ULCERATIVE COLITIS (UC)

EPIDEMIOLOGY

In the United States, about 1 million people are affected with ulcerative colitis (UC).^(1,2) The annual incidence is 10.4 - 12 cases per 100,000 people. The prevalence rate is 35-100 cases per 100,000 people. Ulcerative colitis is 3 times more common than Crohn’s disease.

Ulcerative colitis is more common in the Western and Northern hemispheres; the incidence is low in Asia and the Far East.

In Pakistan true prevalence of this disease is unknown. In a large referral centre the incidence of ulcerative colitis in patients presenting with rectal bleeding was reported to be as high as 25%.⁽³⁾

PATHOPHYSIOLOGY:

A variety of immunologic changes have been documented in ulcerative colitis. Subsets of T cells accumulate in the lamina propria of the diseased colonic segment. In patients with ulcerative colitis, these T cells are cytotoxic to the colonic epithelium. This change is accompanied by an increase in the population of B cells and plasma cells, with increased production of immunoglobulin G (IgG) and immunoglobulin E (IgE).⁽⁴⁾

Anti-colonic antibodies have been detected in patients with ulcerative colitis. A small proportion of patients with ulcerative colitis have smooth muscle and anti-cytoskeletal antibodies.

Microscopically, acute and chronic inflammatory infiltrate of the lamina propria, crypt branching, and villous atrophy are present in ulcerative colitis. Microscopic changes also include inflammation of the crypts of Lieberkühn and abscesses. These findings are accompanied by a discharge of mucus from the goblet cells, the number of which is reduced as the disease progresses. The ulcerated areas are soon covered by granulation tissue. Excessive fibrosis is not a feature of the disease. The undermining of mucosa and an excess of granulation tissue lead to the formation of polypoidal mucosal excrescences, which are known as inflammatory polyps or pseudopolyps.

NATURAL HISTORY:

Patients with ulcerative colitis usually present with attacks of bloody diarrhea that last for weeks to months. With treatment, the course of ulcerative colitis typically consists of intermittent exacerbations alternating with long periods of complete symptomatic remission. However, a small percentage of patients have continuing symptoms and are unable to achieve complete remission.^(5,6) Overall, patients who present initially with proctitis have a more benign disease course and frequently respond to topical therapy, whereas those who present with more extensive disease require systemic therapy and have a higher risk of colectomy.

SIGN AND SYMPTOMS:

Patients with UC predominantly complain of the following:

• Rectal bleeding
• Frequent stools
• Mucous discharge from the rectum
• Tenesmus (occasionally)
• Lower abdominal pain and severe dehydration from purulent rectal discharge (in severe cases, especially in the elderly)

In some cases, UC has a fulminant course marked by the following:

• Severe diarrhea and cramps
• Fever
• Leukocytosis
• Abdominal distention

UC is associated with various extracolonic manifestations, as follows:

• Uveitis
• Pyoderma gangrenosum
• Pleuritis
• Erythema nodosum
• Ankylosing spondylitis
• Spondyloarthropathies

Other conditions associated with UC include the following:

• Primary sclerosing cholangitis (PSC)
• Recurrent subcutaneous abscesses unrelated to pyoderma gangrenosum⁽⁷⁾
• Multiple sclerosis⁽⁸⁾
• Immunobullous disease of the skin⁽⁹⁾

Physical findings are typically normal in mild disease, except for mild tenderness in the lower left abdominal quadrant. In severe disease, the following may be observed:

• Fever
• Tachycardia
• Significant abdominal tenderness
• Weight loss

The severity of UC can be graded as follows:

• Mild: Bleeding per rectum, fewer than 4 bowel motions per day
• Moderate: Bleeding per rectum, more than 4 bowel motions per day
• Severe: Bleeding per rectum, more than 4 bowel motions per day, and a systemic illness with hypoalbuminemia (< 30 g/L).

RATIONALE FOR SCREENING:

No evidence suggests that regular endoscopic screening of patients with ulcerative colitis improves survival. However, the current standard of practice by many gastroenterologists is to continue screening these patients at regular intervals, owing to the risk of cancer development and possible legal implications if it is not detected.

DIAGNOSTIC TESTS:

SEROLOGICAL MARKERS:

Much work in the past decade has focused on the development of serologic markers for inflammatory bowel disease. Antineutrophil cytoplasmic antibodies (ANCA) and anti– Saccharomyces cerevisiae antibodies (ASCA) have been the most intensely studied.

ANCA is most commonly associated with ulcerative colitis. Specifically, perinuclear ANCA (pANCA), found on the inside of the nuclear membrane, is highly associated with ulcerative colitis. ANCA assay results are positive in 60-80% of patients with ulcerative colitis. The presence of pANCA is associated with an earlier need for surgery. The finding of ANCA is roughly 50% sensitive, is 94% specific, and has a 76% positive predictive value for ulcerative colitis.^(10,11,12)

ASCA is more highly associated with Crohn disease and is present in 60% of cases, whereas ASCA is present in only 12% of patients with ulcerative colitis. ANCA is present in only about 40% of patients with Crohn disease. ANCA and ASCA titers are not correlated with disease activity.

In children with ambiguous and mild complaints in whom ulcerative colitis is part of the differential diagnosis, algorithms have been proposed in which the presence of ANCA is used to identify those who require more invasive diagnostic tests.⁽¹³⁾

Attempts have been made to correlate ANCA titers with postoperative complications, although this association has not been proven.⁽¹⁴⁾

OTHER LAB STUDIES:

COMPLETE BLOOD COUNT (CBC):

Findings on CBC count may include the following:

• Anemia (i.e. hemoglobin < 14 g/dL in males and < 12 g/dL in females)
• Thrombocytosis (i.e. platelet count >350,000/µL)

COMPREHENSIVE METABOLIC PANEL:

Findings on the comprehensive metabolic panel may include the following:

• Hypoalbuminemia (i.e. albumin < 3.5 g/dL)
• Hypokalemia (i.e. potassium < 3.5 mEq/L)
• Hypomagnesemia (i.e. magnesium < 1.5 mg/dL)
• Elevated alkaline phosphatase: More than 125 U/L suggests primary sclerosing cholangitis (usually > 3 times the upper limit of the reference range).

ENDOSCOPY AND BIOPSY:

Once ulcerative colitis is suspected, endoscopy must be performed. Flexible sigmoidoscopy may be performed if the symptoms are mild, and the physician is likely to initiate therapy on the basis of the results obtained. However, most physicians perform full colonoscopy if inflammation is found with flexible sigmoidoscopy. Therefore, in most circumstances in which ulcerative colitis is suspected, directly proceeding to full colonoscopy is more cost-effective.⁽¹⁵⁾

HISTOLOGICAL FINDINGS:

Histologically, most of the pathology is limited to the mucosa and submucosa. In fulminant cases, the muscularis propria can be affected. Pathologic features that are typically seen include intense infiltration of the mucosa and submucosa with neutrophils and crypt abscesses, lamina propria with lymphoid aggregates, plasma cells, mast cells and eosinophils, and shortening and branching of the crypts.

RADIOLOGICAL ASSESSMENT OF ULCERATIVE COLITIS:

Inflammatory bowel disease and in the differentiation of ulcerative colitis and Crohn disease plain abdominal radiographs are a useful adjunct to imaging in cases of ulcerative colitis of acute onset. Because of its ability to depict fine mucosal detail, double-contrast barium enema examination also is a valuable technique for diagnosing ulcerative colitis and Crohn disease, even in patients with early disease.

Cross-sectional imaging studies (e.g. ultrasonography [US], magnetic resonance imaging [MRI], computed tomography [CT] scanning) are useful for showing the effects of these conditions on the wall of the bowel.

PATIENT SELECTION FOR TREATMENT:

Patients may present with active symptoms of ulcerative colitis as the initial manifestation or as a clinical recurrence of their disease.

When a patient presents with recurrent symptoms, some aspects of the initial evaluation should be repeated in order to exclude alternative or comorbid conditions as a cause for the symptoms, as well as to assess the current extent and severity of disease. These features are important to guide treatment. In most cases, laboratory studies and endoscopy are required.

TREATMENT OPTIONS:

PHARMACOLOGICAL OPTIONS:

SULFASALAZINE: Sulfasalazine is useful in treating mild-to-moderate ulcerative colitis and maintaining remission. It acts locally in the colon to reduce the inflammatory response and systemically inhibits prostaglandin synthesis.

BALSALAZIDE: Balsalazide is a prodrug that is converted into 5-aminosalicylic acid through bacterial azo reduction. Metabolites of drug may decrease inflammation by blocking the production of arachidonic acid metabolites in colon mucosa.

MESALAMINE: Mesalamine is the drug of choice for maintaining remission. It is useful for the treatment of mild-to-moderate ulcerative colitis. It is better tolerated and has less adverse effects than sulfasalazine. Enema and suppository forms are typically used in patients with distal colitis.

INFLIXIMAB: Infliximab is a chimeric mouse-human monoclonal antibody to TNF. It binds free and membrane-bound TNF and thus prevents the cytokine from binding to its cell surface receptor and exerting biological activity. Infliximab is indicated for the treatment of moderate-to-severe active ulcerative colitis in patients who have experienced inadequate response to conventional therapy. It has been shown to reduce signs and symptoms, to achieve clinical remission and mucosal healing, and to eliminate corticosteroid use.

ADALIMUMAB: Adalimumab is a recombinant human anti-TNF-alpha IgG1 monoclonal antibody that blocks inflammatory activity of TNF-alpha. It specifically binds to TNF-alpha and blocks its interaction with p55 and p75 cell surface TNF receptors. It also lyses surface TNF expressing cells in vitro and modulates the biological responses responsible for leukocyte migration. This agent is indicated for patients with ulcerative colitis unresponsive to immunosuppressant medicines (e.g. corticosteroids, azathioprine, 6-mercaptopurine).

GOLIMUMAB: Golimumab is a human anti-TNF-alpha monoclonal antibody that blocks the inflammatory activity of TNF-alpha. It is indicated for induction and maintenance treatment of adults with moderate-to-severe ulcerative colitis that is resistant to prior treatment or requires continuous corticosteroid therapy. Following a brief induction dosage regimen, the maintenance dose is given SC once each month.

AZATHIOPRINE: Azathioprine is effective as a steroid-sparing or steroid-reducing agent and for use in maintenance therapy. Administration is oral. Onset of action can be delayed up to 3-6 months.

CYCLOSPORINE: Cyclosporine is effective as a means of avoiding surgery in patients with severe ulcerative colitis refractory to intravenous corticosteroids. It is given as an intravenous infusion, but can be switched to PO qd dose as "bridge" therapy for outpatient use.

6-MERCAPTOPURINE: 6-Mercaptopurine is effective as a steroid-reducing or steroid-sparing agent and for use in maintaining remission. Administration is oral. Onset of action can be delayed up to 3-6 months.

TACROLIMUS: Immunomodulator produced by the bacteria Streptomyces tsukubaensis. Mechanism of action of tacrolimus is similar to cyclosporine. It is effective in bringing steroid-resistant disease under control. Tacrolimus should not be used for long-term therapy, owing to the risk of nephrotoxicity.

METHYLPREDNISOLONE: Methylprednisolone is administered intravenously in severe cases.

PREDNISONE: Given orally, is effective for the treatment of active moderate-to-severe ulcerative colitis.

HYDROCORTISONE: High dose corticosteroids such as hydrocortisone are used in the treatment of acute, severe ulcerative colitis. Hydrocortisone decreases inflammation by suppressing migration of polymorphonuclear leukocytes and reversing increased capillary permeability.

BUDESONIDE: Budesonide is a potent glucocorticoid that has poor oral absorption and extensive first-pass metabolism. These properties make it ideal for reducing gastrointestinal inflammation. It is indicated for remission induction of active, mild-to-moderate ulcerative colitis.

BUDESONIDE RECTAL: Budesonide rectal is a corticosteroid available as a 20 mg/metered-dose rectal foam. It is indicated for the induction of remission in adults with active mild-to-moderate distal ulcerative colitis extending up to 40 cm from the anal verge.

VEDOLIZUMAB: Vedolizumab is a recombinant humanized monoclonal antibody that binds specifically to α4β7 integrin. It blocks the interaction of α4β7 integrin with mucosal addressin cell adhesion molecule-1 (MAdCAM-1) and inhibits the migration of memory T-lymphocytes across the endothelium into inflamed gastrointestinal parenchymal tissue. It is indicated for both ulcerative colitis and Crohn disease.

CIPROFLOXACIN: A fluoroquinolone, ciprofloxacin has activity against pseudomonads, streptococci, MRSA, Staphylococcus epidermidis, and most gram-negative organisms but no activity against anaerobes. Inhibits bacterial DNA synthesis and, consequently, growth.

METRONIDAZOLE: Metronidazole is an imidazole ring–based antibiotic active against various anaerobic bacteria and protozoa. Used in combination with other antimicrobial agents but as monotherapy for C difficile enterocolitis.

DIPHENOXYLATE HYDROCHLORIDE + ATROPINE SULPHATE: This drug combination consists of 2.5 mg of diphenoxylate, which is a constipating meperidine congener, and 0.025 mg of atropine to discourage abuse. The preparation inhibits excessive GI propulsion and motility, but it may exacerbate constipation.

LOPERAMIDE: Loperamide which is available over the counter, acts on intestinal muscles to inhibit peristalsis and to slow intestinal motility. It prolongs the movement of electrolytes and fluid through bowel and increases viscosity and loss of fluids and electrolytes. Loperamide improves stool frequency and consistency, reduces abdominal pain and fecal urgency, and may exacerbate constipation.

GOALS OF THERAPY:

Goals of treatment are induction and maintenance of remission of symptoms to provide an improved quality of life, reduction in need for long-term corticosteroids, and minimization of cancer risk

GUIDELINES:

Treatment for Ulcerative Colitis is based on guidelines from the prestigious society such as and American College of Gastroenterology (ACG).

To review the ACG guidelines, click on the link below.

http://gi.org/guideline/ulcerative-colitis-in-adults/

LONG TERM MONITORING:

In a study that aimed to identify a panel of markers associated with the long-term outcome of infliximab therapy for patients with refractory ulcerative colitis (median follow-up, 5 y), Arias et al confirmed that short-term clinical response and mucosal healing—as well as baseline levels of C-reactive protein (CRP) of 5 mg / L or less and albumin of 35 g / L or greater—were independent predictors of colectomy-free survival. Moreover, infliximab levels over 2.5 μg / mL at week 14 of treatment predicted both relapse and colectomy-free survival. A combined risk panel that included clinical response, mucosal healing, and levels of pANCA, CRP, and albumin identified patients at risk for disease relapse or colectomy.⁽¹⁶⁾

In patients with chronic pouch inflammation, villous hypertrophy and dysplasia may occur. Although dysplasia has never been found within the pouch of a pediatric patient, chronic inflammatory changes have been found, leading to the supposition that dysplasia may develop. Yearly screening endoscopy has been recommended for the first 5 years after the procedure. In children who have chronic inflammatory changes in the pouch reservoir, annual screening endoscopy should be performed. If no inflammation is present, screening endoscopy may be performed every 2 years.⁽¹⁷⁾

Patients with extensive colitis or left-sided colitis with negative findings on screening colonoscopy should begin surveillance colonoscopy in 1-2 years. For patients with ulcerative colitis and primary sclerosing cholangitis, screening and subsequent surveillance colonoscopy should begin on an annual basis at the time of onset of primary sclerosing cholangitis.

Patients with proctosigmoiditis have no increased risk for colorectal cancer compared with the general population. However, these patients should be managed according to the current guidelines on colorectal cancer screening. If high-grade dysplasia or cancer is found, colectomy is performed. The management of low-grade dysplasia is controversial;⁽¹⁸⁾ however, most experts would recommend colectomy.

CONSULTATION AND COUNSELING:

• There may be a chance of flare-ups, diarrhea, abdominal pains, and gas coming back and keeping patient from venturing out to public places.
• One practical tip for patient is to map out restroom locations before going to restaurants, shopping areas, and theaters.
• For longer trips, patient should suggest to carry extra underclothing and wet wipes which can help patient. It is also very important to remember to carry enough medication for the length of trip.
• Taking medication as prescribed

Extended relief could be within reach if patient take positive steps, such as

• Take proper diet and exercise that fits his / her needs and helps to manage UC symptoms
• Keeping close track of UC symptoms.

PRECAUTIONS:

DIET:

• Limit dairy products: Many people with ulcerative colitis find that problems such as diarrhea, abdominal pain and gas improve by limiting or eliminating dairy products. Some patients may be lactose intolerant that is, body can't digest the milk sugar (lactose) in dairy foods. Using an enzyme product such as Lactaid may help as well.
• Try low-fat foods: In ulcerative colitis, patient may not be able to digest or absorb fat normally. Instead, fat passes through intestine, making diarrhea worse. Patient should suggest to avoid butter, margarine, cream sauces and fried foods.
• Limit fiber, if it's a problem food: In ulcerative colitis, high-fiber foods, such as fresh fruits and vegetables and whole grains, may make UC symptoms worse. If raw fruits and vegetables bother patient, patient should suggest to try steaming, baking or stewing them. In general, patient may have more problems with foods in the cabbage family, such as broccoli and cauliflower, and nuts, seeds, corn and popcorn. Patient may be told to limit fiber or go on a low-residue diet if have a narrowing of bowel (stricture).
• Avoid other problem foods: Spicy foods, alcohol and caffeine may make UC signs and symptoms worse.

STRESS:

Although stress doesn't cause ulcerative colitis, it can make UC signs and symptoms worse and may trigger flare-ups.

To help control stress, suggest patient to try:

• Even mild exercise can help reduce stress, relieve depression and normalize bowel function.
• This stress-reduction technique helps to reduce muscle tension and slow heart rate with the help of a feedback machine. The goal is to help patient enter a relaxed state so that patient can cope more easily with stress.
• Regular relaxation and breathing exercises. An effective way to cope with stress is to perform relaxation and breathing exercises.

REFERENCES:

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17. Sarigol S, Wyllie R, Gramlich T, Alexander F, Fazio V, Kay M, et al. Incidence of dysplasia in pelvic pouches in pediatric patients after ileal pouch-anal anastomosis for ulcerative colitis.J Pediatr Gastroenterol Nutr. 1999 Apr. 28(4):429-34.
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