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Risk factors Symptoms/Pathology Diagnosis Clinical course / Sequelae / Extraintestinal disease Management
Known risk factors
  • Family history/genetics - most important risk factor; risk is 5 - 16% with affected first-degree relative; monozygotic twins concordance rate is 6 - 13%
  • Ashkenazi Jews

Possible risk factors
Possible protective factors
  • Smoking - smoking appears to protect against the disease and smokers tend to have a milder course
  • Appendicitis - appendectomy before age 20 years or a genetic/environmental predisposition to appendicitis may be protective against UC [1,15]
Symptoms
  • Age of onset - UC has a bimodal peak incidence rate with the main peak occurring at ages 15 - 30 years, and a smaller peak seen at ages 50 - 70 years

    • Common symptoms include:
      • Rectal bleeding
      • Diarrhea
      • Tenesmus - continuous urge to evacuate bowels
      • Abdominal pain
      • Fever (if severe) [1,6]


Pathology
  • The exact pathology of UC is not entirely understood
  • UC is believed to occur when defects in the epithelial barrier of the colon allow commensal bacteria in the lumen to come in contact with underlying tissue
  • Defects in the epithelial barrier may occur secondary to faulty tight junctions and/or impaired mucin secretion
  • In the underlying tissue, immune cells are activated, and they release inflammatory mediators. Other immune cells are recruited and the inflammatory process propagates.
  • T-cell activity also appears to be altered in UC. Natural killer T-cells have been shown to secrete abnormally large amounts of interleukin 13 in patients with UC. Interleukin 13 promotes further inflammation and epithelial cell damage.
  • Inflammatory lesions in UC only involve the mucosal surface of the colon. This distinguishes UC from Crohn's disease where the entire wall (transmural) of the colon is affected.
  • UC lesions typically start at the anorectal verge and extend proximally in a continuous fashion. UC may involve the entire colon or only a small section. In some patients, a small patch of inflammation can be found in the cecum. UC differs from Crohn's disease in that it mostly affects the colon, and the lesions are continuous as opposed to the "skip lesions" seen in Crohn's disease.

  • Intestinal involvement at diagnosis:
    • Rectum and sigmoid colon - 30 - 50%
    • Left-sided colitis (up to splenic flexure) - 20 - 30%
    • Pancolitis - 20% [1]
Overview
  • The diagnosis of UC is established by a combination of clinical symptoms, findings on colonoscopy, and histological features seen in colon biopsies

Colonoscopy
  • Colonoscopy is the gold standard for establishing the diagnosis of UC
  • Findings on colonoscopy include a granular, erythematous mucosa with friability and loss of vascular patterns. In more severe disease, erosions and ulcers are found along with spontaneous bleeding.
  • Inflammation typically begins in the rectum and extends proximally in a continuous fashion to involve part or all of the colon.

Laboratory
  • ESR and C-reactive protein - nonspecific inflammatory markers (e.g. erythrocyte sedimentation rate, C-reactive protein) are often elevated in UC
  • Fecal calprotectin - calprotectin is an antimicrobial substance released by polymorphonuclear granulocytes (PMNs). Fecal calprotectin concentrations are directly proportional to the number of PMNs migrating to the intestinal lumen. In patients with active inflammatory bowel disease, fecal calprotectin levels are typically very high. In studies involving adults with suspected inflammatory bowel disease (IBD) based on symptoms, the sensitivity and specificity of fecal calprotectin in detecting IBD (verified by endoscopy and histology) was 93% and 96%, respectively. In studies involving children and teenagers, the sensitivity was 92% and the specificity was 76%. The cutoff value typically used in the studies was > 50 mcg/g. [2,3]
  • Fecal lactoferrin - lactoferrin is an iron-binding protein that has antimicrobial activity. Lactoferrin is found in neutrophil granules. During intestinal inflammation, neutrophils migrate to the intestinal mucosa and secrete lactoferrin into the lumen. Because of this, fecal lactoferrin levels are often elevated in patients with active inflammatory bowel disease (IBD). In studies involving adults with suspected IBD, the sensitivity and specificity of fecal lactoferrin in detecting IBD (verified by endoscopy and histology) was 78% and 94%, respectively. The cutoff value used in most studies was 7.25 mcg/ml. [4]
Clinical course
  • UC typically follows an undulating course of disease flares followed by periods of remission
  • At diagnosis, most patients have mild to moderate disease, and only about 10% of patients have severe disease
  • For patients with disease confined to the rectum at diagnosis, approximately 14% will progress to extensive colitis over 10 years
  • For patients with left-sided colitis at diagnosis, approximately 28% will progress to extensive colitis over 10 years
  • Patients diagnosed at a younger age (< 30 years) are at greater risk for disease progression [5]
  • Colectomy rates among patients with UC vary depending on the population studied and the treatment options available. In general, patients with UC have a 10-year colectomy rate that ranges from 4% - 30%. The risk of colectomy is highest during the first 2 years after diagnosis. [1,6,7]


Sequelae
  • Rectal bleeding - common; may become severe in 10% of patients; can lead to iron-deficiency anemia [6]
  • Bowel strictures - uncommon; if present, patient may be at increased risk of colon cancer [1,6]
  • Toxic megacolon - a syndrome of severe colonic distension (≥ 6 cm); seen in patients with severe/fulminant disease; perforation may occur; is an indication for colectomy [6,8]
  • Colon cancer - patients with UC are at an increased risk for colon cancer. The risk appears to be higher in patients who are diagnosed in childhood or adolescence and in those with primary sclerosing cholangitis. Recent studies suggest that the risk is decreasing. This is likely due to newer therapies (e.g. TNF inhibitors) and better disease control. See colon cancer screening for recommendations on screening in UC [9]
  • Cytomegalovirus (CMV) - CMV superinfection of the colon may occur in patients with severe, fulminant disease; immunosuppression (e.g. steroids, cyclosporine) also increases the risk; CMV colitis is diagnosed with viral cultures performed on colon biopsies; CMV colitis is treated with ganciclovir [8]
  • Clostridium difficile (C. diff) - C. diff infections may occur in patients with severe disease; oral vancomycin may be more effective than metronidazole for treating C. diff in UC patients [8]
  • Pouchitis - in patients who have had a total colectomy, an ileal pouch–anal anastomosis is typically formed; a syndrome called pouchitis where the ileal pouch becomes inflamed occurs in up to 40% of patients; pouchitis may be chronic in up to 20% of patients; symptoms include incontinence, tenesmus, urgency, bleeding, and increased stool frequency; pouchitis is treated with a short course of antibiotics (metronidazole 250 TID, or ciprofloxacin 500 mg BID); the diagnosis should be confirmed by endoscopy and histology [6,8]

Extraintestinal disease
  • A number of organ systems may be affected by UC
  • Extraintestinal disease occurs in 10 - 30% of patients with UC [6]

  • Arthritis - occurs in 5 - 10% of patients
    • Pauciarticular (affecting < 5 large joints) - knee is commonly involved; typically associated with intestinal disease activity; improves with treatment of bowel disease
    • Polyarticular (affecting ≥ 5 small joints) - MCP joints are commonly involved; typically not associated with intestinal disease activity; may be treated with steroids and COX-2 inhibitors
  • Erythema nodosum - occurs in up to 10% of patients; typically coincides with acute flares; improves with disease treatment
  • Primary sclerosing cholangitis - occurs in up to 7.5% of patients; associated with a higher risk of colon cancer; disease course appears to be independent of UC
  • Eye disease - episcleritis, scleritis, and uveitis; occurs in 2 - 5% of patients
  • Pyoderma gangrenosum - rare; associated with severe disease; typically affects the shin; more common in women and blacks [10]
NOTE: There is no consensus guideline for categorizing and treating UC patients. The information below is derived from a combination of ACG, ACA, and expert opinion recommendations.

  ACTIVE DISEASE  

  • Mild to moderate distal disease - generally defined as disease confined to the rectum and sigmoid colon; minimal systemic symptoms; ≤ 4 stools/day

    • First-line
      • Topical mesalamine ± Oral aminosalicylate ± Topical steroids
    • Refractory
      • Prednisone OR Biological

    • See dosing table below for medications and dosages



  • Mild to moderate extensive disease - generally defined as disease that extends beyond the sigmoid colon; minimal systemic symptoms; ≤ 4 stools/day

    • First-line
      • Oral aminosalicylate ± Topical steroids ± Topical mesalamine
    • Refractory
      • Prednisone, if no response then Thiopurine OR Biological

    • See dosing table below for medications and dosages



  • Severe disease - generally defined as disease that involves much or all of the colon; significant systemic symptoms (e.g. fever; decreased hemoglobin); ESR ≥ 30 mm/hr; ≥ 6 bloody stools/day

    • First-line
      • IV steroids
    • Refractory
      • Infliximab OR Cyclosporine (IV to oral) OR Surgery

    • See dosing table below for medications and dosages

    Reference [1,8,11]

  MAINTENANCE OF REMISSION  

  • Maintenance therapy in UC depends largely upon the treatment that was used to achieve remission and the severity of the disease
  • In most cases, the medication that was used to achieve remission should be continued
  • Steroids (oral and topical) and cyclosporine should be tapered and replaced with one of the regimens below

    • Regimens used to maintain remission:
      • Topical mesalamine and/or oral aminosalicylate - effective in mild to moderate disease
      • Thiopurine ± oral aminosalicylate - effective in moderate and severe disease and in patients who are steroid-dependent
      • Thiopurine ± biological - effective in moderate and severe disease and in patients who are steroid-dependent
      • Biological - effective in moderate and severe disease

    • See dosing table below for medications and dosages

References [1,8,11]







Drug Dosage form Dosage Generic/Price Mechanism/FDA-approved
indications
Side effects
P = % of patients on placebo who experienced side effect
Drug Interactions Contraindications/
Precautions
Budesonide

(Uceris®)
Extended-release tablet
Uceris®
  • 9 mg

Rectal foam
Uceris®
  • 2 mg per actuation
Ulcerative colitis

Uceris tablet
  • Active disease: 9 mg once daily for up to 8 weeks
  • May take without regard to food
  • Swallow whole. Do not cut, crush, or chew tablet.

Uceris foam
  • Active disease: 1 metered dose (2 mg) twice a day for 2 weeks, then 1 metered dose once daily for 4 weeks
  • Foam is approved to treat disease that extends up to 40 cm from the anal verge
Uceris tablet
NO/$$$$

Uceris foam
NO/$$$$
Mechanism
  • Budesonide is a corticosteroid. See corticosteroids for general information.
  • Uceris tablets contain a core that is enteric coated. The enteric coating dissolves in the small intestine, and the core begins to release budesonide in a time dependent matter. The therapeutic effect of budesonide is believed to occur through local effects in the colon.
  • Uceris foam is applied directly to the colonic mucosa through the rectum
  • Budesonide that is absorbed undergoes a high rate of first-pass metabolism (80 -90%). Budesonide has the potential to cause systemic side effects (e.g. HPA suppression), but the risk appears to be less than what is seen with other oral corticosteroids.

FDA-approved indications
Uceris tablet
  • Ulcerative colitis - induction of remission in patients with active, mild to moderate ulcerative colitis

Uceris foam
  • Ulcerative colitis - induction of remission in patients with active mild to moderate distal ulcerative colitis extending up to 40 cm from the anal verge
NOTE: Only side effects that occurred at an incidence of ≥ 2% and ≥ 2% more than placebo are listed. Data presented below is for Uceris tablets.

  • Decreased blood cortisol - 4.3%, P - 0.4%
  • Upper abdominal pain - 3.9%, P - 1.9%
  • CYP3A4 inhibitors - budesonide is a CYP3A4 sensitive substrate. Systemic exposure to budesonide is increased when taken with CYP3A4 inhibitors. Consider stopping Uceris if it is necessary to take a CYP3A4 inhibitor.
  • Grapefruit juice - grapefruit juice inhibits CYP3A4 and should not be taken with Uceris
  • Acid-reducing agents (PPIs, H2-blockers, etc.) - acid-reducing agents may affect the dissolution of Uceris tablets
  • Corticosteroid precautions - see corticosteroids for general precautions regarding corticosteroids. Systemic exposure with Uceris is reduced compared to other oral steroids, so the risks with Uceris therapy are also likely reduced.
  • Hypothalamus-pituitary-adrenal (HPA) axis suppression - HPA suppression is a side effect of oral corticosteroids. Budesonide has reduced systemic exposure compared to other oral steroids, but some systemic exposure does occur. In one study, abnormal ACTH stimulation tests occurred in 47% of patients treated with Uceris tablets (9 mg daily) for 4 weeks and 79% of patients treated for 8 weeks. In studies involving Uceris foam, abnormal ACTH stimulation tests occurred in 37% of patients treated with Uceris foam for 6 weeks compared to 24% of patients treated with placebo.
  • Immunosuppression - immunosuppression may occur. Use caution in patients with active or quiescent infections (e.g. tuberculosis, parasitic infections, etc.)
  • Transferring from other systemic steroids - when transferring from other systemic corticosteroids (e.g. prednisone) to Uceris, the other systemic steroid should be tapered to avoid withdrawal reactions (e.g. HPA suppression).
  • Kidney disease - manufacturer makes no specific recommendation
  • Liver disease - since Uceris undergoes extensive first-pass metabolism, patients with moderate to severe liver disease may have increased systemic exposure to budesonide. Consider dose reductions in these patients.




Drug Dosage form Dosage Generic/Price Mechanism/FDA-approved
indications
Side effects
P = % of patients on placebo who experienced side effect
Drug Interactions Contraindications/
Precautions
Hydrocortisone

(Colocort®)
(Cortenema®)
(Cortifoam®)
Enema
Colocort®, Cortenema®
  • 100 mg/60 ml
  • Comes in box of 7 enemas

Rectal foam
Cortifoam®
  • 80 mg per application
  • Comes in aerosol container that delivers a minimum of 14 applications
Ulcerative colitis
Colocort, Cortenema
  • Active disease: one enema (100 mg) nightly for 21 days
  • Effect typically seen within 3 - 5 days
  • In difficult cases, 2 - 3 months of therapy may be required
  • If therapy extends beyond 21 days, enemas should be tapered when discontinuing by giving every other day for 2 - 3 weeks
  • Enema effects reach the splenic flexure, and have been shown to be beneficial in some patients with transverse and ascending disease

Cortifoam
  • Active disease: one applicatorful 1 - 2 times a day for 2 - 3 weeks, and every second day thereafter
  • Clinical response typically seen within 5- 7 days
  • Foam effects have been shown to reach ∼ 15 - 20 cm into the colon [8]
Colocort/Cortenema
YES/$$-$$$ (#21)

Cortifoam
NO/$$$$
Mechanism
  • Hydrocortisone is a corticosteroid. See corticosteroids for general information.
  • Hydrocortisone enemas and foam work locally in the colon to inhibit inflammation
  • Hydrocortisone in enemas and foam is also absorbed systemically. With enemas, 50% of the hydrocortisone is absorbed systemically. Systemic absorption from the foam may be greater.

FDA-approved indications
Colocort, Cortenema
  • Ulcerative colitis - adjunctive therapy in the treatment of ulcerative colitis, especially distal forms, including ulcerative proctitis, ulcerative proctosigmoiditis, and left sided ulcerative colitis. It has proved useful also in some cases involving the transverse and ascending colons.

Cortifoam
  • Ulcerative colitis - adjunctive therapy in the topical treatment of ulcerative proctitis of the distal portion of the rectum in patients who cannot retain hydrocortisone or other corticosteroid enemas
  • Side effects with Colocort, Cortenema, and Cortifoam are not well-defined. Because a significant amount of systemic absorption occurs, side effects are generally the same as those seen with other systemic corticosteroids.
  • See corticosteroids for more
  • Hydrocortisone undergoes significant systemic absorption. Drug interactions with hydrocortisone are the same as those seen with other systemic steroids.
  • See corticosteroids for more
  • Corticosteroid precautions - see corticosteroids for general precautions regarding corticosteroids. Systemic exposure to hydrocortisone with enemas and foam is significant and carries similar risks as other systemic steroids.
  • Bowel defects - DO NOT USE in patients with obstruction, abscess, perforation, peritonitis, fresh intestinal anastomoses, extensive fistulas, and sinus tracts
  • Hypothalamus-pituitary-adrenal (HPA) axis suppression - HPA suppression is a side effect of oral corticosteroids. Hydrocortisone enemas and foam have significant systemic absorption. If enema therapy extends beyond 21 days, enemas should be tapered when discontinuing by giving every other day for 2 - 3 weeks. Foam should be given every other day after 2 - 3 weeks of therapy.
  • Kidney disease - manufacturer makes no specific recommendation. Use caution.
  • Liver disease - clearance is decreased. Use caution.



  • ULCERATIVE COLITIS STUDIES

    • CONSTRUCT trial - Cyclosporine vs Infliximab in Severe UC, Lancet (2016)
      • The CONSTRUCT trial enrolled 270 patients with steroid-resistant, acute, severe UC
      • Main inclusion criteria: age ≥ 18 years; unscheduled admission for severe UC that had failed to respond to 2 - 5 days of IV hydrocortisone
      • Main exclusion criteria: enteric infection; histological diagnosis inconsistent with UC; treatment with infliximab or cyclosporine within 3 months
      • Baseline characteristics: average age 35 years; female sex - 37%; Montreal score, E3 - 46%, E2 - 47%; median duration of symptoms - 24 days; median duration of IV hydrocortisone - 5 days
      • Patients were randomized to 1 of 2 groups:
        • Group 1 (135 patients) - Infliximab 5 mg/kg IV at baseline, Week 2, and Week 6
        • Group 2 (135 patients) - Cyclosporine 2 mg/kg/day by continuous infusion for up to 7 days, then 5.5 mg/kg/day by mouth in divided doses for 12 weeks
        • Treatment was open-label
        • Oral cyclosporine dosing was adjusted to achieve a trough level of 100 - 200 ng/ml
        • Other therapies were left at the discretion of the patient's provider. Stopping steroids by Week 12 was encouraged in patients who were doing well.
      • PRIMARY OUTCOME: Average quality-adjusted survival over the course of the study defined as the total area under the curve (AUC) of scores from the Crohn’s and Ulcerative Colitis Questionnaire (CUCQ) measured at 3 and 6 months, and then every 6 months from 1 year to 3 years. By convention lower CUCQ scores indicate better health on disease-specific patient-reported outcome measures. For the purposes of presenting the area under the curve, the CUCQ scores were transformed so that lower scores indicated worse health.
      • After a median follow-up of 2.1 years, the following was seen:
        • Primary outcome (average AUC for CUCQ score over course of the study): Group 1 - 564, Group 2 - 587, (adjusted diff - 7.9, 95%CI [-22 to 37.8], p=0.603)
        • Colectomy rates at 3 months: Group 1 - 29%, Group 2 - 30% (p>0.05)
        • Colectomy rates at 12 months: Group 1 - 35%, Group 2 - 45% (p>0.05)
        • Colectomy rates overall: Group 1 - 41%, Group 2 - 48% (p=0.223)
        • Average time to colectomy (days): Group 1 - 811 days, Group 2 - 744 days (HR 1.234, 95%CI [0.862 to 1.768], p=0.251)
        • Median duration of study drug therapy: Group 1 - 43 days, Group 2 - 60 days
        • There was no significant difference between the groups for adverse events
        • There was no significant difference between the groups in patients taking thiopurines or methotrexate (3 months, Group 1 - 43%, Group 2 - 49%; 24 months, Group 1 - 30%, Group 2 - 30%)
        • Nine patients assigned to Group 2 were subsequently given infliximab and 1 patient assigned to Group 1 was given cyclosporine [16]

    • StraightHealthcare analysis:
      • The CONSTRUCT trial found that cyclosporine was as effective as infliximab in patients with severe UC flare for both quality of life outcomes and colectomy rates. Also of note, there was no significant difference in adverse events between the two treatments.
      • Disadvantages of cyclosporine include frequent lab monitoring and an extensive list of drug interactions, but on the upside, it is considerably cheaper than infliximab



Study Criteria Intervention Primary outcome Results

Vedolizumab
vs
Placebo

GEMINI 1 Study

NEJM 2013

PubMed abstract
Main inclusion criteria:
  • ≥ 18 years old
  • Active ulcerative colitis defined as Mayo score 6 - 12 with a sigmoidoscopy subscore of at least 2, and disease that extends ≥ 15 cm from the anal verge
  • Previous unsuccessful treatment or unacceptable side effects with steroids, immunosuppressants, or TNF inhibitors

Main exclusion criteria:
  • TNF inhibitors within previous 60 days
  • Cyclosporine or thalidomide within 30 days
  • History of colectomy
  • Increased risk of infection

Baseline characteristics
  • Average age 40 years
  • Average Mayo score - 8.6
  • Treatment with steroids only - 37%
  • Treatment with immunosuppressants only - 18%
  • Treatment with steroids + immunosuppressants - 17%
  • No steroids or immunosuppressants - 29%
  • Prior TNF inhibitor - 48%
Induction phase
Group 1 (149 patients)
  • Placebo infusion

Group 2 (225 patients)
  • Vedolizumab 300 mg at Weeks 0 and 2

Maintenance phase
Group 1 (126 patients)
  • Placebo infusion

Group 2 (122 patients)
  • Vedolizumab 300 mg every 8 weeks

Group 3 (125 patients)
  • Vedolizumab 300 mg every 4 weeks

  • Participants could continue to take mesalamine, up to 30 mg of prednisone (or the equivalent) per day, or immunosuppressive agents at stable doses
  • The induction phase also had an open-label vedolizumab arm that included 521 patients
  • Vedolizumab-responders from the induction phase (randomized and open-label) were re-randomized into the maintenance phase
Induction phase - clinical response at week 6, defined as a reduction in the Mayo Clinic score (range, 0 to 12, with higher scores indicating more active disease) of ≥ 3 points and a decrease of at least 30% from the baseline score, with a decrease of at least 1 point on the rectal bleeding subscale or an absolute rectal bleeding score of 0 or 1
Maintenance phase - clinical remission at week 52 defined as Mayo Clinic score ≤ 2 and no subscore higher than 1, and mucosal healing, defined as an endoscopic subscore of 0 or 1
Induction phase
  • Primary outcome - Group 1 - 25.5%, Group 2 - 47.1% (p<0.001)

Maintenance phase
  • Primary endpoint - Group 1 - 15.9%, Group 2 - 41.8%, Group 3 - 44.8%
  • Group 1 vs Group 2 (p<0.001); Group 1 vs Group 3 (p<0.001)

Adverse events
  • There was no significant difference in adverse events between the vedolizumab groups and placebo groups



  • PRICING

    • $ = 0 - $50
    • $$ = $51 - $100
    • $$$ = $101 - $150
    • $$$$ = > $151

    • Pricing based on one month of therapy at standard dosing in an adult
    • Pricing based on survey of GoodRX.com®, HEB®, and Costco®, [accessed 12/2015]
    • Pricing may vary by region and availability



  • References:
  • 1 - PMID 22914296 - Lancet review
  • 2 - PMID 20634346 - Calprotectin MA in BMJ
  • 3 - LabCorp website
  • 4 - PMID 25002150 - Lactoferrin MA
  • 5 - PMID 24733679 - UC disease clinical course
  • 6 - PMID 22047562 - NEJM review
  • 7 - PMID 17258717 - Colectomy rates in Europe
  • 8 - PMID 20068560 - ACG GL
  • 9 - PMID 22522090 - Colon cancer risk
  • 10 - PMID 26154136 - Extraintestinal disease
  • 11 - AGA UC treatment algorithm
  • 12 - Manufacturer's PI
  • 13 - PMID 16530532 ADA GL for cyclosporine
  • 14 - PMID 22835577 - Cyclosporine article
  • 15 - PMID 27196591 - Appendicitis and UC risk
  • 16 - CONSTRUCT Trial