g twice daily


Range: 1.5-6.75 g


Selected Corticosteroids


prednisone (Orasone, Deltasone)

Hyperglycemia, increased appetite, insomnia, anxiety, tremors, hypertension, fluid retention, electrolyte imbalances

Active GI bleeding

Taper patient off steroids within 1-2 mo of initiation to decrease risk of long-term side effects.

Start: 40-60 mg daily


Range: 10-100 mg


oral methylprednisolone (Medrol)

Same as above

Same as above

Same as above

Start: 20-50 mg daily


Range: 10-100 mg


IV methylprednisolone (Solu-Medrol)

Same as above

Same as above

IV treatment used for severe exacerbations


Treatment duration should be a maximum of 7-14 d, then switch to oral therapy.

Start: 5-10 mg q6h


Range: 10-50 mg


rectal hydrocortisone suppositories (Anusol-HC)

Same as above

Used only for distal ulcerative colitis treatment

Start: 25 mg twice daily


Range: 25-100 mg


hydrocortisone enema (Cortenema)

Enema is more effective than suppositories for distal colitis.

Start: 100 mg bedtime


Range: 100 mg/d


IV hydrocortisone (Solu-Cortef)

Same as above

Active GI bleeding

IV treatment used for severe exacerbations


Treatment duration should be a maximum of 7-14 d, then switch to oral therapy.

Start: 50-100 twice daily


Range: 25-150 twice daily


dexamethasone (Decadron)

Same as above

Same as above

Has longer onset of action than other agents

Start: 5-15 mg daily


Range: 2-20 mg/d


oral budesonide (Entocort EC)

Minimal nausea

Same as above

Minimal systemic absorption


Taper after 8 wk of therapy.


Effective for mild to moderately active luminal CD and maintenance

Start: 9 mg/day


Maintenance: 6 mg/d for 3 mo


Selected Immunosuppressives


azathioprine (Imuran)

Pancreatitis, fever, arthralgias, nausea, rash, agranulocytosis, diarrhea, malaise, hepatotoxicity

Pregnancy, active liver disease, bone marrow suppression

Decrease dose for patients with severe renal dysfunction

Start: 50 mg/d


Range: 2-2.5 mg/kg


6-mercaptopurine (Purinethol)

Same as above

Same as above

Same as above

Start: 50 mg/d


Range: 1-2.5 mg/kg


oral methotrexate (Rheumatrex)

Hepatic cirrhosis and fibrosis, neutropenia, pneumonitis, skin rash, nausea, diarrhea

Same as above

Same as above

Start: 5 mg three times a week


Range: 5-7.5 mg three times a week


IV cyclosporine

Hypertension, nephrotoxicity, superinfection, hypomagnesemia

Renal failure, hepatic failure

Only used for severely acute UC refractory to steroids; total duration of therapy 7-10 d; has many drug interactions

Start: 4-8 mg/kg/d


Selected Antibiotics


metronidazole (Flagyl)

Nausea, diarrhea, disulfiram reaction, metallic taste, peripheral paresthesias, dizziness

Liver failure, renal failure, first trimester of pregnancy, uncontrolled seizure disorder

Should not be used with alcohol


Most efficacious if used chronically >3 mo

Start: 20 mg/kg/d


Range: 10-20 mg/kg/d


ciprofloxacin (Cipro)

Dizziness, nausea, diarrhea, photosensitivity

Children <12 y, pregnancy, uncontrolled seizure disorder

May cause arthropathies in patients <12 y


Must be administered 2 h before or after divalent and trivalent cations

Start: 500 mg twice daily


Range: 500-2,000 mg/d


Tumor Necrosis Factor Inhibitors


IV infliximab (Remicade)

Infusion reactions (urticaria, dyspnea, hypotension), TB, invasive fungal infections, lymphoma, lupus-like syndrome

Class III/IV heart failure, active TB, hepatitis B or other infections

For severe, refractory UC and luminal and fistulizing CD; administered over 2 h as a single infusion


Induction regimen dosed at weeks 0, 2, and 6; maintenance regimen dosed every 8 wk

Start: 5 mg/kg


Range: 5-10 mg/kg


adalilimumab (Humira)

Opportunistic infections (TB, fungal, bacterial, viral), lymphoma and other cancers, injection site reactions (erythema, pain, swelling)

Active TB, hepatitis B, or other infections

For luminal CD; induction regimen 160 mg initially and 80 mg at week 2

Start: 160 mg SQ


Maintenance: 40 mg every week or every other week


certolizumab pegol (Cimzia)

Opportunistic infections (TB, fungal, bacterial, viral), lymphoma and other cancers, injection site reactions (erythema, pain, swelling)

Active TB, hepatitis B, or other infections

For luminal CD

Start: 400 mg at baseline, week 2, and week 4


Maintenance: 400 mg every 4 wk


Selective Adhesion Molecule Inhibitors


IV natalizumab (Tysabri)

Infusion reactions (urticaria, dyspnea, hypotension), opportunistic infections (TB, fungal, bacterial, viral) progressive multifocal leukoencephalopathy (PML), hepatotoxicity

Active TB, hepatitis B, or other infections, current or history of PML

Taper corticosteroid therapy according to clinical response; discontinue natalizumab if therapeutic benefit is not seen within first 12 wk of therapy.

300 mg IV every 4 wk


IV vedolizumab (Entyvio)

Infusion reactions (urticaria, dyspnea, hypotension), TB, invasive fungal infections, lymphoma, lupus-like syndrome

Active TB, hepatitis B, or other infections

Taper corticosteroid therapy off starting at week 6 of vedolizumab therapy.

Start: 300 mg IV at baseline, week 2, and week 6


Maintenance: 300 mg IV every 8 wk


G6PD, glucose-6-phosphate dehydrogenase.



Sulfasalazine

Sulfasalazine (Azulfidine, Azulfidine EN) is efficacious and cost-effective for CD and UC therapy but has a limited role because of its unfavorable side effect profile. Sulfasalazine is a combination product that is cleaved in the proximal colon by bacterial azo-reductases to release sulfapyridine and mesalamine. The mesalamine compound is responsible for virtually all of the therapeutic effect, whereas sulfapyridine is responsible for many of the side effects associated with sulfasalazine. Sulfasalazine may be administered up to four times a day; the most effective and maximum daily dosage is 8 g daily.


Mesalamine

Mesalamine (Asacol, Rowasa, Pentasa, Lialda, Apriso, Canasa) is available in various formulations, including oral tablets, oral capsules, enemas, and rectal suppositories. Each formulation is released in various areas of the GI tract, allowing for targeted drug therapy; however, in clinical trials, the capsules and tablets had similar efficacy at equivalent doses. Asacol, which is one of the oral tablet products, is formulated with an acrylic resin coating that disintegrates at a pH of 7, allowing the active ingredient to be released in the distal ileum and colon. Similarly, Lialda, another oral tablet formulation, has a coating that disintegrates at a pH of 6 to 7, and the core of the tablet forms a matrix that is released across a pH of 6.8 to 7.2. Pentasa, which is a sustained-release capsule, has ethylcellulose-coated granules that allow for the slow release of the drug beginning in the proximal small intestine and continuing throughout the colon. This formulation has slightly different pharmacokinetics than Apriso, which is also a delayed-release capsule. Apriso capsules are enteric coated; they disintegrate at a pH above 6 and also contain granules that are formulated in a polymer matrix for extended release. Because each of the oral products has different pharmacokinetics, the dosing interval for the products ranges from once to four times a day (see Table 31.4). The rectal suppositories are used primarily for UC-associated proctitis, whereas the enema delivers mesalamine to the distal and sigmoid colon. The enema is typically given at bedtime to allow for direct contact of the drug with the mucosa for at least 8 hours. In patients with distal UC, a combination of oral and rectal mesalamine may be an appropriate therapeutic option. Studies have shown that combination mesalamine therapy is more effective than either single mesalamine formulation.

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Nov 11, 2018 | Posted by in PHARMACY | Comments Off on Inflammatory Bowel Disease

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